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Purpose: Ablative radiation therapy (A-RT) appears to improve outcomes in locally advanced pancreatic cancer (LAPC) yet requires solutions for respiratory and digestive motion. We report outcomes of A-RT for pancreatic cancer using 1.5 T MR-adaptive treatment delivery. Methods: Between March 2020 and July 2021, we treated 30 patients with pancreatic cancer with 50 Gy in 5 fractions (biologically effective dose [BED10] = 100 Gy10) using a novel compression belt workflow and remote planning on the Unity 1.5 T MR linac system. Cumulative incidence of progression was computed from A-RT initiation with death as a competing risk. Overall (OS) and progression-free survival (PFS) were calculated using Kaplan Meier methods. Results: Of 30 patients, most (73 %) were locally advanced, 4 (13 %) were metastatic, 2 (7 %) were medically inoperable, and 2 (7 %) were locally recurrent. Most (73 %) received FOLFIRINOX prior to A-RT. Median follow-up times from diagnosis and A-RT were 17.6 (IQR 15.8–23.1) and 11.5 months (IQR 9.7–16.1), respectively. Cumulative incidences at 1-year of local and distant progression were 19.3 % (95 %CI 6.7–36.8 %) and 47.4 % (95 %CI 26.7–65.6 %), respectively. Median OS from diagnosis and A-RT were not reached. One-year OS from diagnosis and A-RT were 96.4 % (95 %CI 77.2–99.5 %) and 80.0 % (95 %CI 57.3–91.4 %), respectively. Median and 1-year PFS were 10.1 months (95 %CI 4.4–14.4) and 39.7 % (95 %CI 20.3–58.5 %), respectively. No grade 3 + toxicities were observed. Conclusions: A-RT using the 1.5 T Unity MR Linac resulted in promising LC and OS with no severe toxicity in patients with LAPC despite radiosensitive organs adjacent to the target volumes. Longer follow-up is needed to assess long-term outcomes.

Summary: Liquid biopsies based on cell-free DNA (cfDNA) or exosomes provide a noninvasive approach to monitor human health and disease but have not been utilized for astronauts. Here, we profile cfDNA characteristics, including fragment size, cellular deconvolution, and nucleosome positioning, in an astronaut during a year-long mission on the International Space Station, compared to his identical twin on Earth and healthy donors. We observed a significant increase in the proportion of cell-free mitochondrial DNA (cf-mtDNA) inflight, and analysis of post-flight exosomes in plasma revealed a 30-fold increase in circulating exosomes and patient-specific protein cargo (including brain-derived peptides) after the year-long mission. This longitudinal analysis of astronaut cfDNA during spaceflight and the exosome profiles highlights their utility for astronaut health monitoring, as well as cf-mtDNA levels as a potential biomarker for physiological stress or immune system responses related to microgravity, radiation exposure, and the other unique environmental conditions of spaceflight.

A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.

Summary: Background: Obesity represents a major global health challenge with important clinical implications. Despite its recognized importance, the global disease burden attributable to high body mass index (BMI) remains less well understood. Methods: We systematically analyzed global deaths and disability-adjusted life years (DALYs) attributable to high BMI using the methodology and analytical approaches of the Global Burden of Disease Study (GBD) 2021. High BMI was defined as a BMI over 25 kg/m2 for individuals aged ≥20 years. The Socio-Demographic Index (SDI) was used as a composite measure to assess the level of socio-economic development across different regions. Subgroup analyses considered age, sex, year, geographical location, and SDI. Findings: From 1990 to 2021, the global deaths and DALYs attributable to high BMI increased more than 2.5-fold for females and males. However, the age-standardized death rates remained stable for females and increased by 15.0% for males. Similarly, the age-standardized DALY rates increased by 21.7% for females and 31.2% for males. In 2021, the six leading causes of high BMI-attributable DALYs were diabetes mellitus, ischemic heart disease, hypertensive heart disease, chronic kidney disease, low back pain and stroke. From 1990 to 2021, low-middle SDI countries exhibited the highest annual percentage changes in age-standardized DALY rates, whereas high SDI countries showed the lowest. Interpretation: The worldwide health burden attributable to high BMI has grown significantly between 1990 and 2021. The increasing global rates of high BMI and the associated disease burden highlight the urgent need for regular surveillance and monitoring of BMI. Funding: National Natural Science Foundation of China and National Key R&D Program of China.

Abstract Background Our study determined Multiple Mini-Interview (MMI) effectiveness in evaluating specific skill sets based on medical students’ performances during the undergraduate years and compared the academic performances of medical students who appeared for onsite/online MMI. Methods A retrospective study of 140 undergraduate medical students between 2016 and 2020 included data on age, gender, pre-university results, MMI scores, and examination results. Appropriate non-parametric tests were applied to compare the students’ MMI and academic performances. Results Ninety-eight students from cohorts 12 to 15 had an overall MMI score of 69.0(IQR: 65.0—73.2)/100 and an overall Cumulative Grade Point Average(GPA) of 3.64 (3.42—3.78)/5.0. Spearman’s correlation revealed a significantly positive relationship between MMI and cGPA (rho = 0.23) and GPA from the first 2 semesters (GPA1 rho = 0.25, GPA2 rho = 0.27). This observation was similar to that for station A in the first year (cGPA rho = 0.28, GPA1 rho = 0.34, GPA2 rho = 0.24), and in station B (GPA4 rho = 0.25) and D (GPA3 rho = 0.28, GPA4 rho = 0.24) in the second year. Of twenty-nine cohort16 students, 17(58.6%) underwent online and 12(41.4%) offline modes of MMI assessment, respectively. The overall median MMI score was 66.6(IQR: 58.6—71.6)/100, and the overall median cGPA was 3.45 (3.23—3.58)/5.0. When comparing the median marks of cohort16 groups, the online group scored significantly higher marks for station D than the offline group (p = 0.040). Conclusion Correspondence between MMI scores and cGPA predicted MMI scoring during student selection and entry process might ensure the success of their academic performance in medical school.

PurposeThe COVID-19 pandemic has drastically disrupted global healthcare systems. With the higher demand for healthcare and misinformation related to COVID-19, there is a need to explore alternative models to improve communication. Artificial Intelligence (AI) and Natural Language Processing (NLP) have emerged as promising solutions to improve healthcare delivery. Chatbots could fill a pivotal role in the dissemination and easy accessibility of accurate information in a pandemic. In this study, we developed a multi-lingual NLP-based AI chatbot, DR-COVID, which responds accurately to open-ended, COVID-19 related questions. This was used to facilitate pandemic education and healthcare delivery.MethodsFirst, we developed DR-COVID with an ensemble NLP model on the Telegram platform (https://t.me/drcovid_nlp_chatbot). Second, we evaluated various performance metrics. Third, we evaluated multi-lingual text-to-text translation to Chinese, Malay, Tamil, Filipino, Thai, Japanese, French, Spanish, and Portuguese. We utilized 2,728 training questions and 821 test questions in English. Primary outcome measurements were (A) overall and top 3 accuracies; (B) Area Under the Curve (AUC), precision, recall, and F1 score. Overall accuracy referred to a correct response for the top answer, whereas top 3 accuracy referred to an appropriate response for any one answer amongst the top 3 answers. AUC and its relevant matrices were obtained from the Receiver Operation Characteristics (ROC) curve. Secondary outcomes were (A) multi-lingual accuracy; (B) comparison to enterprise-grade chatbot systems. The sharing of training and testing datasets on an open-source platform will also contribute to existing data.ResultsOur NLP model, utilizing the ensemble architecture, achieved overall and top 3 accuracies of 0.838 [95% confidence interval (CI): 0.826–0.851] and 0.922 [95% CI: 0.913–0.932] respectively. For overall and top 3 results, AUC scores of 0.917 [95% CI: 0.911–0.925] and 0.960 [95% CI: 0.955–0.964] were achieved respectively. We achieved multi-linguicism with nine non-English languages, with Portuguese performing the best overall at 0.900. Lastly, DR-COVID generated answers more accurately and quickly than other chatbots, within 1.12–2.15 s across three devices tested.ConclusionDR-COVID is a clinically effective NLP-based conversational AI chatbot, and a promising solution for healthcare delivery in the pandemic era.

Abstract Background The objectives of the study were to investigate the organizational characteristics of acute care facilities worldwide in preventing and managing infections in surgery; assess participants’ perception regarding infection prevention and control (IPC) measures, antibiotic prescribing practices, and source control; describe awareness about the global burden of antimicrobial resistance (AMR) and IPC measures; and determine the role of the Coronavirus Disease 2019 pandemic on said awareness. Methods A cross-sectional web-based survey was conducted contacting 1432 health care workers (HCWs) belonging to a mailing list provided by the Global Alliance for Infections in Surgery. The self-administered questionnaire was developed by a multidisciplinary team. The survey was open from May 22, 2021, and June 22, 2021. Three reminders were sent, after 7, 14, and 21 days. Results Three hundred four respondents from 72 countries returned a questionnaire, with an overall response rate of 21.2%. Respectively, 90.4% and 68.8% of participants stated their hospital had a multidisciplinary IPC team or a multidisciplinary antimicrobial stewardship team. Local protocols for antimicrobial therapy of surgical infections and protocols for surgical antibiotic prophylaxis were present in 76.6% and 90.8% of hospitals, respectively. In 23.4% and 24.0% of hospitals no surveillance systems for surgical site infections and no monitoring systems of used antimicrobials were implemented. Patient and family involvement in IPC management was considered to be slightly or not important in their hospital by the majority of respondents (65.1%). Awareness of the global burden of AMR among HCWs was considered very important or important by 54.6% of participants. The COVID-19 pandemic was considered by 80.3% of respondents as a very important or important factor in raising HCWs awareness of the IPC programs in their hospital. Based on the survey results, the authors developed 15 statements for several questions regarding the prevention and management of infections in surgery. The statements may be the starting point for designing future evidence-based recommendations. Conclusion Adequacy of prevention and management of infections in acute care facilities depends on HCWs behaviours and on the organizational characteristics of acute health care facilities to support best practices and promote behavioural change. Patient involvement in the implementation of IPC is still little considered. A debate on how operationalising a fundamental change to IPC, from being solely the HCWs responsibility to one that involves a collaborative relationship between HCWs and patients, should be opened.

Greater cortical gyrification (GY) is linked with enhanced cognitive abilities and is also negatively related to cortical thickness (CT). Individuals who are congenitally blind (CB) exhibits remarkable functional brain plasticity which enables them to perform certain non-visual and cognitive tasks with supranormal abilities. For instance, extensive training using touch and audition enables CB people to develop impressive skills and there is evidence linking these skills to cross-modal activations of primary visual areas. There is a cascade of anatomical, morphometric and functional-connectivity changes in non-visual structures, volumetric reductions in several components of the visual system, and CT is also increased in CB. No study to date has explored GY changes in this population, and no study has explored how variations in CT are related to GY changes in CB. T1-weighted 3D structural magnetic resonance imaging scans were acquired to examine the effects of congenital visual deprivation in cortical structures in a healthy sample of 11 CB individuals (6 male) and 16 age-matched sighted controls (SC) (10 male). In this report, we show for the first time an increase in GY in several brain areas of CB individuals compared to SC, and a negative relationship between GY and CT in the CB brain in several different cortical areas. We discuss the implications of our findings and the contributions of developmental factors and synaptogenesis to the relationship between CT and GY in CB individuals compared to SC. F.

The obesity epidemic has crossed social-demographic barriers and is a matter of significant concern. Why do individuals fail to restrain from eating high-calorie foods and fail to follow treatment routines that reduce the risk of health complications? These questions have been addressed through behavioral and brain imaging studies on prefrontal cortex inhibitory mechanisms. Failure to inhibit undesirable behaviors has become a hallmark of obesity. In many life situations, obesity risk is increased by inaction (e.g., not taking blood pressure medication, not following a healthy diet). Risk by inaction has been defined as passive risk-taking, and it is correlated with traits such as procrastination, future time perspective, and cognitive avoidance. To the present, passive tendencies, specifically in the context of risk-taking behaviors, have not been addressed in the obesity literature. We introduce a framework in which active and passive risk-taking behaviors are integrated within the scope of bidirectional models of obesity that describe the brain as both the cause and the consequence of obesity vulnerability. The present perspective aims to foster new research on treatment and prevention, and also on the neurobiology of passive behaviors in obesity and other metabolic conditions.

The studies done on developing catalytic, diastereoselective synthesis of beta-hydroxy esters from alpha, beta-epoxy aldehydes and its application to a unique esterification process are discussed. A new catalytic method is developed for the preparation of these important structural motifs from readily available starting materials.

Abstract Background Emergency risk communication is a critical component in emergency planning and response. It has been recognised as significant for planning for and responding to public health emergencies. While there is a growing body of guidelines and frameworks on emergency risk communication, it remains a relatively new field. There has also been limited attention on how emergency risk communication is being performed in public health organisations, such as acute hospitals, and what the associated challenges are. This article seeks to examine the perception of crisis and emergency risk communication in an acute hospital in response to COVID-19 pandemic in Singapore and to identify its associated enablers and barriers. Methods A 13-item Crisis and Emergency Risk Communication (CERC) Survey, based on the US Centers for Disease and Control (CDC) CERC framework, was developed and administered to hospital staff during February 24–28, 2020. The survey also included an open-ended question to solicit feedback on areas of CERC in need of improvement. Chi-square test was used for analysis of survey data. Thematic analysis was performed on qualitative feedback. Results Of the 1154 participants who responded to the survey, most (94.1%) reported that regular hospital updates on COVID-19 were understandable and actionable. Many (92.5%) stated that accurate, concise and timely information helped to keep them safe. A majority (92.3%) of them were clear about the hospital’s response to the COVID-19 situation, and 79.4% of the respondents reported that the hospital had been able to understand their challenges and address their concerns. Sociodemographic characteristics, such as occupation, age, marital status, work experience, gender, and staff’s primary work location influenced the responses to hospital CERC. Local leaders within the hospital would need support to better communicate and translate hospital updates in response to COVID-19 to actionable plans for their staff. Better communication in executing resource utilization plans, expressing more empathy and care for their staff, and enhancing communication channels, such as through the use of secure text messaging rather than emails would be important. Conclusion CERC is relevant and important in the hospital setting to managing COVID-19 and should be considered concurrently with hospital emergency response domains.

Motivated by the recent replicability crisis we tested replicability of functional magnetic resonance imaging (fMRI) group activations in two independent samples. An identical behavioral and fMRI test battery for the longitudinal investigation of stress resilience mechanisms was developed for the Mainz Resilience Project (MARP) and conducted in a discovery (N = 54) and a replication sample (N = 103). The test battery consisted of a stress reactivity task, a reward sensitivity task, a fear conditioning and extinction paradigm, two volitional reappraisal tasks and an emotional interference inhibition task. Replicability of group activations was tested with the Jaccard index and the Intra Class Correlation (ICC). Overall, we observed good to excellent replicability of activations at the whole brain level. Only a minority of contrasts showed unsatisfactory replicability. Replicability at the level of individual regions of interest (ROIs) was generally lower. Tasks with stronger activation in the discovery sample showed better replicability.

Abstract Congenital heart defects are the most common malformation, and are the foremost causes of mortality in the first year of life. Among congenital heart defects, conotruncal defects represent about 20% and are severe malformations with significant morbidity. Insulin gene enhancer protein 1 (ISL1) has been considered a candidate gene for conotruncal heart defects based on its embryonic expression pattern and heart defects induced in Isl1 knockout mice. Nevertheless no mutation of ISL1 has been reported from any human subject with a heart defect. From a population base of 974,579 births during 1999–2004, we used multiplex ligation‐dependent probe amplification to screen for microdeletions/duplications of ISL1 among 389 infants with tetralogy of Fallot or d‐transposition of the great arteries (d‐TGA). We also sequenced all exons of ISL1. We identified a novel 20‐kb microdeletion encompassing the entire coding region of ISL1, but not including either flanking gene, from an infant with d‐TGA. We confirmed that the deletion was caused by nonhomologous end joining mechanism. Sequencing of exons of ISL1 did not reveal any subject with a novel nonsynonymous mutation. This is the first report of an ISL1 mutation of a child with a congenital heart defect.

Synthetic methods for the preparation of carboxylic acid derivatives typically rely on the stoichiometric preparation of an activated carboxylate followed by reaction with an appropriate nucleophile. While these protocols have found widespread utility for the synthesis of esters and related compounds, they suffer from disadvantages including the need to employ significant molar excesses of the coupling reagents and the formation of large amounts of byproducts. As part of a program aimed at developing new approaches to stereoselective, atom-economical esterifications and amidations, authors analyzed the catalytic, diastereoselective synthesis of β-hydroxy esters from α, β-epoxy aldehydes. In addition to providing a new method for the preparation of these important structural motifs from readily available starting materials, this chemistry unveils a mechanistically viable solution to the catalytic generation of activated carboxylates.