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After US Food and Drug Administration (FDA) approval of a new drug, sponsors can submit additional clinical data to obtain supplemental approval for use for new indications. To characterize pivotal trials supporting recent supplemental new indication approvals of drugs and biologics by the FDA and to compare them with pivotal trials that supported these therapeutics' original indication approvals. This is a cross-sectional study characterizing pivotal trials supporting supplemental indication approvals by the FDA between 2017 and 2019 and pivotal trials that supported these therapeutics' original indication approvals. Data analysis was performed from August to October 2020. Number and design of pivotal trials supporting both supplemental and original indication approvals. From 2017 to 2019, the FDA approved 146 supplemental indications for 107 therapeutics on the basis of 181 pivotal efficacy trials. The median (interquartile range) number of trials per supplemental indication was 1 (1-1). Most trials used either placebo (77 trials [42.5%; 95% CI, 35.6%-49.8%]) or active comparators (65 trials [35.9%; 95% CI, 29.3%-43.1%]), and most of these multigroup trials were randomized (141 trials [99.3%; 95% CI, 96.0%-100.0%]) and double-blinded (106 trials [74.5%; 95% CI, 66.6%-81.0%]); 80 trials (44.2%; 95 CI, 37.2%-51.5%) used clinical outcomes as the primary efficacy end point. There was no difference between oncology therapies and those approved for other therapeutic areas to have supplemental indication approvals be based on at least 2 pivotal trials (11.5% vs 20.6%; difference, 9.1%; 95% CI, 2.9%-21.0%; P = .10). Similarly, there was no difference in use of randomization (98.3% vs 100.0%; difference, 1.7%; 95% CI, 1.6%-5.0%; P = .43) among multigroup trials, although these trials were less likely to be double-blinded (50.8% vs 92.3%; difference, 41.5%; 95% CI, 27.4%-55.5%; P < .001); overall, these trials were less likely to use either placebo or active comparators (64.9% vs 86.7%; difference, 21.8% 95% CI, 9.8%-33.9%; P < .001) or to use clinical outcomes as their primary efficacy end point (27.5% vs 61.1%; difference, 33.6%; 95% CI, 14.1%-40.9%; P < .001) and were longer (median [interquartile range], 17 [6-48] weeks vs 95 [39-146] weeks). Original approvals were more likely than supplemental indication approvals to be based on at least 2 pivotal trials (44.0% [95% CI, 33.7%-42.6%] vs 15.8% [95% CI, 10.7%-22.5%]; difference, 28.2%; 95% CI, 17.6%-39.6%; P < .001) and less likely to be supported by at least 1 trial of 12 months' duration (27.6% [95% CI, 17.9%-35.0%] vs 54.8% [95% CI, 46.7%-62.6%]; difference, 27.2%; 95% CI, 14.5%-37.8%; P < .001). Pivotal trial designs were otherwise not significantly different. These findings suggest that the number and design of the pivotal trials supporting supplemental indication approvals by the FDA varied across therapeutic areas, with the strength of evidence for cancer indications weaker than that for other indications. There was little difference in the design characteristics of the pivotal trials supporting supplemental indication and original approvals.

The purpose of this study was to investigate comorbid psychiatric disorders and psychotropic medication use among adults with autism spectrum disorder (ASD) ascertained as children during a 1980’s statewide Utah autism prevalence study ( n  = 129). Seventy-three individuals (56.6 %) met criteria for a current psychiatric disorder; 89 participants (69.0 %) met lifetime criteria for a psychiatric disorder. Caregivers reported a psychiatric diagnosis in 44 participants (34.1 %). Anxiety disorder had the highest current and lifetime prevalence (39.5 and 52.7 %, respectively). Participants with intellectual disability ( n  = 94, 72.8 %) were significantly less likely to have community-based diagnoses of anxiety (χ 2  = 5.37, p  = 0.02) or depression (χ 2  = 13.18, p  < 0.001) reported by caregivers. Seventy-six participants (58.9 %) were taking ≥1 psychotropic medication. Comorbid psychiatric disorders occur frequently in adults with ASD, though identifying these disorders poses a challenge in community settings. A greater understanding of the presentation of these conditions within this population will increase assessment validity and the potential for efficacious intervention.

\"Visual agnosia is a rare but fascinating disorder of visual object recognition that can occur after a brain lesion. This book documents the case of John, who worked intensively with the authors for 26 years after acquiring visual agnosia following a stroke. It revisits John's case over twenty years after it was originally described in the book To See But Not To See, in 1987. As in the previous book, the condition is illuminated by John and his wife, Iris, in their own words. A Case Study in Visual Agnosia Revisited discusses John's case in the context of research into the cognitive neuroscience of vision over the past twenty years. It shows how John's problems in recognition can provide important insights into the way that object recognition happens in the brain, with the results obtained in studies of John's perception being compared to emerging work from brain imaging in normal observers. This book presents a much fuller analysis of the variety of perceptual problems that John experienced, detailing not only his impaired object recognition but also his face processing, his processing of different visual features (colour, motion, depth), his ability to act on and negotiate his environment, and his reading and writing. A Case Study in Visual Agnosia Revisited will be a key reference for those concerned with understanding how vision is implemented in the brain. It will be suitable for both undergraduate students taking courses in cognitive psychology and neuropsychology, and also researchers in the cognitive neuroscience of vision. The presentation of John's case, and the human aspects of the disorder, will also be of great interest to a general audience of lay people interested in perception\"-- Provided by publisher.

Fragile X syndrome (FXS) is a multi-organ disease that leads to mental retardation, macro-orchidism in males and premature ovarian insufficiency in female carriers. FXS is also a prominent monogenic disease associated with autism spectrum disorders (ASDs). FXS is typically caused by the loss of fragile X mental retardation 1 ( FMR1 ) expression, which codes for the RNA-binding protein FMRP. Here we report the discovery of distinct RNA-recognition elements that correspond to the two independent RNA-binding domains of FMRP, in addition to the binding sites within the messenger RNA targets for wild-type and I304N mutant FMRP isoforms and the FMRP paralogues FXR1P and FXR2P (also known as FXR1 and FXR2). RNA-recognition-element frequency, ratio and distribution determine target mRNA association with FMRP. Among highly enriched targets, we identify many genes involved in ASD and show that FMRP affects their protein levels in human cell culture, mouse ovaries and human brain. Notably, we discovered that these targets are also dysregulated in Fmr1 −/− mouse ovaries showing signs of premature follicular overdevelopment. These results indicate that FMRP targets share signalling pathways across different cellular contexts. As the importance of signalling pathways in both FXS and ASD is becoming increasingly apparent, our results provide a ranked list of genes as basis for the pursuit of new therapeutic targets for these neurological disorders. RNA-recognition elements are identified for the fragile-X-syndrome-associated RNA-binding protein FMRP, in addition to its target messenger RNAs; although many of FMRP gene targets discovered are involved in brain function and autism spectrum disorder, a proportion are also dysregulated in mouse ovaries, suggesting cross-regulation of signalling pathways in different tissues. Signalling in Fragile X syndrome Fragile X syndrome (FXS) is caused by mutations in the FMR1 gene, which encodes an RNA-binding protein called FMRP. This study from Thomas Tuschl's laboratory has now defined, on a genome-wide level, the targets bound by FMRP and by a disease-associated mutated version of FMRP. Although many of the top targets are involved in brain function and autism spectrum disorder, a surprising number of targets are also dysregulated in mouse ovaries, suggesting cross-regulation of signalling pathways in different tissues.

The authors discuss the substantive impact of recent advances in genomic technologies on the diagnosis and understanding of intellectual disability and autism. Intellectual disability, which is characterized by significant limitations in both intellectual functioning and adaptive behavior that begin before the age of 18 years, 1 affects 1.5 to 2% of the population in Western countries. 2 A diagnosis of intellectual disability is usually made when IQ testing reveals an IQ of less than 70, which means that often the diagnosis is not made until late childhood or early adulthood. However, most persons with intellectual disability are identified early in childhood on the basis of concern about developmental delays, which may include motor, cognitive, and speech delays. A genetic underpinning of this disorder has . . .

Making Sense of Self-Harm provides an alternative examination of nonsuicidal self-injury, using Cultural Sociology and the conceptual insights of Michel Foucault, Norbert Elias and Ludwig Wittgenstein to map the hidden meanings of self-harm and reveal it more as a kind of practice than an illness; a powerful cultural idiom of personal distress and social estrangement that is peculiarly resonant with the symbolic life of late-modern society.

Background: Limited data exist regarding the correlation between MRI tumour regression grade (mrTRG) and pathological TRG (pTRG) in rectal cancer. Methods: mrTRG and pTRG were compared in rectal cancer patients from two phase II trials (EXPERT and EXPERT-C). The agreement between radiologist and pathologist was assessed with the weighted κ test while the Kaplan–Meier method was used to estimate survival outcomes. Results: One hundred ninety-one patients were included. Median time from completion of neoadjuvant treatment to pre-operative MRI and surgery was 4.1 weeks (interquartile range (IQR): 3.7–4.7) and 6.6 weeks (IQR: 5.9–7.6), respectively. Fair agreement was found between mrTRG and pTRG when regression was classified according to standard five-tier systems ( κ =0.24) or modified three-tier systems ( κ =0.25). Sensitivity and specificity of mrTRG 1–2 (complete/good radiological regression) for the prediction of pathological complete response was 74.4% (95% CI: 58.8–86.5) and 62.8% (95% CI: 54.5–70.6), respectively. Survival outcomes of patients with intermediate pathological regression (pTRG 2) were numerically better if complete/good regression was also observed on imaging (mrTRG 1–2) compared to poor regression (mrTRG 3–5) (5-year recurrence-free survival 76.9% vs 65.9%, P =0.18; 5-year overall survival 80.6% vs 68.8%, P =0.22). Conclusions: The agreement between mrTRG and pTRG is low and mrTRG cannot be used as a surrogate of pTRG. Further studies are warranted to assess the ability of mrTRG to identify pathological complete responders for the adoption of non-operative management strategies and to provide complementary prognostic information to pTRG for better risk-stratification after surgery.