Got an email about these toxicology-focused FOAs so thought it might be worth sharing with fellow toxicologists here -

1. PAS-21-245: Limited Competition: Promoting a Basic Understanding of Chemical Threats to Skin (R34 Clinical Trial Not Allowed)
2. RFA-ES-21-006: CCRP Initiative: Chemical Threat Agent-induced Pulmonary and Ocular Pathophysiological Mechanisms (R01 Clinical Trial Not Allowed)
3. RFA-DA-23-056: Chemical Countermeasures Research Program (CCRP) Initiative: Basic Research on The Deleterious Effects of Acute Exposure to Ultra-Potent Synthetic (UPS) Opioids (R01 Clinical Trial Not Allowed)
4. PAR-23-027: CCRP Initiative: NIH Countermeasures Against Chemical Threats (CounterACT) Basic Research on Chemical Threats that Affect the Nervous System (R01 Clinical Trial Not Allowed)
5. PAR-20-253: Countermeasures Against Chemical Threats (CounterACT) Exploratory/Developmental Projects (R21 Clinical Trial Not Allowed)
6. PAR-22-209: CCRP Initiative: Countermeasures Against Chemical Threats (CounterACT) Therapeutics Discovery and Early-Stage Development (UG3/UH3 Clinical Trial Not Allowed)

Seems to be a big NIH focus - "The National Institutes of Health Chemical Countermeasures Research Program (NIH CCRP): A collaborative opportunity to develop effective and accessible chemical medical countermeasures for the American people"

Hello,
This thread has been incredibly helpful, as I've read quite a few posts here. I am here because I am torn between applying to MD only programs versus MD programs focusing on training "physician-scientists" (e.g. UPitts PTSP or Stanford's Berg Scholars) versus applying to traditional MSTP programs.
I have a strong background in research and absolutely love research and plan to go into academia (easier said than done, of course). I know most will see this as me being naïeve, but I know my intended specialty and subspeciality as it's pretty niche. & I am confident that this is the field that I want to study for several reasons: 1). I have a masters in this area and contemplated getting a Ph.D. in this area, but I ultimately decided that I want to have patient interaction as a part of my career. Therefore I need the M.D., and my research interests are more along the translational side of research. 2). I completed my Fulbright research within this field and found that it lent itself very well to my ideal research style and had quite a few areas I would be interested in exploring so I could never get bored. Also, I have more personal reasons why I want to conduct research in this area.
So here is my thought process after speaking with MANY individuals, and I would love some objective thoughts...
Firstly, a little background and a couple of caveats. I am NOT interested in conducting basic science research using animals. I have worked with animals at the undergraduate and graduate levels and quickly discovered I d not work with them PERSONALLY. I understand entirely why animal models are needed to advance science, however, I despise working with them. Therefore, ideally, I would like to partner with a Ph.D. to conduct any animal experiments needed.
Ideally, I am interested in running a clinical immunology lab similar to the type of work I completed during my Fulbright. We essentially had a lab consisting of MDs and Ph.D. partnered with a basic science-only lab for animal work. Our lab recruited patients, completed biobanking, ran immunophenotyping, and ELISAs, helped create new techniques etc., to identify possible cell populations of interest and other potential disease biomarkers. We then partnered with the basic science lab to develop animal models that could help us test our hypotheses. And finally, if we identified anything of interest in the animal models, we could then use that to ultimately translate our insights into viable therapeutic options for patients (bedside to bench to bedside or reverse translational research).
So now pros and cons:

1. MD: Pros are I don't have to work with animals anymore, and I can develop the clinical background necessary for my research interests. The timeline is also much more streamlined and I could, in theory, complete a research residency or post-doc following residency to acquire the necessary research skills. The cons would be the price associated with medical school and the very real chance that I would be viewed as not having enough research experience to be taken seriously enough to break off into academia and be competitive for NIH grants (e.g., K awards or an R01 or R21).
2. MD programs with physician-scientist focus (e.g., UPITT): Pros, I could get more in-depth training in translational science, and I get protected research time without having to devote 3-4+ years to earn a Ph.D. that I am not entirely sure is needed for my particular career path. Also since most programs like this are five years in length the 2-3+ years saved could also be used to do a research residency or postdoc to acquire any skills I am lacking. Plus, with this type of program, I would get a little more flexibility with my project, and since it is only a year, I could stomach doing something that is not directly related to my ultimate research interest as long as I develop relevant skills and techniques that could benefit my research in the future. Whereas in an M.D/Ph.D. I don't think I could handle 3-4+ years of not enjoying my project just to gain relevant skills.
3. MSTP programs: The main pro is the dedicated research time where I can devote most, if not all, of my time to developing my research skills while also not having to worry about mind-boggling debt following my training. The lack of debt would make a career in academia much more appealing as you're not constantly worried about paying off 300-400k in loans on an academic salary. Also, the dual training is beneficial in research. My PI is an MD/Ph.D. and another mentor is an MD only, so I am privileged to have worked with both on research projects. Their thinking is different (one is not inherently better), just different. Both perspectives were needed, but the M.D./Ph.D is always a little more interested and honestly more skilled in accessing how the actual study will need to be set up (e.g., identifying confounding variables, making sure that the scientific problem being addressed is not only clinically relevant but scientifically feasible and what particular methods would be best to study the problem, whereas the M.D. is more interested in the method of data collection, data analysis, and the overall clinical utility and less of the nitty gritty experimental design, especially the animal model portion.) Again, both perspectives are needed, one is just more interested in the experimental design and can seemingly switch between the clinical and experimental thought process more seamlessly.

Lasly, my ideal set up would be at an academic center where I see patients maybe 1-2 days/week and conduct research the remainder of my time, so ideally a 70/30 split. I know this is a lot but I am in need of help as much as possible.

I am an assistant scientist and I convinced my PI to have a meeting next week to go over data and to look at the possibility of writing a R21 or R03 grant. I was promoted from research associate to assistant scientist a few months ago, after an exodus of other postdocs to industry. I want to think that my PI understood that postdocs/research associates need mentoring/career guidance and not only the graduate students. Now, I wondering how to successfully handle writing a NIH grant without hurting egos or make my PI feels threaded by me. I just want the grant to be successful and to stay in the lab with my PI many more years.

Hi! I'm a postdoc who's just been offered a position as biology-chemistry assistant professor at a medium-large USA teaching college. Yay!
The school tells me that they want me to be research heavy and want me to help push forward the research department. So they are giving me some startup funds. My ideas revolve around cell biology, biochemistry, and molecular biology (Edit - I have a specific idea in mind which I want to investigate and the area is a sweet spot of high funding but not super crowded). I have roughly $100k to startup my research but i'm going to push for a little more. Unfortunately the labs don't have a lot at the moment, but things are moving forwards with some federal grants. We can also get some time at the big famous college across town and occasionally use their flow cytometer and confocal microscope for free (Edit - among other equipment, but i'm not sure what yet).
I'm trying to pool together some ideas - what do you guys think are some essential items I should buy and budget for? I was thinking of getting a LiCor Odyssey XF as a big item because they don't have an imager at all (just film) and I think LiCor match education startup grant funding up to 40%. So maybe $25-30k for that. This'll also hopefully make me popular in the department as people will want to use it, and then I can get favors and use their equipment! There's a piece of specialist equipment I need for the types of experiments i'll be doing and that is $7k.
So $65k left to get my research going and hopefully I can support it further with institutional grants (if we get the federal grants) or my own R03/R21/R01/K01.
Does anyone have any ideas? Thank you!

Retinoid acid, the bioactive metabolite of vitamin A, is a potent signaling molecule in the brains of growing and adult animals, regulates numerous gene products, and modulates neurogenesis, neuronal survival and synaptic plasticity. Vitamin A deficiency (VAD) is a global health problem, yet our knowledge of its effects on behavior and learning is still emerging. Here we review studies that have implicated retinoids in learning and memory deficits of post-embryonic and adult rodent and songbird models. Dietary vitamin A supplementation improves learning and memory in VAD rodents and can ameliorate cognitive declines associated with normal aging. Songbird studies examine the effects of retinoid signaling on vocal/auditory learning and are uniquely suited to study the behavioral effects of VAD because the neural circuitry of the song system is discrete and well understood. Similar to human speech acquisition, avian vocal learning proceeds in well-defined stages of template acquisition, rendition and maturation. Local blockade of retinoic acid production in the brain or excess dietary retinoic acid results in the failure of song maturation, yet does not affect prior song acquisition. Together these results yield significant insights into the role of vitamin A in maintaining neuronal plasticity and cognitive function in adulthood.
Keywords: Learning, Neuromodulation, Neuronal plasticity, Retinoic acid, Vitamin A

1 Introduction

Vitamin A is a fat-soluble micronutrient that is converted into retinoic acid at or near the site of activity in the body for use as a transcriptional regulator. Microarray studies have found retinoid signaling to affect a large number of genes in different tissues [1–3], and by some estimates affects ~15% of known human protein-coding genes [4], thus represents a strong candidate for neuromodulation. Vitamin A deficiency (VAD) is globally one of the most common forms of malnutrition in human populations, with ocular disorders, immunosuppression and impaired growth commonly described [5], and although considerable political efforts have been undertaken to eliminate VAD over the last half-century [5] it today remains a problem in much of the developing world [6, 7]. In light of the recent attention of micronutrients to human cognition, a lack of a strong role for vitamin A is surprising [8, 9]. However, based on evidence from animal models and associative human studies, a significant role of vitamin A is likely. For instance, the acne-control drug, Accutane (a retinoic acid analogue), was recently discovered to reduce hippocampal neurogenesis and proliferation, along with the ability to learn a maze in adult mice [10], while in humans the incidence of depression is ~10% higher among Accutane users [11]. Thus, use of therapeutic retinoids likely has effects on the maturation and maintenance of the adult brain and associated behaviors (though subtle compared to the dramatic effects on embryonic development). Supplementation of vitamin A or retinoid derivatives as therapeutic agents has been widely proposed for psychiatric pathologies including schizophrenia and Alzheimer’s disease [12], and may be used for controlling certain cancers [13, 14]. In light of animal models that show how retinoid signaling affects neuronal maintenance and behavior, we review work that has altered retinoid signaling up or down in the brains of rodents and songbirds with subsequent neurobiological effects that are tied to a specific cognitive function or complex behaviors.

2 Vitamin A and retinoic acid metabolism

The biologically active metabolite of vitamin A, retinoic acid, is the ligand of a set of receptors (retinoic acid and retinoid × receptors) that act as transcriptional regulators restricted to chordates, and it is best known as a signaling molecule during early embryogenesis [15, 16]. However, tightly controlled retinoid signaling is also important throughout adolescence and adulthood, and has been shown to play various roles in the continued formation, differentiation and maintenance of neuronal phenotypes. Owing to its low stability and low abundance in neuronal tissue, retinoic acid has proved challenging to effectively quantify by methods such as HPLC [17], but recent improvements in direct retinoic acid quantification [18] may prompt its quantification in sub-regions of the brain. Rather, retinoid signaling in the brain has often been inferred by the presence of aldehyde dehydrogenase, the terminal enzyme in the retinoic acid synthesis pathway. Three retinaldehyde-specific aldehyde dehydrogenases (RalDH) are present in high levels in the embryo and/or occur in the developing eye [19], but the isoform RalDH2 remains prevalent in post-embryonic and adult brains at lower levels. In embryos, differential expression of RalDHs sets up diffusion gradients of retinoic acid across structures such as the whole body plan, limb bud or eye. These gradients broadly determine patterns of structure formation [20, 21]. However, because adults and juveniles have greater physical structural complexity and lower levels of RalDH2 expression in their bodies than embryos, the spatial scale in which gradients of retinoic acid may act is not clear. It is likely with lower concentrations of retinoic acid present in tissues, concentration gradients must occur across a smaller space, perhaps over several cells. In addition, several gene products in addition to RalDH2, including cellular retinoic acid-binding proteins and retinal dehydrogenases/reductases, and cytochrome degradation enzymes provide additional regulatory control of retinoic acid levels [22, 23], and these regulatory gene products may change with development. Since RalDH2 is expressed by fully differentiated neurons in adults, retinoic acid may be produced in the functional cell bodies of one brain region for axonal transport to other remote regions where it may then direct neuromodulation. In either scenario, poorly understood transport processes and much smaller spatial fields of retinoid signaling are likely the norm in post-embryonic tissues, further necessitating the need for a tightly controlled system of retinoid signaling to maintain critical neuronal function.
Experiments to investigate the actions of retinoid signaling on neural properties and behaviors have either downregulated (e.g. simulated VAD) or upregulated retinoid signaling in the brain. VAD models may be achieved with the use of synthetic diets that are deficient in retinoic acid and all potential retinoic acid precursors, or the synthesis of retinoic acid may be disrupted by pharmacological blockers of retinoic acid synthesis [24]. Research with rodents has employed a transgenic knockout model for the retinoic acid receptor [25], and with the recently released songbird genome [26] in combination with development of viral transfection to generate transgenic songbird models, this may soon be a realistic technique for songbird researchers. Conversely, vitamin A and/or retinoic acid supplementation provides a model to better understand the therapeutic effects of retinoid signaling. This approach complements VAD as it results in excess retinoic acid levels in the brain. This is a significant approach as frequently both deficits of retinoid signaling and overproduction of retinoic acid can have disruptive effects, resulting in a detectable phenotypic response.

3 Rodent studies of neuromodulation by retinoic acid

Rodents models have proven informative on the effects of retinoid signaling on post-embryonic neuromodulation as retinoids affect hippocampal long-term depression (LTD) and potentiation, both measures of long-lasting synaptic plasticity, and neurogenesis [12, 27, 28]. The first clear evidence that retinoids play a role in cognitive function came from work with knockout mice that lacked either one of the retinoic acid receptors, RARβ, or one of the retinoid × receptors, RXRγ [25]. These particular receptors are uniquely expressed in hippocampal regions of the adult mouse brain that are implicated in spatial and relational memory, whereas the other retinoic acid receptors and retinoid × receptors are more uniform in their distribution. Thus, mutant mice for these receptors showed normal development and growth with no abnormal physical or neuronal morphology, yet demonstrated cognitive deficits in learning the Morris water maze and impaired motor control and balance, compared to wild-type mice. These behavioral impairments correlated with electrophysiological differences in hippocampal CA1 cells in that RARβ mutants lost long-term potentiation (LTP) and the RARβ and RXRγ mutants both lost LTD. Both of these correspond to changes in long-term synaptic efficacy that can affect learning and memory.
Following these findings, several studies have demonstrated a dietary link between retinoids and behavior or neuronal plasticity. By experimentally inducing VAD in neonatal mice, Misner et al. [29] showed that poor retinoid nutrition also affects LTP and LDP in mice, along with the more obvious physical and ocular deformities typical of VAD. These electrophysiological effects occurred without apparent physical differences in the underlying neuronal structure of the hippocampus, and in fact when proper retinoid nutrition was returned to retinoid-deprived mice, LTP and LTD returned to normal [29]. Behaviorally, dietary VAD in rodents also results in cognitive declines in memory tasks, but unlike the apparent rescue effect of supplemental retinoids for electrophysiological function, the behavioral rescue effect was not as consistent in all animals as there continue to be age-related effects on susceptibility to VAD. For instance, in a two-arm discrimination maze (baited with food) young VAD mice demonstrated persistent exploratory behaviors over a training period that is characteristic of naive animals, compared to normal mice that readily go to food after they learn the maze [30], and these effects do not go away when normal diets return, compared to older animals. Species differences are also evident: in contrast to mice, rats deprived of vitamin A at an early age showed cognitive decline that seems to improve once a regular diet is resumed [31, 32].
In parallel to the deprivation experiments, high doses of the 13-cis retinoic acid isomer administered to adult mice also results in cognitive deficits, and are correlated with reduced cell proliferation in the hippocampus and the proliferative regions of the ventricle [10]. Thus, excessively high levels of retinoic acid also have detrimental effects, suggesting that it needs to be regulated within a narrow concentration range. The maintenance of the adult olfactory bulb also requires retinoid signaling and is known for high levels of neuronal plasticity in terms of adult neurogenesis or variable profiles of gene expression [33]. Furthermore in a mouse model of Alzheimer’s disease that overexpresses genes for β-amyloid and presenilin 1, mice can be rescued from Alzheimer’s-related learning deficits by therapeutic all-trans retinoic acid (ATRA) administration [34]. ATRA-treated mice showed fewer of the neurodegenerative β-amyloid deposits in their brains, yet the possibility exists that the cognitive improvements were unrelated to the decrease in β-amyloid deposits, as aged wild-type mice that are given retinoic acid also show improvements in their cognitive abilities [35]. Indeed, therapeutic retinoid tools are promising for nervous system injuries, age-related declines in cognitive function as well as dementia-associated diseases; however, because of the multiple gene/signaling pathways and multiple aspects of neuronal plasticity known to be affected by retinoid signaling, careful research is needed.

4 Avian studies of retinoic acid neuromodulation

While rodent models best address spatial and relational memory, the songbird model addresses vocal and auditory learning, a trait shared with humans but that is not possible to test with most other mammal models, including nonhuman primates. Besides being one of the few organisms that evolved vocal learning, songbirds are powerful models for examining the neural basis of vocal learning because the brain areas that control song are composed of a series of discrete nuclei that have been well-characterized anatomically and physiologically [36, 37]. Birdsong consists of a learned complex vocal-motor sequence that is reinforced through sensorimotor learning during a critical period of high neuronal plasticity in the song system of juveniles [38]. Young zebra finches (Taeniopygia guttata) that hear song from male tutors during the Sensory Acquisition Period (20–60 days post hatch [dph]; Fig. 1) will acquire a stored template of the tutor’s song in their memory. They then enter the Sensorimotor Phase (~40–90 dph) where individuals develop their songs by matching the highly variable song that they produce to that of the tutor’s song stored in their memory. By adulthood (~90 dph) their songs mature and “crystallize” to the point that variability is minimal and the songs that they produce show a strong resemblance to that sang by their tutors [39]. In zebra finches these critical periods are well characterized [38] and this model provides a system that closely resembles the acquisition of human speech where infants first exhibit variable babbling, followed by experimentation with the sounds and pronunciation of spoken language [40].
📷Figure 1
Timeline of critical periods within the zebra finch (T. guttata) song development and patterns of zRalDH expression in the song nuclei HVC, LMAN and RA (see text for proper names) of the zebra finch brain.
The avian song system consists of several well-defined song nuclei that function in two complementary circuits. Birdsong begins in the song nucleus HVC (hyperstriatum ventrale, pars caudalis), which originates the neuronal pathways that are responsible for the learning and the production of song (Fig. 2). Projection neurons from the HVC to the robust nucleus of the arcopallium (RA) begin the posterior vocal-motor pathway and provide direct control to vocal and respiratory motor neurons (Fig. 2, black arrows). The anterior pathway originates as projection neurons from HVC to area X of the medial striatum (gray arrow), and from there sequentially to the dorsal lateral nucleus of the medial thalamus and to the lateral magnocellular nucleus of the nidopallium (LMAN) and into RA. Retinoic acid production in adults seems to be tightly linked to this anterior pathway. The large neurons that originate in the HVC and project to area X (Fig. 2, shown as a gray arrow) and the large neurons within LMAN are major sources of zRalDH (the zebra finch analog of RalDH2) expression in the adult song system, while song nucleus RA shows only a transient expression pattern in juveniles that disappears by 50 dph (Fig. 1). By 4 dph zRalDH is detectable within HVC, LMAN and RA and levels gradually increase as these song nuclei grow. During this time, neuronal connections among the song nuclei are being established and new cells are migrating in from the proliferative regions along the ventricle. zRalDH expression in RA is characteristic of juvenile songbirds between ~10 and 50 dph and levels peak at ~38 dph [41] which corresponds to the invasion of HVC projection neurons into the RA [42] and the first attempts at song in the juvenile. While zRalDH in the RA is largely absent after 50 dph, its expression continues in HVC and LMAN into adulthood, indicating a persistent production of retinoic acid in the adult song system [41].
📷Figure 2
(A) Parasaggital view of direct and anterior pathways of the zebra finch (T. guttata) song system. Bold arrows show the direct motor pathway, while thin arrows delineate the anterior forebrain loop. Projections and nuclei that are known to express zRalDH are shown in gray, and nuclei with no expression are shown in white. (B) In situ hybridization of antisense riboprobe for the zRalDH shows strong expression in HVC and in the nidopallial layer of the telencephalon, including LMAN.
The anterior pathway is responsible for song learning in juveniles and for modulating plasticity in learned song in adults. For instance, ablation of LMAN during the critical period of juvenile song acquisition reduces variability in juvenile song prematurely and inhibits learning ability [43, 44]. Thus, this circuit contributes to the neuronal and behavioral plasticity that is necessary to learn a complex behavior such as song. Our lab has altered retinoid signaling in the songbird brain with the application of pharmacological blockers of retinoic acid synthesis locally over HVC [41]. Disulfiram disrupts the final step in the synthesis of retinoic acid production by inhibiting retinaldehyde-specific zRalDH, while expression of other known class 1 aldehyde dehydrogenases does not occur in the songbird brain [24]. Birds treated with disulfiram at 30–35 dph (compared to controls who received saline implants in HVC or disulfiram implants in another brain region) showed evidence of song acquisition from a tutor male, but songs remained variable into adulthood, with frequent omission or variability of song elements into adulthood, indicating that maturation and crystallization did not occur. Song of disulfiram-treated birds resembled closely the variable song of juveniles, with poor note morphology and instability of fast frequency modulations. In contrast, adult birds with disulfiram placed over their HVCs showed no detrimental effects to their already crystallized songs [41].
In a similar study, male finches were supplemented with a high daily dose of ATRA (oral administration in corn oil vehicle between 30 and 120 dph) to test for possible changes to the qualities of their song compared to controls given vehicle alone [45]. Songs were recorded at 120 dph to analyze vocal development and the brains were examined for the expression of several candidate retinoid-regulated genes. ATRA-treated birds sang a complex song that contained normal features of conspecific song, including a motif with syllables that were presumably copied from the adult songs in the aviary. However, based on the analysis of multiple consecutive renditions (minimum 10 motifs per bird), the songs of ATRA-treated birds demonstrated more variability than controls. These songs had lower consistency, linearity and stereotypy [46], indicating lower levels of syntactic stereotypy compared to controls. These effects were largely due to frequent note additions and/or omissions in comparison with the most typical motif for each bird, as well as higher variability in the duration of syllables and inter-syllabic intervals than in controls. ATRA-treated birds also had lower similarity and accuracy scores [47]. The lower scores in the ATRA-treated group reflect higher variability in several acoustic features (such as pitch, spectral continuity, entropy) across multiple song renditions for each individual. In sum, songs from ATRA-treated birds resembled the plastic song of juveniles. Thus, song maturation appears to be arrested prior to song crystallization when retinoid signaling is upregulated through dietary supplementation, similar to birds where the production of retinoic acid was locally blocked in HVC [41]. In both scenarios of increased and decreased retinoid levels, birds show elements of song acquisition, but fail to crystallize their songs.
These results raise several important questions regarding the roles of retinoid signaling on genetic and cellular processes in the song system during the juvenile song-development period and over the adult life-span. Retinoic acid drives neuronal differentiation by effects on gene expression [21, 23], thus in the context of the song system, genes with differential expression in the HVC and that are shown to be affected by changes in retinoic acid levels, are likely to have important effects on the development of the song system. Indeed, microarray studies that have examined positive or negative induction of genes in tissues such as breast carcinoma tissue, Xenopus larva and lymphoid tissue have yielded different patterns of induction among the various systems [1–3]. Thus, neuronal tissue is likely to have a unique induction of genes in response to changes in retinoic acid levels, compared to other tissues. Four genes, (neurogranin) nrgn, BMP/RA-inducible neural-specific protein brinp1 (a.k.a. dbc, deleted in bladder cancer in humans) and a retinal short-chain dehydrogenase/reductase, sdr2/scdr9, retinoic acid receptor alpha, rar-α, have shown altered expression in the brain with the previously described feeding trial [45]. Of these brinp1 and nrgn have prominent expression in HVC – nrgn is associated with synaptic development and remodeling [48, 49] and decreases in HVC in response to ATRA, while brinp1 is an inhibitor of the cell cycle, possibly through the TrkC/NT3 receptor [50] and shows broad increases in neural tissues in response to ATRA. The function of both these genes is consistent with a role in modulating different kinds of neuronal plasticity in the song system, in fact, a positive linear relationship was shown between nrgn expression levels in both LMAN and area X with the degree of song stereotypy. Retinoic acid is known to modulate neuronal proliferation, migration, differentiation and synaptic connectivity, but at this point we know little about how genetic programs directed by retinoic acid drive these cellular processes in the avian song system. In terms of the histological structure of the song system and volume of song nuclei there are no apparent effects of altered retinoid signaling [45], similar to a lack of an effect in the volume of the murine hippocampus [29]. Sdr2/scdr9 has low expression in the song system, but shows increased expression with increased levels of retinoic acid in area X and LMAN of the anterior loop of the song system, consistent with a likely role of this gene product in providing an inhibitory regulatory role in retinoic acid signaling.

5 Concluding remarks

Even though this is a relatively new area of research, the evidence strongly suggests that vitamin A, through its main metabolite retinoic acid, continues to exert important actions on brain physiology and behavior in post-embryonic and adult life. Avian and murine studies suggest that a balance of retinoic acid is required to attenuate the behavioral plasticity that is required for the storage and recovery of memory. That is, levels of retinoic acid are maintained at moderate levels by a complex of control mechanisms and feedbacks, so that too much or too little of this ligand will result in similar deficits in learned behaviors. However, it is still unclear how underlying pathways of retinoic acid signaling change with different levels of the ligand and how this differs in different neuronal systems. Retinoic acid is broadly implicated in neurogenesis, cell differentiation, synaptic connectivity and electrophysiological potentiation – all processes that affect what we commonly think of as neuronal plasticity. Furthermore, neurobiological systems may respond to retinoic acid differently at various stages of development, but additional work is needed to fully understand this issue. In terms of learned behavior, plasticity is required for neural systems to be able to adapt to broad and constantly changing environmental conditions, yet excessive plasticity may be detrimental for an animal to effectively learn and consolidate very specific patterns, particularly behaviors as complex as learned vocalizations.
The studies discussed here indicate the continued importance of vitamin A as a nutrient for the brain not only during embryonic development but also during adulthood. The study of retinoic acid effects on the song system offers a unique opportunity to identify the molecular regulators of a complex behavior such as vocal learning. With the avian song system, we have detailed knowledge on the composition and physiology of specific neuronal elements, and thus presents an opportunity to identify the retinoic acid targets at a cellular and molecular level. Overall, research in basic model organisms to further our knowledge of how vitamin A affects the brain and behavior will expand our understanding of the significance of VAD to human populations in terms of learning ability. This is significant as measuring cognitive abilities across multiple cultures is notoriously difficult.
The decline in cognitive ability is one of the classic hallmarks of human aging, and in animal models under conditions of poor vitamin A nutrition. Resumption of vitamin A and proper levels of retinoic acid signaling may have restorative effects, but again, research to identify the extent of possible recovery and the critical periods during the life stage is needed. Indeed, VAD at early stages in the life cycle of rodents seems to have irreversible effects on the brain, but adult animals may be more tolerant to episodes of retinoid malnutrition [31]. Compared to short-lived rodents, birds are very long-lived for their body sizes [51], and thus may be an appropriate model for the long-term effects of VAD in humans. Therapeutic doses of retinoic acid may ameliorate age-related dementia and psychosis, yet may also exert undesirable effects on the brain through other pathways. Further studies on animal models like rodents and songbirds are poised to further reveal the importance of vitamin A and retinoid signaling for brain function and behavior.

Acknowledgments

This research was supported by grants 2R01-DC002853 for C.V. Mello and 1F32-NS062609 for C.R. Olson. The authors’ use of animal models for research is covered under the OHSU IACUC ]0721. This review benefited from the thoughtful comments of K.L. Horback and two anonymous reviewers.

Abbreviations

ATRA all-trans retinoic acid
HVC hyperstriatum ventrale, pars caudalis
LMAN lateral magnocellular nucleus of the nidopallium
LTD long-term depression
LTP long-term potentiation
RalDH retinaldehyde-specific aldehyde dehydrogenases
RA robust nucleus of the arcopallium
VAD vitamin A deficiency

Footnotes

The authors have declared no conflict of interest.

"I’m perfectly prepared."

Seiya Ryuuguuin

Background

Summoning Japanese teenagers into alternate worlds of fantasy has become such a common occurrence in the vast, interconnected multiverse, that the gods that govern it make names for themselves isekai'ing people and saving more and more difficult worlds.
One of these gods, the goddess of healing Ristarte, is assigned one of the highest difficulty worlds to save from the Demon Lord - S-Class. In a panic over saving a world so high above her paygrade, she scours through her options before finding a one-in-a-million individual, with starting statistics that would make it a cakewalk to save even difficult worlds. In her haste to summon him, however, she failed to read the fine print that was his personality...
"Overly Cautious."

Source Guide

Light Novel Thread Manga Thread Anime Thread
Light Novel feats are sourced with Volume and Chapter. Note that chapters are numbered per arc, not per volume (ex. chapter numbers continue to increase between Vol 1-2, the Gaeabrande Arc).
Web Novel feats from unpublished chapters utilize fan translations, and are marked with the overall chapter.
Feats marked with [Berserk] signify Seiya was using a power amplifying skill he gained in the series' second arc. Some feats are marked and organized by the series arc it took place in, this is because his skills and levels reset at the beginning of them.

Physicals

Note that named attacks are listed separately below under "Skills", many of which incorporate physical force or speed.

Strength

Gaeabrande

• Sends a Dragonnewt flying dozens of meters, crashing into a table
• In every chapter preceding 45, was wearing well over forty bracers around his arms, legs, and body that were each individually heavy enough to shatter into the floor of a cathedral when dropped
• Exchanges some inordinate amount of attacks with the Warmaster after he turned into a demon, of which one individual hit could reduce a section of a marble floor to dust

Ixphoria

• Shatters a table with a blow from his sword
• Hits Rista hard enough that she's sent through the floor of a mansion and half-into the dirt under it
• Impacts an earth doll he created hard enough with his sword to reduce it and the floor it was standing on to dust, and leave a massive crater behind
• Sends Cerceus flying dozens of meters with a kick
• [Berserk] Slices numerous Beastkin in half the moment they realize his presence
• [Berserk] Throws one of his sword enough to hit a red skull that had formed out of clouds in the sky
• [Berserk 2] Clashed with Grandleon with his sword, who previously split the ground open with an attack
• [Berserk 2] Him exchanging attacks with Grandleon sent out a large shockwave, and he was able to cut into and break Grandleon's armor
• [Berserk 2] Shatters Oxerio's head, which was implied to be made of metal stronger than steel - Oxerio is over 50 meters tall
• [Berserk 2.7] Cleanly decapitates Ultimaeus, despite him growing larger in size and power

Corrupted Worlds

• [Berserk] After leveling up to half his max level, goes from being overpowered by Cerceus to casually catching his attacks with one hand
• [Berserk 2.8] Reduces a frozen Dragonnewt to powered ice after freezing it, which was previously able to survive two of Seiya's Meteor Strikes
• [Berserk] Smashes a bullet in his fingers
• [Berserk] Snaps a man's neck with his bare hands, each of the citizens of the town he was in at the time had stats that were many times higher than enemies Seiya had fought previously, such as Chaos Machina

Speed

Gaeabrande

• Dodges a sword strike after the sword is already moving towards his neck, then repeatedly avoid more sword swings
• Does this again after the opponent in question increased their speed by a factor of three
• Slices apart an undead too fast for a group of observers to realize
• Moved so fast it appeared like he teleported to a group of observers
• Catches a woman's arm after she had already moved to slap him, as her hand was so close it had looked like her hand already connected with his cheek, then slaps her
• Rista takes an entire lengthy paragraph to explain that he moves faster than she can observe

Ixphoria

• [Berserk] His speed stat exceeds that Beel Bub's in this state, who is fast enough to dodge supersonic projectiles
• [Berserk 2] Triples his regular speed. Was able to block an attack from a monster that moved so fast it appeared he teleported from Rista's perspective
• [Berserk 2] Moves so fast it looks like he vanished out of sight, moving as a red line over long distances
• [Berserk 2] Reacts to electricity fired by Ultimatus
• [Berserk 2.491] Incercepts one of Grandleon's Volts after it was fired, which he was barely able to react to in Berserk 2
• [Berserk 2.6] Dodges an extremely large amount of lasers fired by Oxerio, moving as a red blur
• [Berserk 2.7] Is able to dodge a punch from the Demon Lord at point-blank after he threw it, despite the Demon Lord being able to move significant distances after Rista blinked. They both move too fast for her to track
• [Berserk 2.8] Moves so fast that it appeared like he teleported behind Ultimaeus even after he threw strikes at Seiya

Corrupted Worlds

• [Berserk] Matches Mash while he was using Igzazion's Full Haste, even very easily avoiding attacks from him later on
  • A much weaker Mash using Full Haste for the first time was able to blitz Beel Bub
• [Berserk] Strikes a man, sending him flying into a nearby garbage can, while a bullet was mid-air

Durability

Gaeabrande

• Is fine after a high-speed icicle hits him, this only doing a tiny fraction of damage compared to his health stat
• Doesn't particularly care/fight less efficiently after having one of his arms removed
• Received a direct hit from the Demon Lord that sent him flying back, while he starts vomiting blood he immediately gets back to fighting afterwards

Ixphoria

• At level 50, only takes minimal damage from regular townsfolk collectively attacking him
• Immediately starts fighting after bursting through a wooden floor
• Isn't too affected by the pain of ramming his sword through his hand
• Hides in a pottery kiln that had a fire he was inside of for an extensive period without much issue
• [Berserk 2] Takes a large number of hits from Grandleon directly after being unable to dodge them

Corrupted Worlds

• Does not care about pain equivalent to having entire sections of his body rot away, being eaten by maggots
• [Berserk] His skin can't be penetrated by bullets that are several times more powerful than normal bullets

Gaeabrande Arc Spells/Skills

Skills and Magic used by Seiya in the first Arc, which comprises the first two novels.
Note that there's some overlap with later arcs, as he occasionally goes back to using his fire magic and sword skills.

• Utilized hypnosis to make a group of dragonewts more open to suggestion
• Uses the skill "Oscillatory Wave", what's normally a martial arts skill, to vibrate the molecular structure of a special magic-based flame into a mundane flame

Flight

• Flies up to Chaos Machina in the air
• Flies much faster than Ristarte, who claims to fly between 60-80 kilometers per hour
• Uses it to maneuver around a large dragon as he was using Phoenix Drive
• Ristarte remarks his flight as "superspeedy" while she flies a distance that would take ~ an hour on horseback in ten minutes
• Uses flight to avoid a ground-based attack on him before it was even initiated

Sword Skills

Phoenix Drive

• Cuts Chaos Machina's true form into charred chunks too fast for her to do anything about it, who was three meters tall at the time - accompanying art of this
• Uses it on a dragon while also deploying his flight skill to strike all over her body, dealing significant damage with each hit through heat and impacts, this dragon being ten meters long, and claimed to have scales "stronger than any metal".
  • Even then he was actually targeting her wings the entire time in anticipation of her putting down her defenses, having dealt significantly more damage in those areas
• Uses it repeatedly to break apart the Warmaster's armor, before finally defeating him, despite Seiya only having one arm
• Reduces Ultimaeus's arms to ash before they even hit the ground

Phoenix Thrust

• Uses it to pierce into and shatter an ice enemy that he couldn't use "Phoenix Drive" to kill
• Utilizes the skill "Valhalla Thrust" after obtaining a blade that can pierce into the Demon Lord, which goes clean into his skull
• Uses it during the Ixphoria Arc to pierce through the skull of a large Rhino beastkin

Eternal Sword

• Lets him effectively hit a spot at multiple angles at once, using it repeatedly to shatter a stone seal
• Uses "Double Eternal Sword" to perform the same attack but with two swords, making "afterimages which create yet more afterimages"
• Finally, uses "Eternal Sword EX", which causes him to be able to exchange attacks with an enemy so many times, so fast, that the various collisions sound like one, continuous, grating noise
• Still has the skill during the Ixphoria Arc - using it makes him go so fast that he reduces a monster to bloody ribbons in the blink of an eye while producing countless afterimages
• Uses "Eternal Sword EX" with his fire magic to rapidly slice apart Lucifer Crow, reducing her body to charred chunks of meat

Atomic Split Slash

• Obliterates a slime, carving out the ground a distance ahead of himself - accompanying art of this
• Pierces right into Bunogeos' corpse's skull, annihilating the floors of a mansion and leaving him in a crater in the ground
• Destroys Cerceus' cake, the table it was on, and the ground that was under it
• [Berserk 2.7] Broke through Adenela's guard, the shockwave of blow severely damaging the Summoning Chamber
• [Berserk 2.7] Shatters the floor under the Ultimaeus

Wind Blade

• Lets him perform a sword attack that travels > 20 meters, tearing up the ground as it heads towards an enemy
• Uses the same skill with two swords, "Double Wind Blade", carves into a large Dragon, sending them off-balance, this dragon being ten meters long, and claimed to have scales "stronger than any metal"
• Uses it to block a lightning-based spell and cleave the God of Death in half

Other

• Uses the skill "Dimension Blade" to attack an opponent that was in a completely different location through a magic mirror he was using to communicate with Seiya
• Uses it once more after a spirit had dragged Mash into an alternate dimension Seiya couldn't reach, hitting her despite her being in that dimension

Fire Magic/Skills

Hellfire / Maximum Inferno

• Razes the field a slime was on with it, repeatedly alternating between it and Atomic Slash until a "comet-like crater" had formed
• Does this again on the remains of a Demon General, repeatedly casting Hellfire 10+ times before scorching everything in a 10 meter radius with Maximum Inferno, then continues doing this until being kicked out of a town for lighting it on fire
• Does this a third time, collapsing a church that the enemy was in
• For the first time using it on something other than an already dead opponent, instantly lights an undead on fire after chanting the name of the attack
• Uses it to cremate hundreds of dead human-sized flies
• Reduces a group of beastkin to charred corpses in an instant with "Maximum Inferno"
• Reduces a crowd of zombified beastkin to ash with the same attack
• Can cast it thousands of times even after reducing his MP by two fifths

Automatic Phoenix

• Causes a firebird to attack monsters around him in a 50 meter radius, causing an orc to burst into flames
• There's three of them active at any given time - they burst a group of living trees and giant ants into fire and move fast enough to out-speed Elulu's Fire Arrow skill
• Can actively summon dozens of them at a time. Each of them can lift one of Seiya's bomb boulders
• He can link his vision to them to get a bird's eye view of a town
• [Corrupted Worlds] "Automatic Phoenix Infinity" allows him to summon thousands of them at once, however he has them immediately fly away
  • It's revealed he did this for two reasons. One, he was able to survey an entire continent with them by linking his vision to them, Two, he was able to absorb them later on to restore his mana

Meteor Strike

• Takes out an army of 10,000 undead, affecting an entire square kilometer of land, with a meteor only a few dozen meters in diameter by causing it to hit at high speeds. It has a number of restrictions that doesn't make it practical for regular fights, though
• Doing this twice barely drained his mana reserve
• Reduces an entire village of Dragonnewts, Edona, to ash then immediately destroys the surrounding suburbs with several more

Fire Salamanders (Corrupted Worlds Arcs)

• Creates fire salamanders. Snuck one of them onto Slauri without him noticing to light him on fire when he turned invisible
• Can create a massive amount of them and link his vision to them to scout an entire village for living beings
• Strong enough to pin Lagos, a dragonnewt, to the ground, and also quickly defeat an entire army of dragonnewts
  • Dragonnewts are generally much stronger than humans
• Uses his summoned fire lizards to sneak bullets off of a gunman's weapon, leaving them with no rounds to fire

Other

• Learns Fire Arrow, which lets him produce a bow and arrow of flames, shoots an arrow that goes so far it stops being visible, and it accurate enough to hit a narrow tree trunk dozens of meters away
• His fire magic works on incorporeal ghosts
• Can coat his sword in fire magic
• Developed a new fire skill called "Self-Immolation", which coats his entire body in flames that burn away bandages that approach him
• [Berserk 2] Incinerated a bunch of icicles that were about to fall on him with "Phoenix Spear"
• [Ixphoria, Berserk 2.7] Combined numerous sword techniques, his fire magic, and Berserk mode to slice apart and enemy's body dozens of times in two attacks, before reducing them to dust with another fire attack

Shining Arrow

• Lets him summon a bow and arrow, which he uses to headshot an extremely horny goddess
• Allows him to fire three arrows so fast that it looked like he had only fired one, hitting that same goddesses' eyes and mouth precisely as she was charging him
• Does this again but with five arrows, crucifying the goddess to a tree
• Cloud fire a light arrow from inside clouds that were below Ristarte and a monster and still have it be in its effective range
• Manages to fire off seven light arrows so fast they appear to be shot at once, with each moving faster than sound. After missing, they transformed into familiars which then exploded and killed Beel Bub while they were distracted
• Uses this skill again without transforming them into familiars to take out a nest of hundreds of flies in "the blink of an eye", these flies were too fast for regular arrow volleys to hit them to the point where it looked like they weren't moving at all when dodging the arrows

Ixphoria Arc Spells/Skills

Skills and Magic used by Seiya in the second arc, which comprises the volumes 3-5.

General

• Seiya can't specialize in multiple different skills/abilities in Ixphoria and can't fly anymore due to that world's magic system
• The skill "Appraise" gives him relevant information on whatever he uses it on. Includes stuff like edibility and magical properties of weapons and equipment
• Learns how to change his 'class' to get around his skill limitations in a fight, changing classes gives him the equipment of that class (such as a sword for a swordmaster)
  • After learning "Quick Change", he can rapidly switch between classes mid-combat
• Learned the Hexagram Ritual of Retribution. It requires placement of certain stones and 3 hours of unobserved dancing in an area before using in on an enemy, and severs the blessing of the Dark God from a target - in the case of a ghost revived by the Dark God it just began erasing them with white light
• Learned a spell that allowed him to slowly build up energy while taking attacks, uses this after some time fighting to reduce one of the Demon Generals to dust alongside the strip of land he was on
• Has the skill of Divination, which allowed him to determine which passageways lead to the correct destination in a maze, but only with a 60% success rate
• Learned Chain Destruction, a skill that allows one's attacks to completely destroy the soul of the opponent
• Learned Anti-Clock Field, a skill that prevents his opponents from stopping, rewinding, advancing, or otherwise manipulating time

Earth Magic

Earth Serpents
Combat

• Can summon Earth serpents from the ground. Individually they're strong enough to cause the Demon Bunogeos to collapse to the ground, and he could prepare hundreds of them in three days
• They could tear holes through various walls and the floor of Bunogeos' mansion, but aren't particularly durable
• Can turn these snakes into sand to disguise them as dead, and later turn them back into living snakes, even after being eaten by Bunogeos. They rip apart his body after Seiya activates "Transform: Automatic Naga"
• They could rip apart an undead's legs like piranhas, eating them until nothing was left
• Can make hundreds of them at once out of garden soil
• Jammed Oxerio's laser cannon with a bunch of them, causing it to backfire and explode his torso

Reconnaissance

• Can link his vision or scrying pools to their sight, 2, 3, 4
• Can return them to sand and manipulate that sand to spell letters to communicate to Rista even at large distances
• Can speak through them for long-distance communication, 2
  • Works even if Seiya is unconcious
• Fast enough travel 50 kilometers in all directions between a brief exchange of words, and scour an entire continent over the course of a conversation
• His snakes have telescopic vision, getting a detailed close up on a woman from over 30 meters away

Stone Golems

• Later learns the ability to create Stone Golems, which he can utilize so much to the point where he develops an army of tens of thousands of them
• These golems are strong enough to crush and destroy robots that are slightly taller than regular humans
• They were strong enough to throw boulders at flying drones that were trying to maneuver above a wall that was fifty meters tall
• Crushes skeletons and sends them flying
• They defeat a cyclops, dragon, and chimera, the latter two being ripped into pieces by them
• Makes hundreds of them at once with a stomp of his foot or by putting his hand on the ground

Mega Rista

• Made one golem in the likeness of Rista that was larger than Oxerio, a giant robot that was described as taller than a fifty meter tall wall, although this required a catalyst of Rista's hair
• Receives a large number of hits from an opponent of comparable size, who was swinging their fists with high speed relative to their own size
• Counterattacks the same opponent, before grappling and physically overpowering them - accompanying art of this
• Fine after getting hit point-blank by a set of lasers that burned off her clothes, these lasers exploded Oxerio's torso when they backfired on him
• Intercepts a laser that was heading towards Seiya

Cave Along

• Using the spell , he can create a mobile cavern that lets him freely move underground
• When shoving other people and objects affected by Cave Along into the dirt surface above him, he can move them through the earth like water
• Can control the size of the cave produced by the skill is
• Later evolves to where he can effectively use it up to ten meters under the surface and have it block sound he produces from inside of it. Can surveil an entire town area from underground with it and Clear Ceiling in tandem
• Can draw people from above ground into his caverns created by Cave Along
• Is later able to produce much larger caves, making one with a radius of 10 meters

Clear Ceiling

• Lets him view the roof of his cave all the way to the surface as if it wasn't there. With "Ground Penetration" he can fire projectiles through the earth as if it wasn't there. These in tandem let him continuously snipe off enemies with his flute snipe
• He can't use "Clear Ceiling" to look into wood floored buildings
• Later learns "Clear Wall", which lets him view through sections of the underground caves he creates

Endless Fall

• Causes dead bodies to phase through the earth, falling to the planet's core to be incinerated.
• Works on undead enemies just as well
• Later, can work even if the enemy is alive and with a high magic resistance, but only sinks one such enemy into the earth down to his forehead
• Even later, causes an enemy to sink completely into the ground

Great Iron Wall

• A skill that produces an earthen wall to surround an entire kingdom, which was 50 meters tall, 1 meter thick, and was as strong as steel. Spoke as if sinking the entire kingdom underground was also something he was capable of
• Immediately does this again four more times, creating a five-layered wall around the kingdom
• Can almost instantly repair holes in these walls. While setting up the kingdom's defenses, he also put pit traps that could suck in and cover a third of the machine army
• He can remotely control how durable this wall is
• Later on he can extend the walls over the air to make a dome over the entire kingdom, blocking out the Sun
• The walls are also extended underground, the first four going 50 meters underground and the last 100 meters
• With a snap of the fingers, retracted four of the outer walls to make the last one five times denser and longer in all directions
• With another snap, repairs damage done all across this wall, makes it 20 times thicker, and makes it extend two kilometers underground
• Can also extend this new wall into a dome form at basically no mana cost

Bomb Boulders

• Combines a large variety of magic to create them - by detonating they reduce dozens of metal machines into dust and cause Rista to get knocked off her feet despite there being a 2 meter thick wall between her and the explosion in the middle of a large cavern. Can continuously summon them one after the other. For reference these machines are slightly tallebulkier than a human
• Programmed one of them to talk, somehow
• Armed tens of thousands of golems with them, each of which could take out entire groups of these robots
• He can turn his snakes into bombs similar to this, making them act as landmines

Other

• Hardens and shapes a piece of earth into something resembling a rifle bullet, making it more aerodynamic
• Can finely control his earth magic to separate out one robot of many and move it between his underground caverns
• Able to make complex, elaborate buildings in moments via Earth Magic, 3
• Defends allies with walls of stone

Jolly Piper Skills

• Fires a bullet crafted from his Earth magic out of his flute with sufficient speed to instantly hit a target from dozens of meters away, blowing off their head entirely, 2
  • Repeatedly uses this over the course of days to kill hundreds of beastkin by sniping them even while underground
• "Modest Flute" reduces the noise he makes while using his flute as a projectile weapon. It also increases his range, with Rista comparing it to a sniper rifle with a silencer
• "Platinum Blowpipe—Type: Cannon" releases a burst of air so powerful it ripped apart the bodies of a group of priests at a distance

Other Elemental Magic

• Can use Wind Magic after training with various gods and goddesses. Used the move "Wind Shield" to block a gust of black wind from the Ultimatus that hit with sufficient force to disintegrate his stone golems
• Similarly learned lightning magic, firing out a blast of electricity to cancel out one fired by Ultimatus
• Using "Thunder Strike", he paralyzed the Demon Lord long enough to talk about the fact he did that, and retaliate with Phoenix Spear

Shapeshifting

• Allowed him to turn his arm into a giant cyclopean arm, and alter his voice into that of a cyclops
• Takes the form of the Demon Bunogeos, to the point where Rista couldn't tell his appearance and voice apart from that of the demon's
• Mastered it to the point where he could use "Transform Target", letting him utilize his shapeshifting magic on other beings. Using it he changed Rista's appearance into an upright fish person
• Disguising himself as Bunogeos also made it appear he had Bunogeos' statistics, scent, and aura
• Combines his Earth Magic, Shapeshifting, and Fake Out to populate a room full of animated earth dolls that have the appearance and shown statistics of human slaves, making it seem like he convincingly killed one of them
• Disguises Earth Serpents he hid on Rista's body as fish while he turned her into a fish beastkin
• Disguises a clay doll as himself to the point Rista mistakes it for him, using it as a body double
• Combined his shapeshifting and Earth magic to make an entire proxy control room for his underground bunker
• Uses it on an animated Clay Doll of his to make it appear like he had duplicated and was attacking the Demon Lord from two points at once
• Uses his shapeshifting on his golems to transform them into dozens of clones of himself
• Disguised himself as a corpse

Spirit/Ghost Skills

• Learned "Ghost Buster", a skill that imbues his sword with energy that lets him harm incorporeal ghosts
  • Can use it on his allies' swords, giving them to his golems to tear through a large group of ghosts
  • Despite existing as an amorphous mass of clouds in the sky, damage done by Seiya through Ghost Buster remains on the Death Emperor even after he dissipates and reforms his body. Seiya continued throwing swords this way with his many backups that it forced his enemy to switch from an astral one to a physical one
• Additionally learned a skill that let him separate an enemy's spirit and body by bonking them in the head with his fist. This causes their regular body to go prone
  • Each of his summons can apply this skill independent of Seiya, letting him remove the souls of the people in a town en-mass and bind them to his summons

Corrupted Worlds Arc Spells/Skills

Skills and Magic used by Seiya in the current third arc, which comprises everything from Volume 6 onwards. Note that Seiya no longer loses his levels and skills when moving from one world to another, now, although he's still bound by the rules of that world.

• Gained the ability, "Conversion", which lets him change his elemental affinity, allowing him access to ice magic that he couldn't previously learn
  • Can also change his mastery in Dark magic to mastery in Holy Magic
• Learns a skill that allows him to become invisible, mastering it after watching someone do it once
  • Also gains the ability to turn other people or even specific objects they are holding invisible
• With "Share Info", he can display what one of his allies is thinking onto a wall like a projector

Ice Magic

Fenrir Shot

• Can fire high-speed icicles using his magic. While they are not individually accurate, he can fire off so many of them to the point where accuracy isn't needed
• These move fast enough to cross 10 meters in a matter of seconds
• Takes 10 seconds for one of his hands to recharge, but can fire from the other hand continuously for 10 seconds, letting him effectively use it constantly until running out of mana, which would require him to use it 30,000 times
• Once enough of them make contact, they begin to freeze the opponent's body solid, doing so even to an opponent who was covered in flames previously

Other

• With "Fenrir Beat", he can imbue his sword strikes with ice magic, causing a large number of glancing hits with his sword to trigger a spell that froze them completely solid

Mimicry

• Allows the user copy the voice and even the skills of the person they're mimicking
• This allows Seiya to mimic skills he was previously incapable of learning, such as Rista's healing, healing over a sword wound on Cerceus
• Only lets him use the skill he observed for a few minutes, and using a skill he doesn't normally have the aptitude for makes it cost a significant amount of mana
• Mimics a dragonnewt's ability to physically duplicate its body into smaller clones
• Copies Lucifer Crow's Diablos Rain, an attack that causes a massive floating eyeball-ball to fire out lasers that strikes specific targets in a wide area. His matches her accuracy, quantity, and power, completely canceling out her attack before she could kill every human in a fortress/city
  • Accompanying visual of this
• Can mimic spells/skills he hasn't observed completely by mimicking the chant/wind-up of that spell
• Copies Giga Haste, a speed boost granted to Mash through Igzasion and various draconic abilities
• Can chain attacks he copies into a combo

Dark Magic

• Dark-type attacks let him more efficiently damage those who are protected by holy auras. Learns to coat his sword in dark magic

Phantom Hands

• Learns the skill "Phantom Hands", which lets him summon hands out of the floor and other surfaces. They can damage divine enemies by just contacting them
• Ends up being able to summon thousands of them, using them to pass himself a sandwitch
• Uses many of them to cover and restrain the Great Mother, who is a giant dragon
• Can regrow them faster than Mash can cut them away with Igzasion, grappling him to the ground
• After being destroyed, their dark mana caused plants around them to grow uncontrollably and attack Mash

Infect Lover

• Learns the skill "Infect Lover", lets him cause a woman he kisses activate a curse that causes both her and a target she is attacking to die from a disease that causes convulsions and foaming blood at the mouth if she lands 66 attacks on that enemy
• If used on more than one woman at once, it counts the number of hits the group lands as a whole

Death Confession

• The spell "Death Confession" summons a worm that crawls into a victim's facial orifices to control their body
• After inserted, victims follow Seiya's commands, and he can force them to activate their skills or give him information
• Needs to re-insert worms continuously to keep constant control over someone

Holy Magic

• Releases a burst of holy energy that shatters an illusion caused by dark magic, and burns away the body of a devil with bright light
• Traps a devil in a cage of holy light, then fires a beam of light ingo that cage that endlessly reflects inside of it, piercing through her over and over again until there's nothing left of her body

Well, it's a little late, but who cares at this point, it is the 2021 AFL Supercoach Brownlow, brought to you by many hours arranging spreadsheets instead of studying for exams.
Since the official Brownlow medal was last weekend, and we're headed towards the Grand Final, it's as good as time as ever to hold the unofficial Supercoach Brownlow because I didn't have time to run results when the season was over, and still probably don't.
The rules are very similar to the regular Brownlow medal count. The player who scored the most Supercoach points in every game is granted 3 votes, the second most receives two, and the third-highest receives a single vote. All data was collected manually from https://www.fanfooty.com.au/, who has archives of all the stats and scores for each game.
If two or more players scored the same amount of points, the player who had less time on ground was awarded the points, as they had a higher points per minute stat. If they were still even at that point, don't ask because I don't know.
Also, I am very aware of some inconsistencies, but don't know where they went wrong or how to address them.
I'll go over a brief summation of each round, with the full results in the google doc linked: https://docs.google.com/document/d/1IMqUM2aZw-gUfdG4gN7rrKqkDCML68eJ/edit?usp=sharing&ouid=111149946652330442879&rtpof=true&sd=true
Here, I will provide brief commentary as well as a round by round leaderboard showcasing up to 8 players in the top spots at each point in the year. Feel free to skip this section as it is pointless.
R1
Well, this round is really the most uninteresting. Some interesting names are in the lead, like M Flynn (GWS) and J Lever (MEL), with Martin's early domination showing, along with Tex picking up the three as well.

Rank	Player	Votes
1	T Walker (ADE)	3
	J Bowes (GCS)	3
	M Flynn (GWS)	3
	T Mitchell (HAW)	3
	J Lever (MEL)	3
	T Boak (POR)	3
	D Martin (RIC)	3
	C Mills (SYD)	3
	B Smith (WBD)	3

R2
Another boring round vote wise. Only 6 players managed to score on both occasions, and in the case of Jordan Ridley and Adam Cerra, two 1 vote games. Coincidentally, both Noah and Jed Anderson polled votes in the North Melbourne vs Gold Coast clash way back when. Tex Walker continued his early dominance, with another 3 vote haul.
​

Rank	Player	Votes
1	T Walker (ADE)	6
2	D Martin (RIC)	5
3	E Gulden (SYD)	4
	A Brayshaw (FRE)	4

R3
In a flashback to when we had hope that Adelaide might have a miracle rebuild, we see two players in the top 4. Tex polls again, but only one this time and the forseen dominance of ruckmen begins, with Gawn and Grundy springing up into second position. Two 'O's poll in one match, with O'Meara and O'Connor both polling in the otherwise forgettable Geelong Hawthorn clash.
​

Rank	Player	Votes
1	T Walker (ADE)	7
2	B Grundy (COL)	6
	M Gawn (MEL)	6
4	R Slone (ADE)	5
	J Ridley (ESS)	5
	D Martin (RIC)	5

R4
Tex freezes in place, as he is leapfrogged by a dominant Gawn in the standings. The top players are beginning to separate themselves from the stragglers, and the most interesting thing that happened here was that 3 games had a 3-2-1 sweep, the most of any round so far.
​

Rank	Player	Votes
1	M Gawn (MEL)	8
2	T Walker (ADE)	7
3	B Grundy (COL)	6
	J Ridley (ESS)	6
	L Parker (SYD)	6

R5
Big Max surges, almost a full two games in front of the 4th placed players with his last 4 weeks totalling a massive 11 votes. Walker is still frozen, and will remain that way until the end of the year. We also see the first appearance of Macrae on the leaderboard, a sight which will remain constant throughout the rest of the year.
​

Rank	Player	Votes
1	M Gawn (MEL)	11
2	B Grundy (COL)	8
3	T Walker (ADE)	7
4	J Ridley (ESS)	6
	D Mundy (FRE)	6
	L Parker (SYD)	6
	J Macrae (WBD)	6

R6
Max polls a disappointing 2, allowing Grundy and Macrae to catch up. Mundy keeps rising, and Miller and Ziebell climb up with three vote performances
​

Rank	Player	Votes
1	M Gawn (MEL)	13
2	B Grundy (COL)	10
3	J Macrae (WBD)	9
4	D Mundy (FRE)	8
5	T Walker (ADE)	7
	T Miller (GCS)	7
	J Ziebell (NOR)	7

R7
With four games having all new pollers, not much has changed up top. Walsh has jumped up from just outside the leaderboard, and Guthrie's consistent start to the year is also acknowledged. Grundy has also caught up to Gawn, who fails to poll in their win over North Melbourne.
​

Rank	Player	Votes
1	B Grundy (COL)	13
	M Gawn (MEL)	13
3	S Walsh (CAR)	9
	J Macrae (WBD)	9
5	D Mundy (FRE)	8
	C Guthrie (GEE)	8

R8
We have a new leader! But not much else happens. All players in the leaderboard are players who have been here at one stage or another.
​

Rank	Player	Votes
1	B Grundy (COL)	15
2	M Gawn (MEL)	13
3	S Walsh (CAR)	9
	J Macrae (WBD)	9
5	D Mundy (FRE)	8
	C Guthrie (GEE)	8
	T Miller (GCS)	8
	C Mills (SYD)	8

R9
Shorter leaderboard here because of the abundance of players on 8 votes, but there we see Lyons and Bontempelli join the higher groups with high scoring polling in each of their games.
​

Rank	Player	Votes
1	B Grundy (COL)	15
2	M Gawn (MEL)	13
3	C Guthrie (GEE)	11
4	S Walsh (CAR)	9
	J Macrae (WBD)	9

R10
Grundy pulls a full game away from Gawn, while more players join up on 11 votes, including some newcomers to the leaderboard. Official Brownlow winner Ollie Wines is nowhere to be found, even on a leaderboard of 15 like seen in the google doc.
​

Rank	Player	Votes
1	B Grundy (COL)	17
2	M Gawn (MEL)	14
3	J Lyons (BRI)	11
	C Guthrie (GEE)	11
	T Miller (GCS)	11

R11
While Miller equals Gawn for second place, Macrae outplays Oliver for the three votes, placing him a single vote above at the halfway point of the season. Parish also joins the leaderboard for the first time this season.

Rank	Player	Votes
1	B Grundy (COL)	17
2	T Miller (GCS)	14
	M Gawn (MEL)	14
4	J Macrae (WBD)	13
5	C Oliver (MEL)	12
6	J Lyons (BRI)	11
	D Parish (ESS)	11
	C Guthrie (GEE)	11

R12
Well, there is a fairly obvious mistake in these, with Bontempelli somehome gaining 4 votes in one round via the leaderboards, but his standard 3 in the game-by-game totals. Anyways, big movements here, with four players in equal third. Gawn finally wakes up from his dormancy, claiming equal first position once again.
​

Rank	Player	Votes
1	B Grundy (COL)	17
	M Gawn (MEL)	17
3	D Parish (ESS)	14
	T Miller (GCS)	14
	M Bontempelli (WBD)	14
	J Macrae (WBD)	14
7	J Lyons (BRI)	12
	C Oliver (MEL)	12

R13
In the middle of bye weeks, movement is limited in these next two rounds. Gawn retakes top position with his one vote against the Pies, but an unchanged list minus some drop-offs.
​

Rank	Players	Voters
1	M Gawn (MEL)	18
2	B Grundy (COL)	17
3	D Parish (ESS)	14
	T Miller (GCS)	14
	M Bontempelli (WBD)	14
	J Macrae (WBD)	14

R14
With only 5 games, very limited options with changes here. However, with the Demons and Magpies bye, the Bont is able to squeeze into the top 2
​

Rank	Players	Votes
1	M Gawn (MEL)	18
2	B Grundy (COL)	17
	M Bontempelli (WBD)	17
4	J Lyons (BRI)	14
	D Parish (ESS)	14
	T Miller (GCS)	14
	J Macrae (WBD)	14

R15
Well either it's a massive coincidence or both the Bont and Grundy knew about this, as they both played BOG in either of their games, placing them at the top of the leaderboard. Gawn now sits dormant, and will slowly drop from here one out, with Tom Mitchell finally rejoining the leaderboard
​

Rank	Player	Votes
1	B Grundy (COL)	20
	M Bontempelli (WBD)	20
3	M Gawn (MEL)	18
4	D Parish (ESS)	16
	J Macrae (WBD)	16
6	J Lyons (BRI)	14
	T Miller (GCS)	14
	T Mitchell (HAW)	14

R16
Grundy tops again, and late charger Steele joins the board. Gawn drops to fifth and will continue to fall with a dry patch in these later rounds.
​

Rank	Player	Votes
1	B Grundy (COL)	22
2	M Bontempelli (WBD)	20
3	D Parish (ESS)	19
	J Macrae (WBD)	19
5	M Gawn (MEL)	18
6	T Miller (GCS)	17
7	J Steele (STK)	16

R17
Well, Macrae keeps coming... 9 votes in 3 games places him in career-best form, and is one of the many reasons why the Bulldogs dominance was so consistent. Walsh rejoins, and Gawn continues to fall. Wines is still unseen. Grundy pulls up again, sitting on a solid 24 votes.
​

Rankes	Player	Votes
1	B Grundy (COL)	24
2	T Miller (GCS)	22
	M Bontempelli (WBD)	22
4	D Parish (ESS)	19
	J Steele (STK)	19
	J Macrae (WBD)	19
7	M Gawn (MEL)	18
8	S Walsh	17

R18
Well, it's the pointy end of the season... and the leaderboard is beginning to take shape. Macrae gets another 3, making it 12 from 4 in an unprecedented run. More well known is Steele's run in the second half of the season, wherein the last 4 he has received 8 in the last 4 games.
​

Rank	Player	Votes
1	B Grundy (COL)	24
2	T Miller (GCS)	22
	J Macrae (WBD)	22
4	D Parish (ESS)	21
	J Steele (STK)	21
6	S Walsh (CAR)	20
	M Bontempelli (WBD)	20

R19
Macrae is on top. With 15 votes in 5 games, he has a perfect run since the bye rounds. Little to no change has occurred in the top 8 this round.
​

Rank	Player	Votes
1	J Macrae (WBD)	25
2	B Grundy (COL)	24
3	T Miller (GCS)	22
4	D Parish (ESS)	21
	J Steele (STK)	21
6	S Walsh (CAR)	20
	M Bontempelli (WBD)	20

R20
Well the perfect once again continues, but that's getting boring now. 18 votes in 6 games...
​

Rank	Player	Votes
1	J Macrae (WBD)	28
2	B Grundy (COL)	24
3	T Miller (GCS)	23
	J Steele (STK)	23
5	S Walsh (CAR)	21
	D Parish (ESS)	21
7	M Bontempelli (WBD)	20

R21
Another round, another three votes for Jackson Macrae. It's looking insurmountable by this stage. Grundy has fallen outside of the top two, after the injuries throughout the season. Steele and Miller take home three, and Mitchell catapults himself into the top 8.
​

Rank	Player	Votes
1	J Macrae (WBD)	31
2	T Miller (GCS)	26
	J Steele (STK)	26
4	B Grundy (COL)	24
5	T Mitchell (HAW)	22
6	S Walsh (CAR)	21
	D Parish (ESS)	21
8	M Bontempelli (WBD)	20

R22
Well, it's over. Macrae has won it all, with another 3 votes. With 24 votes in 8 games, this was always going to happen.
​

Rank	Player	Votes
1	J Macrae (WBD)	34
2	T Miller (GCS)	26
	J Steele (STK)	26
4	B Grundy (COL)	24
5	T Mitchell (HAW)	22
6	S Walsh (CAR)	21
	D Parish (ESS)	21

R23
Is there even any point anymore? Anyways...
​
​
And the winner of the 2021 SuperCoach Brownlow medal with 34 votes is.... JACK MACRAE from the Western Bulldogs!!!!
Honestly, after he took over that top spot, it was over. No one was catching him. Here is the top 20.
​

RANK	PLAYER	VOTES
1	J Macrae (WBD)	34
2	J Steele (STK)	29
3	T Miller (GCS)	27
4	T Mitchell (HAW)	25
5	B Grundy (COL)	24
6	S Walsh (CAR)	21
	D Parish (ESS)	21
	M Gawn (MEL)	21
	C Oliver (MEL)	21
10	S Darcy (FRE)	20
	O Wines (POR)	20
	M Bontempelli (WBD)	20
13	Z Merrett (ESS)	18
14	J Lyons (BRI)	17
15	R Laird (ADE)	16
	C Guthrie (GEE)	16
	C Petracca (MEL)	16
	N Naitanui (WCE)	16
19	C Mills (SYD)	13
	L Parker (SYD)	13

Overall, there seems to be a more even distribution of votes compared to the official Brownlow, which is obviously due to the randomness of the algorithm than the imperfect minds of the umpire. There were 210 players who received votes in this competition.
Now, the next question is who received the most votes for each team?
Well here are the results: (ties listed in alphabetical by last name)
​

TEAM	PLAYER	VOTES
Adelaide	Rory Laird	16
Brisbane	Jarryd Lyons	17
Carlton	Sam Walsh	21
Collingwood	Brodie Grundy	24
Essendon	Darcy Parish	21
Fremantle	Sean Darcy	20
Geelong	Cameron Guthrie	16
Gold Coast	Touk Miller	27
Greater Western Sydney	Josh Kelly	12
Hawthorn	Tom Mitchell	25
Melbourne	Max Gawn, Clayton Oliver	21
North Melbourne	Jack Ziebell	9
Port Adelaide	Ollie Wines	20
Richmond	Jack Graham, Jayden Short	6
St Kilda	Jack Steele	29
Sydney	Callum Mills, Luke Parker	13
West Coast	Nic Naitanui	16
Western Bulldogs	Jack Macrae	34

​
Well, which team scored the most votes? Well, I configured that as well...
In order from highest to lowest (with equals decided by average votes per polled player)

TEAM	VOTE NUM	NUM of POLLED PLAYERS	AVE per POLLED PLAYER	RANK BASED ON AVERAGE
Melbourne	87	12	7.25	1
Sydney	87	16	5.4375	12
Western Bulldogs	86	12	7.1667	2
Essendon	78	12	6.5	6
Geelong	78	14	5.5714	9
St Kilda	77	14	5.5	10
Port Adelaide	75	14	5.3571	13
Brisbane	69	11	6.2727	7
Greater Western Sydney	67	15	4.4667	15
Collingwood	64	11	5.8182	8
Fremantle	59	9	6.5556	5
Adelaide	55	8	6.875	3
Gold Coast	55	10	5.5	11
Hawthorn	53	8	6.625	4
Carlton	52	12	4.3333	17
West Coast	50	10	5	14
North Melbourne	48	11	4.3636	16
Richmond	46	15	3.0667	18

And there we have it... This took far too long to make and I'm about to fall asleep so it's probably a good time to call it off here.
Hopefully people enjoyed this different perspective on who the best player in the league was this year, and if people have improvements for next years one (If that happens) that would be much appreciated.

So one thing I always hoped for as a resource for Brownlow Medal stats was to see a rolling tally where you could easily scroll through and see, for example, "who was leading the count after 5 rounds in 2010". However I couldn't seem to find that information anywhere.
The closest I got was AFL tables listing out which players polled the 3-2-1 votes for each round in a table like this, but there was no rolling tally. Using this information I decided to go through myself and make a spreadsheet of a round by round count for every Brownlow from 1990-2020, the AFL era. In doing so, these were some stats that I found that I feel are worth sharing.
If you guys have any questions related to players leading after X amount of rounds I may be able to answer them in the comments.
I have more stats prepared to share on Brownlow night but for now here is a small collection of some stats that I found interesting.
What are the fewest amount of rounds (excluding R1) where a player was leading the league in Brownlow votes to win the Brownlow?.

• for players that won the Brownlow that season because the leagues higher vote getter was ineligible.

Year	Player	Rounds Leading	Rounds Total
2012	Sam Mitchell*	NA	0
2012	Trent Cotchin*	NA	0
2014	Matt Priddis	23	1
1996	James Hird	22	1
2008	Adam Cooney	21-22	2
2006	Adam Goodes	21-22	2
2003	Mark Ricciutio	21-22	2
1997	Robert Harvey*	18-20	3

What are the most amount of rounds (excluding R1) where a player was leading the league in Brownlow votes for a player that didn’t win the Brownlow?.

• for players that led the league in Brownlow votes that season but were ineligible to receive the award.

Year	Player	Rounds Leading	Rounds Total
2012	Jobe Watson*	6-23	18
2008	Simon Black	2, 4-6, 8-20	17
1996	Corey McKernan*	3, 9-22	15
2014	Gary Ablett	3, 5-18	15
1993	Wayne Schwass	3-17	15
1991	Craig Turley	2, 4-11, 15-18	13
1997	Chris Grant*	4, 6-9, 14-17, 21-22	11
2003	Andrew McLeod	3-7, 9-10, 13-16	11
2019	Patrick Cripps	2-10, 12	10
2006	Scott West	4-5, 11-17, 20	10

What is the record for most consecutive rounds leading the Brownlow Medal Count?.

Year	Player	Rounds Leading	Rounds Total
2009	Gary Ablett	1-22	22
2015	Nat Fyfe	4-23	20
2012	Jobe Watson	6-23	18
1990	Tony Liberatore	6-22	17
2010	Chris Judd	7-22	16
1994	Greg Williams	9-24	16
2020	Lachie Neale	4-18	15
1993	Wayne Schwass	3-17	15
2014	Gary Ablett	5-18	14
1996	Corey McKernan	9-22	14
2004	Chris Judd	10-22	13
2008	Simon Black	8-20	13
1998	Robert Harvey	10-22	13
2016	Patrick Dangerfield	12-23	12
2019	Nat Fyfe	13-23	11
2013	Gary Ablett	10-20	11

What is the record for most Brownlow votes for a player that didn’t poll in the first X rounds?.

Didn't Poll Until Round X:	Year	Player	Team	FINAL
2	2020	Lachie Neale	BL	31
3	1998	Robert Harvey	SK	32
4	2010	Chris Judd	CA	30
4	1994	Greg Williams	CA	30
5	2017	Tom Mitchell	HW	25
5	2013	Steve Johnson	GE	25
6	2006	Adam Goodes	SY	26
7	2012	Trent Cotchin	RI	26
8	2015	Dustin Martin	RI	21
9	1998	Mark Ricciuto	AD	21
10	1996	Robert Harvey	SK	17
11	2002	Des Headland	BL	16
12	2007	Adam Goodes	SY	20
13	1993	Robert Harvey	SK	12
14	1996	Paul Salmon	HW	18
15	1994	Tony Francis	CW	11
16	2012	David Mundy	FR	12

What is the record for most Brownlow votes for a player polled their last votes for the season with X rounds remaining?

Didn't Poll in final X Rounds	Year	Player	Team	FINAL
1	2011	Dane Swan	CW	34
2	2019	Nat Fyfe	FR	33
3	2012	Jobe Watson	ES	30
3	2011	Sam Mitchell	HW	30
4	2019	Tim Kelly	GE	24
5	2014	Patrick Dangerfield	AD	21
6	2015	Nat Fyfe	FR	31
7	2007	Simon Black	BL	22
8	2014	Gary Ablett	GC	22
9	2003	Andrew McLeod	AD	18
10	2018	Nat Fyfe	FR	16
10	1992	Stewart Loewe	SK	16
11	2001	Shane OBree	CW	12
11	1998	Matthew Burton	FR	12
12	1993	Wayne Schwass	NM	14
13	1994	Ashley McIntosh	WC	11
14	2007	Chris Judd	WC	16
15	1992	Brad Tunbridge	SY	8

Additional small facts.

• In 2014 Shane Mumford was leading the league in total Brownlow votes after one round (R3), the same amount of rounds as eventual winner Matt Priddis who was also leading the league in total Brownlow votes after just one round (R23)
  
• In 2009 Gary Ablett Jnr was leading the Brownlow Medal Count after every round of the season! He was BOG in round 1, tied with Bryce Gibbs on 5 votes in round 2 and tied with Nic Dal Santo during rounds 3,4,7 and 8 but no player ever had more votes than him after the completion of a round.
  
• In 2003 Ben Cousins was leading the Brownlow Medal Count from rounds 17-21, 5 rounds, but failed to win the Brownlow after not leading after round 22. This is the only instant where an eligible player led for at least the last 3 rounds before the final round and failed to win the Brownlow.
  

Here is a visulisation to help understand, where X signifies that the player was leading the count.

Year	Player	R17	R18	R19	R20	R21	R22
2003	Ben Cousins	X	X	X	X	X
2003	Adam Goodes	X	X	X	X		X
2003	Nathan Buckley			X	X	X	X
2003	Mark Ricciutio					X	X

My fellow main lab members (and myself) have been putting in 60, 70, 80+ hours a week for almost three months straight.
I’m exhausted. They’re exhausted. Our new brilliant PhD student is thinking about quitting. I’m thinking about quitting. Our only post doc is at his witts end.
Meanwhile, my PI hasn’t spent a full week in the lab in at least a year and a half. They are CONSTANTLY on vacation, and CONSTANTLY pushing their grant/review/administrative duties onto us. (Especially me).
I nearly flipped when my PI gave my undergrad 24 hours to finish his research paper (that isn’t due for a week) because… you guessed it, another vacation. Then, pushed off an R21 on me to finish, gave a first year PhD student less than one month to finish a manuscript for actual publication, and made demands to have a full publishable perspective in 2 days.
Mind you, this is the same PI that gave my majorly funded grant to another student 3 weeks before my committee meeting last year, effectively scooping two years of work… along with a bundle of other unethical decisions.
Fuck, it’s so frustrating.

https://www.sciencedaily.com/releases/2021/05/210506183353.htm

Sugar-sweetened drinks linked to increased risk of colorectal cancer in women under 50, study finds

Sugary beverage consumption in adolescence, young adulthood associated with increased risk

Date:May 6, 2021Source:Washington University School of MedicineSummary:Colorectal cancer diagnoses have increased among people under age 50 in recent years and researchers are seeking reasons why. A new study has found a link between drinking sugar-sweetened beverages and an increased risk of developing colorectal cancer in women under age 50. The findings suggest that heavy consumption of sugary drinks during adolescence (ages 13 to 18) and adulthood can increase the disease risk.
Colorectal cancer diagnoses have increased among people under age 50 in recent years and researchers are seeking reasons why. A new study led by Washington University School of Medicine in St. Louis has found a link between drinking sugar-sweetened beverages and an increased risk of developing colorectal cancer in women under age 50. The findings suggest that heavy consumption of sugary drinks during adolescence (ages 13 to 18) and adulthood can increase the disease risk.
The study, published online May 6 in the journal Gut, provides more support for public health efforts that encourage people to reduce the amount of sugar they consume.
"Colorectal cancer in younger adults remains relatively rare, but the fact that the rates have been increasing over the past three decades -- and we don't understand why -- is a major public health concern and a priority in cancer prevention," said senior author Yin Cao, ScD, an associate professor of surgery and of medicine in the Division of Public Health Sciences at Washington University. "Due to the increase in colorectal cancer at younger ages, the average age of colorectal cancer diagnosis has gone down from 72 years to 66 years. These cancers are more advanced at diagnosis and have different characteristics compared with cancers from older populations.
"Our lab is funded by the National Cancer Institute (NCI) and the National Comprehensive Cancer Network to identify risk factors, the molecular landscapes, and precision screening strategies for these cancers so that they can be detected earlier and even prevented," said Cao, who also has a master's of public health. "In past work, we have shown that poor diet quality was associated with increased risk of early-onset colorectal cancer precursors, but we have not previously examined specific nutrients or foods."
Compared with women who drank less than one 8-ounce serving per week of sugar-sweetened beverages, those who drank two or more servings per day had just over twice the risk of developing early-onset colorectal cancer, meaning it was diagnosed before age 50. The researchers calculated a 16% increase in risk for each 8-ounce serving per day. And from ages 13 to 18, an important time for growth and development, each daily serving was linked to a 32% increased risk of eventually developing colorectal cancer before age 50.
Sugar-sweetened drink consumption has been linked to metabolic health problems, such as type 2 diabetes and obesity, including in children. But less is known about whether such high-sugar beverages could have a role in the increasing incidence of colorectal cancer in younger people. Like early-onset colorectal cancer rates, consumption of such drinks has increased over the past 20 years, with the highest consumption level found among adolescents and young adults ages 20 to 34.
The researchers analyzed data from the Nurses' Health Study II, a large population study that tracked the health of nearly 116,500 female nurses from 1991 to 2015. Every four years, participants answered surveys that included questions about diet, including the types and estimated amounts of beverages they drank. Of the total participants, over 41,000 also were asked to recall their beverage habits during their adolescence.
The researchers identified 109 diagnoses of early-onset colorectal cancer among the nearly 116,500 participants.
"Despite the small number of cases, there is still a strong signal to suggest that sugar intake, especially in early life, is playing a role down the road in increasing adulthood colorectal cancer risk before age 50," said Cao, also a research member of Siteman Cancer Center. "This study, combined with our past work linking obesity and metabolic conditions to a higher risk of early-onset colorectal cancer, suggests that metabolic problems, such as insulin resistance, may play an important role in the development of this cancer in younger adults."
With the increasing rates in mind, the American Cancer Society has recently lowered the recommended age for a first screening colonoscopy to 45, down from the previously recommended age 50 for people at average risk. Those with additional risk factors, such as a family history of the disease, should start even earlier, according to the guidelines.
Since the study only included female nurses, most of whom were white, more work is needed to examine this link in people of more diverse races, ethnicities and genders.
While sugar-sweetened beverages were linked to an increased risk of early-onset colorectal cancer, some other drinks -- including milk and coffee -- were associated with a decreased risk. This observational study can't demonstrate that drinking sugary beverages causes this type of cancer or that drinking milk or coffee is protective, but the researchers said that replacing sweetened beverages with unsweetened drinks, such as milk and coffee, is a better choice for long-term health.
"Given this data, we recommend that people avoid sugar-sweetened beverages and instead choose drinks like milk and coffee without sweeteners," Cao said.
Co-authors of the study include Ebunoluwa Otegbeye, MD, a general surgery resident at Washington University working in the Cao lab. Otegbeye is supported by the Surgical Oncology Basic Science and Translational Research Training Program. Collaborators include researchers at the Harvard T.H. Chan School of Public Health and Harvard Medical School.
This work was supported by the National Institutes of Health (NIH), grant numbers U01 CA176726, R01 CA205406, R21 CA230873, R01 CA151993, R35 CA197735, R35 CA253185, R03 CA197879, R21 CA222940, R37 CA246175, K07 CA218377 and T32 CA009621; the Department of Defense, grant number CA160344; the Project P Fund; the Stuart and Suzanne Steele MGH Research Scholarship; and an Investigator Initiated Grant from the American Institute for Cancer Research.
Story Source:
Materials provided by Washington University School of Medicine. Original written by Julia Evangelou Strait. Note: Content may be edited for style and length.
Journal Reference:

1. Jinhee Hur, Ebunoluwa Otegbeye, Hee-Kyung Joh, Katharina Nimptsch, Kimmie Ng, Shuji Ogino, Jeffrey A Meyerhardt, Andrew T Chan, Walter C Willett, Kana Wu, Edward Giovannucci, Yin Cao. Sugar-sweetened beverage intake in adulthood and adolescence and risk of early-onset colorectal cancer among women. Gut, 2021; gutjnl-2020-323450 DOI: 10.1136/gutjnl-2020-323450

Source

For proper formatting, please use Old Reddit

The AMA began with the following, fairly lengthy message:

Hello everyone, thank you for joining the Reddit AMA for rare diseases. To start, we’d like to provide the U.S. definition for a rare disease (as defined in the Orphan Drug Act of 1983, and the Rare Disease Act of 2002): In the United States, a rare disease is defined as a disease or condition that affects fewer than 200,000 people in this country. Rare diseases are sometimes called orphan diseases, and we tend to use “rare disease” and “orphan disease” interchangeably.
A few FAQs:

• Most rare diseases are genetic disorders, typically affecting a single gene.
• At the current time, there are about 7,000 different rare diseases, each affecting only a few hundred to a few thousand people (sometimes fewer). As we continue to uncover the underlying genetics of more rare diseases, the number of known rare diseases increases by about 200-250 diseases each year.
• Only about 5% of rare diseases have an FDA-approved treatment. (The FDA estimates about 450-500 drugs and biologics are approved to treat a variety of rare diseases)
• NIH devoted around $6 billion to rare diseases research in Fiscal Year 2019. This research is very diverse, ranging from basic science to translational science to clinical trials in a broad array of diseases and conditions.
• The National Center for Advancing Translational Sciences (NCATS) within NIH has identified rare diseases as a priority research area. Some examples of NCATS-supported rare diseases research programs include:
  
  • The Rare Diseases Clinical Research Network (RDCRN).
  • The Genetics and Rare Diseases Information Center (GARD). Did you know GARD can accept individual inquiries for rare diseases questions and concerns? You may contact a GARD information specialist at 1-888-205-2311, or online.
  • The Therapeutics for Rare and Neglected Diseases program (TRND). TRND works with companies, academic centers and patient groups to further preclinical development of candidate therapies, with the goal of moving these candidates toward clinical trials.
  • The Platform Vector Gene Therapy program (PaVe-GT). PaVe-GT is a new program whose goal is to try to develop 4 gene therapies for 4 diseases in parallel to try to improve the efficiency of gene therapy development.
  • Please visit the NCATS website for more information.

Rare Disease Day at NIH will virtually take place on March 1. Please join us! Registration is open. - Dr. Anne Pariser, NCATS ORDR Director

Rows: ~40

Questions	Answers
With COVID-19 cases surging there is an estimate that 10% of severely impacted COVID-19 patients will go onto developing "long covid." Dr. Faucci and Deputy Director Tedros Adhanom have said these people best identify with the Myalgic Encephalomyelitis patients and have expressed concerns that these symptoms could last indefinitely. What are we doing for these people with ME/CFS?	We do not yet know how many people will develop ME/CFS following infection by SARS-CoV-2 and we do not have data regarding the effect of the virus on people who have ME/CFS. I have recently started a study that will be following individuals who are recovering from COVID-19 to understand how their symptoms change over time. We will also be recruiting people who have now developed ME/CFS after COVID infection and will compare them to participants in our current ME/CFS protocol. Research on long-term effects of COVID will teach us about diseases with similar symptoms, such as ME/CFS.
​	The CDC is hosting the Interagency ME/CFS Working Group meeting on Feb. 25-26. The focus on Day 2 of the meeting will be long COVID. For more information about the meeting, please visit: https://www.nih.gov/mecfs/events. - Dr. Avindra Nath, NINDS Clinical Director
How do/can researchers study a disease accurately and thoroughly when there's so much diversity in how every patient expresses the disease and when there might also not be many scientists studying the specific disease too? How quickly can treatments be given to these patients, and what can be done to increase funding and research support?	This is an excellent question. Even for a rare disease caused by a well understood genetic misspelling, individuals may have widely different manifestations. An example is a condition that my lab used to research called neurofibromatosis. In that instance individuals in the same family who have the exact same DNA misspelling may be almost without symptoms or severely affected. Obviously care of patients with rare diseases needs to take into account their individual situation and this can’t be done in a formula based approach. This is the whole concept of precision medicine, which is the opposite of one-size-fits-all. Researchers are actively pursuing reasons for these differences in disease presentation. They might be other genetic modifiers or they might be environmental. The more we know about them, the better chance we’ll have to factor them into effective treatment. - Dr. Francis Collins, NIH Director
​	Most rare diseases have considerable diversity within a disease for symptoms, disease progression, patients affected and many other factors. To best understand a disease, many researchers and patient groups undertake disease registries or natural history studies to better understand the full spectrum of a disease. This can happen in parallel with basic or clinical research. The information obtained in the registry can help in clinical study designs, identifying outcome measures as well as patients for inclusion in trials, among other factors. For patient groups interested in starting and conducting good-quality registries and NHS, additional resources are available through NCATS’ RaDaR program.
​	The therapy development process varies considerably depending on the disease, candidate therapeutic approaches and how much is known about a disease. NCATS’ mission is to improve the research process so that more treatments can be delivered to more patients more quickly. Some examples of these programs include:
​	* The Platform Vector Gene Therapy program (PaVe-GT). PaVe GT is a new program whose goal is to try to develop 4 gene therapies for 4 diseases in parallel to try to improve the efficiency of gene therapy development.
​	* The Rare Diseases Clinical Research Network (RDCRN), where multiple rare diseases are studied at the same time within centers of excellence.
​	Please visit the NCATS website for more information on some of these programs intended to speed delivery of candidate therapeutics to patients.
​	- Dr. Anne Pariser, NCATS ORDR Director
Hi all! I recently joined NIH and am very excited for Rare disease day, as I have hypermobile Ehlers-Danlos syndrome (with all of the associated conditions- CFS, POTS, MCAS, etc..) It took me 21 years to get a correct diagnosis. Most of that time was me being blessed with a background in medicine, standing up for myself and not letting my struggles be dismissed by doctors... and having the funds to pay for an innumerable amount of visits. My questions are, what are all of your personal disease group interests? Are you familiar with people’s struggles with doctors - being ignored, gaslighted, told they’re not actually suffering etc? If so, what advice do you have for the medical world, and the patients experiencing this treatment? Also, are you aware of any EDS research being done at NIH? Thank you for your time, and your dedication to rare disease research!!	NCATS ORDR, like all of NCATS, is “disease agnostic.” That is, we focus on the research process to try to improve the research environment for all rare diseases, with the goal of bringing more treatments to more patients more quickly. Diagnosis is a difficult and common problem for patients with rare diseases. Because they are rare, many doctors may never have seen a patient with a specific rare disease before, frequently making rare diseases hard to recognize. There are also more than 7,000 different diseases (with more being recognized every day), and it is difficult for doctors to be familiar with each disease and the rapidly changing environment. New strategies to accelerate diagnosis are needed.
​	To try to help this situation, NCATS has recently published a funding opportunity announcement (FOA) called “Multi-disciplinary Machine-assisted, Genomic Analysis and Clinical Approaches to Shortening the Rare Diseases Diagnostic Odyssey.” This FOA requests applications that combine machine-assisted learning, genomic analysis and clinical approaches that could be adopted by frontline providers to improve and shorten the diagnostic odyssey.
​	NCATS also runs the GARD information center that includes information on more than 6,500 different rare diseases.
​	There is ongoing NIH-supported research on EDS. The primary NIH Institute for EDS is the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS). Additional information can be found on the NIAMS Heritable Disorders of Connective Tissue webpage. You can search for grants to researchers on various topics and disease areas on the NIH RePORTER website. (Type the term of interest into the “TEXT SEARCH” box.)
​	Additionally, we note that every year hundreds of patients face uncertainty when health care providers are unable to discover the cause for their symptoms. The Undiagnosed Diseases Network (UDN) is a research study backed by the National Institutes of Health Common Fund that seeks to provide answers for patients and families affected by these mysterious conditions.
​	- Dr. Anne Pariser, NCATS ORDR Director
Hi! First I want to say thank you for doing this! I am signed up for Rare Across America and am attending rare disease day at NIH, so this is a fun bonus! I have idiopathic hypersomnia and there are currently no FDA approved medications for it. What do you think the answer is to advancing clinical research to understand disease and help get them under control? What can we as patients do to help this along? I am part of the CoRDS registry and have participated in every clinical research trial that has come my way, but I'm interested to know if there is more I could be doing. Thank you again!	I am sorry to hear of your diagnosis with idiopathic hypersomnia (IH), which is a chronic disorder that results in daytime sleepiness, unrefreshing sleep and difficulty awakening, among other symptoms. A first step for many rare diseases is to better understand the disease course through natural history studies (NHS) and registries, as you are doing.
​	For patient groups interested in starting and conducting good quality registries and NHS, additional resources are available through NCATS’ RaDaR program.
​	Another option is to find a patient organization for your disorder, or start a foundation or patient group if one doesn’t exist. Patient advocacy groups (PAGs) or foundations can help you to find and work with other patients and advocates to fully understand the disease, and to work together toward research and care.
​	The NCATS Toolkit for Patient-Focused Therapy Development (Toolkit) provides a resource that describes the process for starting a patient group.
​	Joining together with other patients to start to develop a research agenda can help to develop a priority list for next steps in a disease.
​	Some other suggestions:
​	* Explore the NCATS Toolkit for more information on the research process and how you can start or support research on your condition.
​	* Work with larger rare disease organizations to bring attention to rare diseases, and to take part in educational programs to empower patients.
​	* Meet with the researchers conducting clinical research trials. Ask the researchers how you can contribute to research, such as helping to inform the patient community about ongoing research and research needs, and meeting the research team to help them understand your disease, among others.
​	* Consider working with researchers and clinicians to hold a scientific meeting to help you develop or organize a scientific agenda.
​	​ * NCATS and other Institutes/Centers (ICs) at NIH help support scientific conferences through grants. Please see NCATS’ conference grants page for more information.
​	* The primary NIH IC that works on idiopathic hypersomnia is the National Institute of Neurological Disorders and Stroke (NINDS). Please see their information page for more resources and information - Dr. Anne Pariser, NCATS ORDR Director
How do biases and inequities in healthcare affect the rare disease community in particular? For example, there are issues around access to treatments, but there are also biases that may lead to a delayed or incorrect diagnosis. What has been done to address this? Does the NIH have a role in overcoming these issues? Thank you!	It is unfortunately true that our healthcare system is not free of bias. Rare diseases are no exception. Clearly in the United States, there are health inequities that affect certain populations’ access to healthcare. In addition, rare diseases may encounter a version of bias from providers who are simply unfamiliar with the particular condition and are therefore unprepared to offer the optimal clinical recommendations. NIH seeks to make all of its information on rare diseases accessible to patients and providers. NIH also has a major program in health disparities that aims to identify factors that contribute to bias and to test interventions to try to address those inequities. Our most important partners in addressing these problems are patients and their families, so it is a really good thing that the rare disease community is so active in this space.
​	- Dr. Francis Collins, NIH Director
How do you feel about the ethics of CRISPR editing? Where should the line be, and for what reasons?	>CRISPR gene editing is one of the most exciting developments in biomedical research in the last 10 years. It provides an opportunity to correct DNA misspellings that contribute to disease, including rare diseases. Applying this to somatic cells for conditions like Sickle Cell Disease may make it possible to provide a cure. In fact, such trials are already underway for a few diseases. The ethical dilemma relates to the possible use of CRISPR editing of human embryos. The strong consensus of the ethical community, with which I agree, is that heritable changes in the human genome ought not to be undertaken since that would open the door to reengineering ourselves in a circumstance where actual medical need is hard to identify.
​	>- Dr. Francis Collins, NIH Director
Thanks for the AMA. Given that MG (Myasthenia Gravis) is classed as a rare disease, what are your thoughts on the findings that people are presenting with MG after a Covid19 infection? Would this mean that Covid19 sets certain gene mutations in motion? Or could it be possible that all MG cases are, at the root, driven by viral infections?	That is a very good question. The RDCRN has established the MGNet, which studies myasthenia gravis. This multisite consortia would be a good group to reach out to to explore this question. They have been highly interested in the impact of COVID-19 on their patients. - Dr. Anne Pariser, NCATS ORDR Director
My sons were diagnosed with CGD https://rarediseases.org/rare-diseases/chronic-granulomatous-disease/ at ages 16 and 18. What progress is being made with gene based approaches to treating and curing CGD? What are the obstacles? Who is leading these efforts? Thank you for all of your work on rare diseases and for participating in this event. We really, really appreciate it.	Thank you for the question. There is research going on at the NIH Clinical Center on CGD, including the laboratories of Dr. John Gallin and Dr. Harry Malech. Dr. Suk See De Ravin in Dr. Malech’s group is working on genetic therapies for CGD.
​	-Dr. Anne Pariser, NCATS ORDR Director
I have HNPP, ( www.Hnpp.org) It's caused by mutations in the PMP22 gene, it took 9 years to diagnose ( confirmed by blood test) and I still have to ‘educate’ Doctors today about it, any resources you could share on this condition would be appreciated. From my support group I see all ranges of prognosis, not all good as it’s progressive, and it’s hard to know where it’s going, but would be good to know there is research or something going on to challenge this disease. Thank you for your time Edit to add I also was diagnosed with Fibromyalgia/Raynards, ( not so rare) but are some peoples genetics just prone to being hit by the ‘genetic sick stick’?	Diagnosis is a difficult problem for rare diseases. Please also see the response to u/HumbertHum which lists a number of resources and programs to try to improve the diagnostic odyssey. HNPP = Hereditary neuropathy with liability to pressure palsies (MedlinePlus and GARD provide more information).
​	The primary NIH Institute researching HNPP is NINDS. The NINDS hereditary neuropathy page contains more information and resources. - Dr. Anne Pariser, NCATS ORDR Director
Hi, thank you so much for doing this! What do you see as the biggest barriers to developing therapies for these diseases? As a researcher in the basic sciences, my experience has been that there seems to be a considerable amount of applicable research ongoing even for rare diseases in the academic/preclinical world, but that these have not been pursued for development as therapy. Is this a sentiment you would classify as more broadly true, and if so, what are some of the policy steps that you feel can be taken to improve the situation! Again, thanks so much for doing this!	Much has been written about the so-called “Valley of Death.” Basic science discoveries can lead to fundamental understandings of the causes of disease, but translating that into clinical benefit is a long and difficult journey. For rare diseases where the commercial benefits of a successful therapy may be insufficient to inspire private sector interest, good ideas about therapy may simply not get pursued. NIH is intensely interested in developing ways to cross this valley. One way is for NIH-supported researchers to push the research agenda further along--essentially de-risking a project which may then be appealing to a private sector partner. This is a lot of what the National Center for Advancing Translational Sciences (NCATS) does. NIH can also work with Food and Drug Administration (FDA) to identify ways to facilitate clinical developments that can utilize a template which has already been approved, so that every project doesn’t have to start from square one. We are doing that right now for gene therapy.
​	Read more about basic science research at NIH: https://www.nih.gov/news-events/basic-research-digital-media-kit
​	- Dr. Francis Collins, NIH Director
What is the best way to create a patient support group if one doesn't exist for your rare disease to advocate for funding and research?	Joining together with other patients is an important way to support your community and it also can help to start the development of a research agenda for a disease. Here is one resource available through the NCATS Toolkit for Patient-Focused Therapy Development (Toolkit) that describes the process for starting a patient group.- Dr. Anne Pariser, NCATS ORDR Director
Hi, I would like to thank you for all efforts on gene therapy studies. Just a short question: As a father of an adorable, 6-years old girl with CMD, we’re also awaiting the final results of one of the gene therapy studies that continues at NIH. We’ve seen that especially after 2017, there have been very successful results/achievements. How do you see the future of the gene therapies? Specifically about the muscular dystropies... Thank you again. Best Regards and greetings from Istanbul, Turkey. Onur Cakir	Thank you for your question. At the present time, gene therapy using adeno-associated virus (AAV) vectors is showing promise for multiple diseases, and has led to some approved therapies. Looking to the future, genome editing is of great interest. Indeed, last year, an NIH grantee, Dr. Jennifer Doudna, and her collaborator, Dr. Emmanuelle Charpentier, were awarded the Nobel Prize in Chemistry for their discovery of the CRISPCas9 system. Part of the interest in genome editing is the possibility that a single gene editor enzyme might be used for multiple diseases, just by changing the sequence of the “guide” RNA for different diseases. Notably, the NIH Common Fund is supporting a large program on somatic genome editing, with a major focus on better ways to deliver genome editors to more cell types, including the muscle. - Dr. Anne Pariser, NCATS ORDR Director
Hi there and thank you for doing this. My two year old grandson has 3MCC and it’s like chasing a ghost. Are there cures for these types of issues? Are there initiatives studying this and if so, who and how? We have a geneticist team in Boston and they are great but there are so many questions with no answers. Thank you, again.	3MCC deficiency = 3-methylcrotonyl CoA carboxylase deficiency, a rare organic acid disorder (https://rarediseases.info.nih.gov/diseases/10954/3-methylcrotonyl-coa-carboxylase-deficiency). We suggest trying to locate a disease expert who is familiar with the treatment of “Organic Acidemias” (OA). OAs are currently being studied at NIH within the Medical Genetics and Metabolic Genetics Branch. You may wish to consider reaching out to them to see if they have available information or resources that may be available to you, or know of other resources closer to where you live.
​	You also may wish to contact the GARD information center, which may be able to connect you with other researchers or treating clinicians. You may contact a GARD information specialist at 1-888-205-2311, or online.
​	While there are many promising areas of research into therapies for the treatment of OAs, such as gene therapy, at this time there are no approved therapies specifically for 3-MCCD. However, there are management options for patients, such as low-protein diet and appropriate supplements, that can be overseen by a disease specialist.
​	-Dr. Anne Pariser, NCATS ORDR Director
Thank you for doing an AMA! How are you all doing today? Has the internet changed how the rare disease community organizes and generates support? Do you think this has had any impact on the development of treatments? Thank you!	The internet has opened many doors for rare disease community organizations including: 1. Bringing people together from around the world - it can lessen the isolation that many individuals with rare diseases and their families experience; 2. It provides the ability to share vetted information and best practices; 3. It gives patients and families a voice - they are able to share their experiences with a broad audience, thereby educating people about the rare disease experience; 4. It gives the groups the opportunity to address inaccurate information; 5. It provides the ability to help bring patients together to assist in recruitment efforts for clinical trials.
​	- Dr. Anne Pariser, NCATS ORDR Director
I am a computer scientist. I work with big data. I have been in awe of things like CRISPR and the general advancement happening in computer aided genetic research. If I was given a chance, I would like to see or build a system that could help the researchers. Although, I have never deeply researched, but always interested. (I apologise for my insincerity) I wanted to know what kind of toolings, computer systems, and analytics goes into detecting, and possibly finding a cure to such diseases. I would love to look up the resources and companies that work in this field that are leveraging modern computation power to tackle this issue.	Computation, machine learning, artificial intelligence and other aspects of data science are playing increasingly large roles in biomedical research, given their ability to augment human capacities for aggregation and analysis of the very large amounts of data being produced from basic to translational to clinical research. Resources you could consider are the NIH Office of Data Science Strategy, as well as the recent report from an NIH Advisory Committee to the Director (ACD) Working Group on Data and Informatics. From NCATS, you may find our National COVID Cohort Collaborative (N3C) project and ASPIRE Program particularly interesting, in addition to this story of the citizen-scientist driven Mark2Cure initiative to study rare diseases. - Dr. Chris Austin, NCATS Director
Thank you for hosting this AMA! No field depends more on equitable data sharing than rare diseases, but neither academic researchers nor private institutions (companies) have much incentive to do so. In fact, the opposite is generally true, since keeping data access exclusive ensures a competitive advantage. What can NIH / government do to further promote (enforce?) data sharing by academic and private institutions?	Data sharing is critical to all science, and as such NIH has recently announced an important – and more demanding – policy on sharing of data from NIH-supported research. ClinicalTrials.gov is another very important required data-sharing program. Complete, open and prompt sharing of data in an interpretable fashion is particularly critical for NCATS, because translational science is a fundamentally integrative discipline, deriving general insights from the aggregation of many individual translational research efforts. But as with so many other issues in translational science, the methods, standards and operational best practices required to efficiently produce translationally useful new insights from the aggregated data that facile sharing allows have yet to be developed and demonstrated, and are major areas of NCATS innovation. Our open informatics work in drug development (e.g., OpenData Portal) and rare diseases (e.g., GARD), the NCATS-coordinated Rare Diseases Clinical Research Network (RDCRN) Data Management and Coordinating Center, and the unprecedented National COVID Cohort Collaborative program are all examples of NCATS data sharing and dissemination initiatives that are accelerating translational discovery. Watch for my February Director’s Message, which will be posted in the next few days, on just this topic of data sharing! - Dr. Chris Austin, NCATS Director
Thanks for doing this AMA! Given the problems inherent in translating results from one species to another and the ethical concerns with animal research, what is NIH doing to advance non-animal research into rare diseases?	Several NIH Institutes and other government agencies have been working to advance non-animal research and animal alternatives for many years; see for example https://www.niehs.nih.gov/research/atniehs/dntp/assoc/niceatm/index.cfm. NCATS has been at the forefront of this work, both in its Tox21 collaboration with NIEHS/NTP, EPA and FDA and in its Tissue Chip for Drug Screening program, which has developed many human cell-based microfluidic bioreactors to mimic human responses to drugs and toxicants, and to model rare diseases and responses to therapeutics. - Dr. Chris Austin, NCATS Director
Do you know of any effective treatments for psoriatic arthritis that aren't immunosuppressive?	Research into psychedelics, including psilocybin and LSD, has undergone something of a renaissance in recent years, focusing on their potential use as treatments for a range of neuropsychiatric disorders, including Parkinson’s disease and Alzheimer’s disease. The work is mainly at early clinical stage testing in small numbers of people. - Dr. Chris Austin, NCATS Director
Funding mechanisms for rare disease research? R21, R01?	The majority of grants funded at NIH fall under the category of investigator initiated research. Don’t panic if you don’t find a specific funding opportunity announcement (FOA) for the disorder that you are studying. You can use the Research Portfolio Online Reporting Tools to find which part of NIH may be the best fit for your science. NIH program directors at specific institutes or centers can answer your questions regarding the best funding mechanism for your research. NCATS’ Office of Rare Diseases Research can help you navigate NIH to find the right institute and person to contact. Funding opportunity announcements can be found on NCATS’ website.
​	- Dr. Chris Austin, NCATS Director
the below is another reply to the original question
To jump on this, what are the best current mechanisms for getting basic research into the clinic? Are their ways the current system could be adapted or improved? Rare diseases are always going to be intrinsically difficult to get into the clinic since they are by definition challenging to build a business case for in pharma, so it seems like we’re always going to have to give them some kind of an assist.	Thanks for your question. The National Center for Advancing Translational Sciences was created in 2011 precisely to address the first part of your question, which is how to translate basic research into the clinic. For the second part of your question, there is increasing interest in better approaches to develop treatments for rare disease of no commercial interest. These include the NCATS Platform Vector Gene Therapy Program and the Bespoke Gene Therapy Consortium.
​	More broadly, another approach to more efficient clinical trials is to group rare disease patients according to the underlying disease mechanism, rather than “one disease at a time.” This approach has been valuable in the cancer field. Here are two recent funding announcements: https://grants.nih.gov/grants/guide/rfa-files/RFA-TR-20-031.html and https://grants.nih.gov/grants/guide/rfa-files/RFA-TR-21-010.html. - Dr. Chris Austin, NCATS Director
[deleted]	We see and speak with rare disease patients, parents and families almost every day, and study rare diseases on a daily basis. Rare diseases are individually rare (by disease) but collectively they are common. There are about 7,000 different rare diseases, each of which affects a few hundred to a few thousand people (sometimes fewer), which collectively affect an estimated 25-30 million people in the US.
​	The number and diversity of rare diseases makes it impossible for any one person to be an expert on all rare diseases. However, there are experts and expert centers who focus on clusters of related rare diseases, such as metabolic diseases, bone disease, or rare eye diseases, which allows for expert patient care at these centers. Some examples include the individual rare disease clinical research consortia (RDCRC) within the RDCRN – here is a link to the different RDCRC and the diseases that they study: https://www.rarediseasesnetwork.org/. There are other examples as well, such as Children’s hospitals which often specialize in rare pediatric diseases. Researchers often focus on narrow areas of study for rare diseases as well. For example, there are researchers who exclusively study muscular dystrophy, or specific types of muscular dystrophy and have extensive knowledge within these areas or single diseases.
​	We recommend that patients and their families try to seek care for a rare disease at an expert center whenever possible. Should you need assistance finding disease experts, please contact the GARD information center who may be able to provide assistance. https://rarediseases.info.nih.gov/
​	- Dr. Anne Pariser, NCATS ORDR Director

I am seeing a lot of misinformation being passed around ottawa and not just limited to this board relating to covid. People either citing outdated information, stuff thats proven wrong, or just a general misunderstanding usually to back up their own moral justification to keep on doing whatever is convenient to them. Its not ill-intent, for the most part, i believe, but it is causing problems- things are getting worse and there's no end to this pandemic in sight, hospitals are getting overwhelmed and we have freezer trucks full of bodies in ontario. so let's take a step back and review the most recent scientific literature-- its what the good people of Ottawa do- study the shit out of everything. and please, please No More Magical Thinking. Just because you are outdoors and transmission is 60x less likely, it can STILL HAPPEN. the coronavirus does not care, you cannot take it to court and say 'but I was outdoors!'

Transmission Dynamics of Severe Acute Respiratory Syndrome Coronavirus 2 Are More Complex Than Previously Believed

Infection control measures for respiratory diseases traditionally distinguish droplets (large, heavy, and believed to account for transmission within 1 to 2 meters) from aerosols (smaller, lighter, and believed to account for more distant transmission) (7). Precautions aimed at contact and droplet control include surface cleansing, handwashing, physical distancing, and wearing masks if less than 6 feet apart; those aimed at controlling airborne diseases include ventilation and wearing masks if sharing air.
Well-documented examples of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection between persons separated by several meters (8, 9), identification of a potentially viable virus in the air after many hours (10, 11), and detailed case analyses of “superspreader events” (12) lend weight to the hypothesis that airborne spread can occur (13). There is growing evidence to support replacing an oversimplified, droplet-or-aerosol model of disease spread with one that accounts for multiple interacting influences on how the virus travels in and through the air (7, 10, 14–25) (Table 1).
When an infected person speaks, shouts, coughs, or sneezes, the (more or less turbulent) gas cloud emitted can carry many particles of different sizes. Depending on their size, ballistic drops may fall to the ground within seconds, whereas smaller particles, aided by humidity and warmth of the exhaled air, can be carried several meters and linger in the air for extended periods (25). Four key factors influence the transmission of airborne respiratory viruses: ventilation, duration of contact, vocalization, and masking (7).
Severe acute respiratory syndrome coronavirus 2 does not spread uniformly. Many infected persons do not infect anyone else, whereas a small proportion infect many—a phenomenon known as overdispersion (κ statistic) of the reproduction number (27). The κ statistic for COVID-19 has been estimated at 0.1 to 0.45 (20, 21), indicating higher dispersion than in, for example, pandemic influenza (where κ is closer to 1, indicating that infected persons all have similar infectivity) (28). In effect, overdispersion of this magnitude means that about 10% of infectious persons, so-called superspreaders, may be responsible for about 80% of secondary transmissions (21).
Scientists and policymakers initially expressed concern that masks or face coverings could cause risk compensation (the wearer reduces other protective behaviors out of a false sense of security) or increase risk for transmission by acting as fomites (especially if there is increased face touching followed by touching of an environmental surface) (70, 71).
A narrative review summarized evidence that refuted the risk compensation hypothesis in the examples most commonly cited by mask skeptics (cycle helmets, seat belts, and interventions to prevent sexually transmitted diseases) (72). The authors also found no evidence to support the claim that risk compensation occurs with masks or face coverings and identified 3 studies that showed that if a person is wearing a mask, protective behaviors seem to increase in those around them (73–75). A fourth study, from Germany, found no evidence of risk compensation when masks were introduced for the public (76). Video evidence from public settings (for example, stations, parks, and shopping malls) in many countries before and after the introduction of masking policies found that those wearing masks touched their faces significantly less frequently than those not wearing masks (77). A systematic review designed to identify harms from mask wearing found no evidence of risk compensation or increased face touching (71).

Claims of Physiologic Decompensation Are Not Substantiated

We found no empirical evidence to support the claim that medical masks or cloth face coverings interfere with gas exchange to a clinically significant extent in healthy persons at rest. In nurses wearing medical masks through a 12-hour shift, no changes were seen in blood carbon dioxide or oxygen levels; minor changes in carbon dioxide levels were detected after wearing a respirator for 12 hours (88). Another study, on surgeons wearing surgical masks, showed a decrease in blood oxygen levels from 98% to 96% during prolonged surgery—a difference that was statistically significant but not clinically relevant (89).
The hypothesis that masks may cause potentially harmful physiologic changes during exercise (90) has limited empirical support (91), perhaps partly because respirators and medical masks need to comply with standards for maximum airflow resistance. Although clinically minor physiologic changes have sometimes been shown when healthy volunteers do intensive exercise while wearing tightly fitting respirators (68, 92–94), those wearing medical (94, 95) and cloth (96) masks showed no physiologic changes during moderate or intensive exercise.
Although many policies acknowledge that some persons should be exempt from mask wearing (on the assumption that such persons could come to harm), there is no consistency—and little firm evidence—on who should be exempt (Table 4) .

Benefits Must Be Balanced Against Harms and Acceptability

The observational studies summarized earlier (45–47, 63), along with the modeling studies (32–38, 48), suggest that across a range of scenarios the use of masks among the general public is an effective strategy in mitigating transmission of SARS-CoV-2. Even with a limited protective effect, masks can reduce total infections and deaths (especially in relation to presymptomatic transmission) and delay the peak time of the epidemic.
However, mandatory masking is unpopular with some and an infringement (albeit a relatively minor one) of individual freedom. Therefore, it should be restricted to situations where it is likely to be both effective and cost-effective (that is, when faced with a disease that is both prevalent and dangerous). It is not justified if the targeted disease is innocuous or can be prevented by other means that are more effective, more acceptable, less risky, or less expensive.
Coronavirus disease 2019 is not innocuous: It has killed millions of persons around the world (105), produced a cohort of survivors with chronic symptoms and unknown long-term prognosis (106), stretched health systems to (and sometimes beyond) their limits (107), and devastated economies (108). Voluntary masking has been successful in many Asian countries (notably Japan, South Korea, Hong Kong, and Taiwan) but less so in Western countries where the measure was less culturally acceptable (109).
Because of potential airborne transmission, COVID-19 is inherently difficult to contain. As with public masking, the effects and costs of school closures, gathering bans, border closures, quarantine regulations, travel restrictions, working from home, closing restaurants and nonessential shops, physical distancing rules, coughing etiquette, handwashing, and restricting visits to hospitals and nursing homes are difficult to quantify. Moreover, these measures play out differently and have different personal costs depending on the situation. For example, schools need to balance their duty of care to vulnerable pupils and staff with their educational mission and student welfare, which includes meeting the needs of pupils of different ages and abilities and those with (for example) autism and hearing impairments. Masking for only some groups, in some parts of schools and with exceptions granted, may be more appropriate than rigid universal mandates.
Concerns about environmental pollution from mask waste (110, 111) are well founded given that medical masks are made from petrochemicals and are nonbiodegradable. Homemade washable cloth face coverings are more environmentally friendly and may have greater cultural appeal (and hence, better adherence) (66, 109).

Conclusion

This narrative review has summarized a heterogeneous body of evidence on population masking in the context of the COVID-19 pandemic. Evidence that the virus can be airborne (and therefore be inhaled) and that masking policies, when effectively delivered, save lives is now strong. There is no evidence of serious harms from masks and face coverings, although discomfort, communication difficulties, and environmental effects are not insignificant. Psychological effects, which are culturally framed, shape acceptance and adherence.
As masking has become recommended or mandated, there is an urgent research agenda to develop alternatives that are more efficient, more comfortable, more acceptable, less disruptive of normal communication practices, and more environmentally friendly than currently available products.
Until the threat of the pandemic is behind us, we recommend that the public wear masks or face coverings in situations and settings where risk for transmission is high—notably where ventilation is poor, when large numbers of persons are gathered, when some are vocalizing (especially singing or shouting), and when contact is prolonged (7).
https://www.acpjournals.org/doi/10.7326/M20-6625
​
edit: tl;dr per request:
scientists say for protection you should wear masks ALL the time whenever you are in public, but ESPECIALLY poorly ventilated or crowded areas. But policy makers don't want to say that because it risks ANY compliance in places like Alabama and Arkansas, which leads to targeted high impact mask enforcing, like inside of stores only etc.-- but isn't Ottawa better than that???? we had this thing at effing 0 for multiple, multiple days just 6 months ago... Can we all just please stop ripping off our masks the instance we step outside a store, cos honestly, some of the air you breathe/in out then does go into / come from the store and other peoples' lungs. Maybe walk away for a minute first at least, please??
​

Has anyone seen this? Is this something we can look into ourselves?
https://grantome.com/grant/NIH/R21-MH100700-01

Numerous studies like these! have found a negative effect of SSRIS on puberty and normal growth in teens, it also says "this drug may affect growth In teens" on the drug pamphlet. In my case, I took SSRIS during puberty and now at 22 I notice small stature, I'm 5'7, my brother is about 5'10 despite having the same parents and he never took SSRIS. I also notice impeded facial bone growth like low cheekbones and recessed jaw and little facial hair which is causing self esteem issues. Anyone else take SSRIS during puberty?

Wanted to share something I learned about recently that's making me mull over my future options. There's a promising endo diagnosis/treatment option involving a nanoparticle/dye that can target exclusively endo cells, show them with high or perfect accuracy on a scan, and then be heated with infrared light to kill the cells. Pretty mind-blowing. Here's more:
https://www.sciencedaily.com/releases/2020/04/200406190449.htm
They're running trials on macaques this year, to be concluded at the beginning of 2022. I would imagine there'd be another 2+ years of human trials after that -- not certain. Here's the one in progress:
https://grantome.com/grant/NIH/R21-HD098642-01A1
Obviously, one of the biggest wins of this treatment would be its precision and accuracy.
My situation is that an endo specialist agreed it's highly likely I have it, and he wanted to go through with surgery. I've chosen not to follow up, partly because I'm dubious about how much endo material can get missed/left behind for how invasive the procedure is, partly because I'm strongly opposed to the hormonal therapy if I can help it, and partly because my symptoms are "manageable" (ish) (and I'm not interested in pregnancy). But I realize I'm running a risk that my abdominal organs could be compromised by the endo, even in the absence of symptoms.
So now the question I have to ask of myself is, do I put weight in this possible treatment (or another) and keep biding my time, or is this a really dumb risk to take...
Curious how this research sits with others :)

Hey all,
I'm a third year PhD student in infectious disease research.
When I started in my lab and expressed interest to my PI about submitting an F31 proposal, she seemed supportive and encouraged the application.
Now I have the data to support the F31 I wanted to submit. I have received an institutional fellowship, and one of the requirements for my fellowship is to apply for external funding. I brought this up to my PI and mentioned the F31, and she rejected the idea, suggesting I apply to a different organization.
Turns out I found out this week that she wants to use my data to support an R21 grant for herself.
I feel kinda betrayed, and at a loss. She has been a very supportive mentor up to this point. She currently has and R01 and R21, both of which expire in 2022, as well as some internal funding from the university.
Any advice would be appreciated.