Definition and clinical variability of SHANK3-related Phelan-McDermid syndrome.

Phelan-McDermid syndrome (PMS) is an infrequently described syndrome that presents with a disturbed development, neurological and psychiatric characteristics, and sometimes other comorbidities. As part of the development of European medical guidelines we studied the definition, phenotype, genotype-phenotype characteristics, and natural history of the syndrome. The number of confirmed diagnoses of PMS in different European countries was also assessed and it could be concluded that PMS is underdiagnosed. The incidence of PMS in European countries is estimated to be at least 1 in 30,000. Next generation sequencing, including analysis of copy number variations, as first tier in diagnostics of individuals with intellectual disability will likely yield a larger number of individuals with PMS than presently known. A definition of PMS by its phenotype is at the present not possible, and therefore PMS-SHANK3 related is defined by the presence of SHANK3 haploinsufficiency, either by a deletion involving region 22q13.2-33 or a pathogenic/likely pathogenic variant in SHANK3. In summarizing the phenotype, we subdivided it into that of individuals with a 22q13 deletion and that of those with a pathogenic/likely pathogenic SHANK3 variant. The phenotype of individuals with PMS is variable, depending in part on the deletion size or whether only a variant of SHANK3 is present. The core phenotype in the domains development, neurology, and senses are similar in those with deletions and SHANK3 variants, but individuals with a SHANK3 variant more often are reported to have behavioural disorders and less often urogenital malformations and lymphedema. The behavioural disorders may, however, be a less outstanding feature in individuals with deletions accompanied by more severe intellectual disability. Data available on the natural history are limited. Results of clinical trials using IGF-1, intranasal insulin, and oxytocin are available, other trials are in progress. The present guidelines for PMS aim at offering tools to caregivers and families to provide optimal care to individuals with PMS.

Trajectories of the evolution of post-COVID-19 condition, up to two years after symptoms onset.

OBJECTIVES: We aimed to identify trajectories of the evolution of post-COVID-19 condition, up to 2 years after symptom onset. METHODS: The ComPaRe long COVID e-cohort is a prospective cohort of patients with symptoms lasting at least 2 months after SARS-CoV2 infection. We used trajectory modeling to identify different trajectories in the evolution of post-COVID-19 condition, based on symptoms collected every 60 days using the long COVID Symptom Tool. RESULTS: A total of 2197 patients were enrolled in the cohort between December 2020 and July 2022 when the Omicron variant was not dominant. Three trajectories of the evolution of post-COVID-19 condition were identified: "high persistent symptoms" (4%), "rapidly decreasing symptoms" (5%), and "slowly decreasing symptoms" (91%). Participants with highly persistent symptoms were older and more likely to report a history of systemic diseases. They often reported tachycardia, bradycardia, palpitations, and arrhythmia. Participants with rapidly decreasing symptoms were younger and more likely to report a confirmed infection. They often reported diarrhea and back pain. Participants with slowly decreasing symptoms were more likely to have a history of functional diseases. CONCLUSION: Most patients with post-COVID-19 condition improve slowly over time, while 5% have rapid improvement in the 2 years after symptom onset and 4% have a persistent condition.

Segmental Colitis Associated with Diverticulosis (SCAD).

PURPOSE OF REVIEW: A distinctive, possibly "novel" form of a segmental inflammatory colonic disease process associated with diverticular disease (so-called SCAD or segmental-colitis-associated-diverticulosis) is reviewed. RECENT FINDINGS: Although this phenotype of inflammatory colonic disease was initially recognized decades ago, mainly in the elderly, recent evidence from long term natural history studies along with meta-analyses confirms that its clinical course is usually benign and drug-responsive. Interestingly, its appearance in some treated with monoclonal agents (eg., ipilimumab associated colitis) or infected with coronavirus-19 may have critical implications for its pathogenesis. This review further explores the implications of recognition of this pattern of colonic inflammatory disease, with relevance for physicians involved in both clinical practice and clinical trials of newer therapeutic agents.

Implementing a Data Integration Infrastructure for Healthcare Data – A Case Study

Conducting epidemiologic research usually requires a large amount of data to establish the natural history of a disease and achieve meaningful study design, and interpretations of findings. This is, however, a huge task because the healthcare domain is composed of a complex corpus and concepts that result in difficult ways to use and store data. Additionally, data accessibility should be considered because sensitive data from patients should be carefully protected and shared with responsibility. With the COVID-19 pandemic, the need for sharing data and having an integrated view of the data was reaffirmed to identify the best approaches and signals to improve not only treatments and diagnoses but also social answers to the epidemiological scenario. This paper addresses a data integration scenario for dealing with COVID-19 and cardiovascular diseases, covering the main challenges related to integrating data in a common data repository storing data from several hospitals. Conceptual architecture is presented to deal with such approaches and integrate data from a Portuguese hospital into the common repository used to explore data in a standardized way. © 2023, The Author(s), under exclusive license to Springer Nature Switzerland AG.

The effect of the COVID-19 pandemic on US Food and Drug Administration-funded clinical trials and natural history studies for rare diseases.

BACKGROUND: Since 1983, the Orphan Product Grants Program, administered by the US Food and Drug Administration, provides funding for clinical trials and natural history studies in rare diseases. The COVID-19 pandemic created new challenges in rare disease product development. This study sought to determine the effects of the pandemic on rare disease studies using data from grantees of this program, and determine lessons learned that can potentially be applied to future trials in rare diseases. METHODS: All grants that were being funded by the Orphan Products Grants Program between March 2020 and March 2021 were included in the study. Data was gathered from grantees and described the effects of the pandemic on multiple aspects of the studies including enrollment, patient follow-up, protocol, and budget. RESULTS: There were 62 grants active during the study period, and of these 54 (87%) were clinical trials and 8 (13%) were natural history studies. 94% of the grantees reported their studies being affected by the COVID-19 pandemic, and the addition of virtual capabilities was reported by 34 (55%) of grantees. CONCLUSIONS: This study suggested two important lessons learned. First, virtual capabilities, when appropriate, can be an important component of trials because they decrease the travel burden on participants and reduce in-person risks, which should increase patient recruitment and retention. Second, building in flexibility in clinical trials is critical in the post-COVID era and could include increasing the use of multi-site trials, clinical networks, and innovative designs and collaborations to speed up trials without compromising study data.

SARS-CoV-2 incidence and risk factors in a national, community-based prospective cohort of U.S. adults.

BACKGROUND: Prospective cohort studies of SARS-CoV-2 incidence complement case-based surveillance and cross-sectional seroprevalence surveys. METHODS: We estimated the incidence of SARS-CoV-2 infection in a national cohort of 6,738 U.S. adults, enrolled March-August 2020. Using Poisson models, we examined the association of social distancing and a composite epidemiologic risk score with seroconversion. The risk score was created using LASSO regression to identify factors predictive of seroconversion. The selected factors were household crowding, confirmed case in household, indoor dining, gathering with groups ≥ 10, and no masking in gyms/salons. RESULTS: Among 4,510 individuals with ≥1 serologic test, 323 (7.3%, 95% confidence interval [CI] 6.5%-8.1%) seroconverted by January 2021. Among 3,422 participants seronegative in May-September 2020 and retested during November 2020-January 2021, 161 seroconverted over 1,646 person-years of follow-up (9.8 per 100 person-years [95%CI 8.3-11.5]). Seroincidence rate was lower among females compared to males (IRR: 0.69, 95% CI 0.50-0.94) and higher among Hispanic (IRR: 2.09, 95% CI 1.41-3.05) participants compared to White non-Hispanic. In adjusted models, participants who reported social distancing with people they did not know (IRRalways vs. never: 0.42, 95% CI 0.20-1.0) and with people they knew (IRRalways vs. never 0.64, 95%CI 0.39-1.06; IRRsometimes vs. never 0.60, 95% CI 0.38-0.96) had lower seroconversion risk. Seroconversion risk increased with epidemiologic risk score (IRRmedium vs. low 1.68, 95% CI 1.03-2.81; IRRhigh vs. low 3.49, 95% CI 2.26-5.58). Only 29% of those who seroconverted reported isolating and 19% were asked about contacts. CONCLUSION: Modifiable risk factors and poor reach of public health strategies drove SARS-CoV-2 transmission across the U.S.

Primary lateral sclerosis natural history study - planning, designing, and early enrollment.

Introduction/Aims. Primary lateral sclerosis (PLS) is exceedingly rare and has been an enigmatic disease. Recent progress has drastically changed this perception, with early biomarkers being investigated and potential medications for PLS emerging at the preclinical stage. The aim of this paper is to describe a study of PLS natural history and discuss the limitations and proposed solutions to the study of a rare and slowly progressive disease. Methods. The PLS Natural History Study is a 30-site, 24-month, prospective study that is supported by multiple funding sources. The study aims to enroll 50 early PLS (disease duration ≤4 years) and 50 definite PLS (disease duration 4 to 15 years) participants using modified PLS Diagnostic Criteria. Smartphone-based assessments including semi-quantitative and quantitative measures and patient-reported outcomes are utilized. In-person quantitative measures are also completed during site visits. The change in the PLS Functional Rating Scale score is the primary outcome. The study utilizes the NeuroBANK® patient-centric data capture and management platform. The biostatistical analysis plan has been developed. Results. In one year, 28 participants have been recruited. Enrollment has been much slower than anticipated due to the COVID-19 pandemic, the rarity of PLS, and potential study competition for internal resources from ALS clinical trials. Discussion. We discuss the need for more innovative methods to enroll and study individuals with such rare diseases and propose a number of mechanisms by which more efficient enrollment could be facilitated.

The impact of the post- COVID 19 pandemic elective waiting list delays on patient reported symptoms and intention to proceed with planned upper limb surgeries-A prospective cohort study.

INTRODUCTION: The aim of this study was to evaluate patient reported outcome measures using the EQ5D-5L and EQ5D-5L visual analogue scale (VAS) following elective shoulder and elbow orthopaedic list delays. This was further correlated with patients' intention to proceed with the planned surgery. METHODS: Patients on the waiting list for more than 26 weeks were included in the study. Telephone interviews were conducted utilising the EQ5D-5L and the EQ5D-5L VAS at the time of addition to the waiting list and presently. RESULTS: 75 out of 324 screened patients were eligible. 62 (82.7%) patients still wanted to proceed with their planned procedure while 13 (17.3%) patients in the other group no longer wanted to proceed. There was no statistically significant difference in the mean age, gender, initial trial of conservative treatment and limb laterality between these groups (p < 0.05). There was a statistically significant difference in the mean duration of being on the waiting list between these groups (40.4 ± 19 vs. 62.9 ± 17.5 weeks respectively). Furthermore, statistically significant differences (p < 0.05) in the current EQ5D-5L VAS scores were observed between these groups (52.4 vs. 65.8 respectively). CONCLUSION: This study has shown that majority of patients on elective shoulder and elbow orthopaedic lists with prolonged waiting list delays and improved EQ5D-5L scores are likely to decline the planned procedure and vice versa. Nevertheless, the unplanned 'watchful waiting' caused by the COVID-19 pandemic and leading to patients deciding to decline surgery, is not a substitute for timely planned surgery to alleviate patients' suffering.

A comparative study of RNA yields from museum specimens, including an optimized protocol for extracting RNA from formalin-fixed specimens

Animal specimens in natural history collections are invaluable resources in examining the historical context of pathogen dynamics in wildlife and spillovers to humans. For example, natural history specimens may reveal new associations between bat species and coronaviruses. However, RNA viruses are difficult to study in historical specimens because protocols for extracting RNA from these specimens have not been optimized. Advances have been made in our ability to recover nucleic acids from formalin-fixed paraffin-embedded samples (FFPE) commonly used in human clinical studies, yet other types of formalin preserved samples have received less attention. Here, we optimize the recovery of RNA from formalin-fixed ethanol-preserved museum specimens in order to improve the usability of these specimens in surveys for zoonotic diseases. We provide RNA quality and quantity measures for replicate tissues subsamples of 22 bat specimens from five bat genera (Rhinolophus, Hipposideros, Megareops, Cynopterus, and Nyctalus) collected in China and Myanmar from 1886 to 2003. As tissues from a single bat specimen were preserved in a variety of ways, including formalin-fixed (8 bats), ethanol-preserved and frozen (13 bats), and flash frozen (2 bats), we were able to compare RNA quality and yield across different preservation methods. RNA extracted from historical museum specimens is highly fragmented, but usable for short-read sequencing and targeted amplification. Incubation of formalin-fixed samples with Proteinase-K following thorough homogenization improves RNA yield. This optimized protocol extends the types of data that can be derived from existing museum specimens and facilitates future examinations of host and pathogen RNA from specimens.

Natural history and cycle threshold values analysis of COVID-19 in Xiamen City, China.

Objective: This study elaborated the natural history parameters of Delta variant, explored the differences in detection cycle thresholds (Ct) among cases. Methods: Natural history parameters were calculated based on the different onset time and exposure time of the cases. Intergenerational relationships between generations of cases were calculated. Differences in Ct values of cases by gender, age, and mode of detection were analyzed statistically to assess the detoxification capacity of cases. Results: The median incubation period was 4 days; the detection time for cases decreased from 25 to 7 h as the outbreak continued. The average generation time (GT), time interval between transmission generations (TG) and serial interval (SI) were 3.6 ± 2.6 days, 1.67 ± 2.11 days and 1.7 ± 3.0 days. Among the Ct values, we found little differences in testing across companies, but there were some differences in the gender of detected genes. The Ct values continuous to decreased with age, but increased when the age was greater than 60. Conclusion: This epidemic was started from aggregation of factories. It is more reasonable to use SI to calculate the effective reproduction number and the time-varying reproduction number. And the analysis of Ct values can improve the positive detection rate and improve prevention and control measures.

Reflections on Multimodal Delivery of a Laboratory Course for Nonscience Majors and Opportunities for Improved Student Engagement

A rudimentary level of scientific literacy is necessary in the general public. At the undergraduate level, this literacy can be achieved through general education courses offered in areas of natural sciences. Over the past several years, practical courses have been developed to make the teaching of chemistry concepts in the laboratory more interesting and appealing to nonscience majors. This article provides insights and reflections from teaching a general education, liberal arts chemistry course at a private university using different teaching delivery modes during a pandemic. Specifically, the unique circumstances of the COVID-19 pandemic allowed faculty to deviate from the traditional face-to-face delivery and explore the use of virtual delivery, experimentation at home, and hybrid instruction to meet learning objectives. The article reflects on the lessons from this experience to improve course delivery and student engagement in science laboratory courses for nonscience majors. [ FROM AUTHOR] Copyright of Journal of College Science Teaching is the property of National Science Teachers Association and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full . (Copyright applies to all s.)

Biogeography of northeastern Atlantic Neogene chitons (Mollusca, Polyplacophora): New data from the Pliocene of Portugal

Based on extensive new material, 2088 valves resulting from search sampling of ~500 kg of sediment, the Pliocene chiton biodiversity of the Mondego Basin (Portugal) is reassessed. Twelve species were identified, assigned to seven genera. Eight species are new for the Pliocene of Portugal, as well as two of the genera: Hanleya, Acanthochitona. Two taxa are described as new: Ischnochiton loureiroi n. sp. and Lepidochitona rochae n. sp. Until now, the polyplacophoran European Neogene record was too poorly known to be of help in generating a clear picture of the Miocene to present-day biogeography of the group. This new wealth of data from western Iberia, in conjunction with recent data from the Loire Basin Upper Miocene assemblages (France), allows clarification the Late Miocene to Recent eastern Atlantic and Mediterranean biogeography of the Polyplacophora. The northern range of warm-water northeast Atlantic and Mediterranean Polyplacophora experienced a sharp contraction since, at least, Late Miocene to Early Pliocene times. Warm-water chiton species represented in the Upper Miocene of the Loire Basin of NE France (European-West African Province) and the Pliocene of the Mondego Basin of central-west Portugal (Pliocene French-Iberian Province) are today confined to the southern Mediterranean-Moroccan Molluscan Province.UUID: http://zoobank.org/a2a550c0-caed-449a-aa45-9492c45f882e

PSA Level During Midlife and Undiagnosed Prostate Cancer at Autopsy: Understanding Tumor Biology and Racial Disparities

Black men have a higher risk of prostate cancer diagnosis and death, but there remains a dearth of research investigations specifically focused on black populations and an inadequate evidence base for creation of screening guidelines for black men. Data from our group and others has shown that a single baseline PSA measured in midlife strongly predicts long-term risk of prostate cancer, particularly risk of aggressive disease, in both black and white men. We propose to further develop the evidence basis for a risk stratified baseline PSA screening strategy by conducting an autopsy study among black and white men to assess how PSA in midlife relates to the pre-diagnosis natural history of prostate cancer, and how this varies by race. This study is designed to explore the underlying biology by which midlife PSA predicts prostate cancer risk.

Mário C. C. de Pinna Robert H. Gibbs, Jr. Memorial Award for Excellence in Systematic Ichthyology- 2020

Mário C. C. de Pinna, the winner of Robert H. Gibbs, Jr. Memorial Award for Excellence in Systematic Ichthyology, is featured. De Pinna's research interests run the gamut of systematic ichthyology, from phylogenetic relationships, taxonomy, and biogeography, to theoretical considerations of phylogeny reconstruction, species concepts, the history of comparative biology and its place within the sciences. And his contributions across each of these arenas have been profound and impactful. Indeed, while still a graduate student in the joint City University of New York and American Museum of Natural History program, they published a paper on "Concepts and tests of homology in the cladistic paradigm," a contribution that has been cited over 1,093 times since its publication and almost two decades later has been cited 90 times in the past five years alone. His professional career began while an undergraduate with a publication on a cave population of Trichomyctems, and in the ensuing years has published over 90 peer-reviewed papers. Most of these have focused on the broad sweep of catfish systematics from the resolution of basal relationships across the order to numerous analyses of the composition and inter- and intrarelationships of individual catfish families and genera.

Investigating the Effect of Disturbance on Prey Consumption in Captive Congo Caecilians Herpele squalostoma

Maintaining Gymnophiona in captivity provides opportunities to study the behaviour and life-history of this poorly known Order, and to investigate and provide species-appropriate welfare guidelines, which are currently lacking. This study focuses on the terrestrial caecilian Herpele squalostoma to investigate its sensitivity to disturbances associated with routine husbandry needed for monitoring and maintaining adequate wellbeing in captivity. Fossorial caecilians gradually pollute their environment in captivity with waste products, and substrate must be replaced at intervals;doing so disturbs the animals directly and via destruction of burrow networks. As inappetence is frequently associated with stress in amphibians, the percentage consumption of offered food types, river shrimp (Palaemon varians) and brown crickets (Gryllus assimilis), was measured as an indicator of putative stress following three routine substrate changes up to 297 days post-substrate change. Mean daily variation in substrate temperatures were also recorded in order to account for environmental influences on food consumption, along with nitrogenous waste in tank substrate prior to a substrate change and fresh top soil in order to understand the trade-off between dealing with waste accumulation and disturbing animals. We found a significant negative effect of substrate disturbance on food intake, but no significant effect of prey type. Variations in daily soil temperatures did not have a significant effect on food intake, but mean substrate temperature did. Additionally, substrate nitrogenous waste testing indicated little difference between fresh and tank substrate. In conclusion, this study provides a basis from which to develop further welfare assessment for this and other rarely kept and rarely observed terrestrial caecilian species.

Long-term impact of HPV vaccination and COVID-19 pandemic on oropharyngeal cancer incidence and burden among men in the USA: A modeling study.

BACKGROUND: Oropharyngeal cancer (OPC) incidence is rising rapidly among men in the United States of America (USA). We aimed to project the impact of maintaining the current HPV vaccination uptake and achieving 80% national (Healthy People) goal on OPC incidence and burden. METHODS: We developed an open-cohort micro-simulation model of OPC natural history among contemporary and future birth cohorts of men, accounting for sexual behaviors, population growth, aging, and herd immunity. We used data from nationally representative databases, cancer registries from all 50 states, large clinical trials, and literature. We evaluated the status quo scenario (the current HPV vaccination uptake remained stable) and alternative scenarios of improvements in uptake rates in adolescents (aged 9-17 years) and young adults (aged 18-26 years) by 2025 to achieve and maintain the 80% goal. The primary outcome was to project OPC incidence and burden from 2009 to 2100. We also assessed the impact of disruption in HPV vaccine uptake during the COVID-19 pandemic. FINDINGS: OPC incidence is projected to rise until the mid-2030s, reaching the age-standardized incidence rate of 9·8 (95% uncertainty interval [UI] 9·5-10·1) per 100 000 men, with the peak annual burden of 23 850 (UI, 23 200-24 500) cases. Under the status quo scenario, HPV vaccination could prevent 124 000 (UI, 117 000-131 000) by 2060, 400 000 (UI, 384 000-416 000) by 2080, and 792 000 (UI, 763 000-821 000) by 2100 OPC cases among men. Achievement and maintenance of 80% coverage among adolescent girls only, adolescent girls and boys, and adolescents plus young adults could prevent an additional number of 100 000 (UI, 95 000-105 000), 118 000 (UI, 113 000-123 000), and 142 000 (UI, 136 000-148 000) male OPC cases by 2100. Delayed recovery of the HPV vaccine uptake during the COVID-19 pandemic could lead to 600 (UI, 580-620) to 6200 (UI, 5940-6460) additional male OPC cases by 2100, conditional on the decline in the extent of the national HPV vaccination coverage and potential delay in rebounding. INTERPRETATION: Oropharyngeal cancer burden is projected to rise among men in the USA. Nationwide efforts to achieve the HPV vaccination goal of 80% coverage should be a public health priority. Rapid recovery of the declined HPV vaccination uptake during the COVID-19 pandemic is also crucial to prevent future excess OPC burden. FUNDING: National Cancer Institute and National Institute on Minority Health and Health Disparities of the USA.

Age dependence of the natural history of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2): an analysis of Diamond Princess data.

BACKGROUND: Following an outbreak of coronavirus disease 2019 (COVID-19) on the cruise ship Diamond Princess, passengers and crew were followed-up to determine prognosis. This study examined the epidemiological determinants of COVID-19 natural history using these follow-up data. METHODS: Infection status, diagnosis, clinical symptoms and prognosis were analysed for all passengers and crew members on the Diamond Princess. In addition, the risk of infection associated with exposure within cabin rooms, as well as the risks of various clinical manifestations of disease, along with their epidemiological determinants, were analysed. RESULTS: The adjusted odds ratio (aOR) of infection for individuals tested by polymerase chain reaction on or after 12 February 2020 compared with individuals tested before this date was 0.53 [95% confidence interval (CI) 0.39-0.72], reflecting decreased transmission during onboard quarantine. Among infected individuals, older age was associated with elevated odds of symptomatic illness (aOR 1.01, 95% CI 1.00-1.02), severe disease (aOR 1.08, 95% CI 1.05-1.12) and death (aOR 1.12, 95% CI 1.05-1.21). CONCLUSIONS: Severe COVID-19 disease, death and symptomatic illness were more frequent among older individuals on the Diamond Princess. Older elderly cases (age ≥80 years) had the highest risks of severe disease and death. Inter-room transmission was prevented successfully by the onboard quarantine.

Remote Delivery of Motor Function Assessment and Training for Clinical Trials in Neuromuscular Disease: A Response to the COVID-19 Global Pandemic.

Clinical outcome assessments of function or strength, assessed by physical therapists, are commonly used as primary endpoints in clinical trials, natural history studies and within clinics for individuals with neuromuscular disorders. These evaluations not only inform the efficacy of investigational agents in clinical trials, but also importantly track disease trajectory to prospectively advise need for equipment, home and work modifications, and other assistive devices. The COVID-19 pandemic had a global impact on the safety and feasibility of in-person visits and assessments, necessitating rapid development of mitigation strategies to ensure ongoing collection of key clinical trial endpoints and access to expert clinical care despite travel restrictions. Physical therapists who are expert in neuromuscular disorders working across clinics, countries, and clinical trials developed initial guidelines and methods for the suitability and feasibility of performing remote evaluations. A number of Sponsors introduced amendments to their study protocols to enable remote evaluations, supported by live video streaming of the assessment to their local clinical evaluators. Similarly, application of these techniques to clinical telemedicine enabled objective evaluations for use in payer discussions, equipment procurement, and general access to expert physical therapy services. Here we report on our methodology for adapting current practices to remote testing and considerations for remote evaluations.