Search

Hemagglutinins (HAs) are the receptor-binding and membrane fusion glycoproteins of influenza viruses. They recognize sialic acid-containing, cell-surface glycoconjugates as receptors but have limited affinity for them, and, as a consequence, virus attachment to cells requires their interaction with several virus HAs. Receptor-bound virus is transferred into endosomes where membrane fusion by HAs is activated at pH between 5 and 6.5, depending on the strain of virus. Fusion activity requires extensive rearrangements in HA conformation that include extrusion of a buried "fusion peptide" to connect with the endosomal membrane, form a bridge to the virus membrane, and eventually bring both membranes close together. In this review, we give an overview of the structures of the 16 genetically and antigenically distinct subtypes of influenza A HA in relation to these two functions in virus replication and in relation to recognition of HA by antibodies that neutralize infection.

Migraine, a common and disabling neurological disorder, is among the top reasons for outpatient visits to general neurologists. In addition to pharmacotherapy, lifestyle interventions are a mainstay of treatment. High-quality daily diary studies and intervention studies indicate intraindividual variations in the associations between lifestyle factors (such as stress, sleep, diet, and physical activity) and migraine attack occurrence. Behaviour change interventions can directly address overlapping lifestyle factors; combination approaches could capitalise on multiple mechanisms. These findings provide useful directions for integration of lifestyle management into routine clinical care and for future research.

Objectives We characterized real-time patient portal test result viewing among emergency department (ED) patients and described patient characteristics overall and among those not enrolled in the portal at ED arrival. Methods Our observational study at an academic ED used portal log data to trend the proportion of adult patients who viewed results during their visit from May 04, 2021 to April 04, 2022. Correlation was assessed visually and with Kendall's τ. Covariate analysis using binary logistic regression assessed result(s) viewed as a function of time accounting for age, sex, ethnicity, race, language, insurance status, disposition, and social vulnerability index (SVI). A second model only included patients not enrolled in the portal at arrival. We used random forest imputation to account for missingness and Huber-White heteroskedasticity-robust standard errors for patients with multiple encounters (α = 0.05). Results There were 60,314 ED encounters (31,164 unique patients). In 7,377 (12.2%) encounters, patients viewed results while still in the ED. Patients were not enrolled for portal use at arrival in 21,158 (35.2%) encounters, and 927 (4.4% of not enrolled, 1.5% overall) subsequently enrolled and viewed results in the ED. Visual inspection suggests an increasing proportion of patients who viewed results from roughly 5 to 15% over the study (Kendall's τ = 0.61 [p Conclusion We observed increased portal-based test result viewing among ED patients over the year since the 21st Century Cures act went into effect, even among those not enrolled at arrival. We observed disparities in those who viewed results.

SummaryAfrican populations are the most diverse in the world yet are sorely underrepresented in medical genetics research. Here, we examine the structure of African populations using genetic and comprehensive multigenerational ethnolinguistic data from the Neuropsychiatric Genetics of African Populations-Psychosis study (NeuroGAP-Psychosis) consisting of 900 individuals from Ethiopia, Kenya, South Africa, and Uganda. We find that self-reported language classifications meaningfully tag underlying genetic variation that would be missed with consideration of geography alone, highlighting the importance of culture in shaping genetic diversity. Leveraging our uniquely rich multi-generational ethnolinguistic metadata, we track language transmission through the pedigree, observing the disappearance of several languages in our cohort as well as notable shifts in frequency over three generations. We find suggestive evidence for the rate of language transmission in matrilineal groups having been higher than that for patrilineal ones. We highlight both the diversity of variation within the African continent, as well as how within-Africa variation can be informative for broader variant interpretation; many variants appearing rare elsewhere are common in parts of Africa. The work presented here improves the understanding of the spectrum of genetic variation in African populations and highlights the enormous and complex genetic and ethnolinguistic diversity within Africa.

Fatty acids are critical bioactives for fetal and neonatal development. Premature delivery and current nutritional strategies pose several challenges in restoring fatty acid balance in the preterm infant. The impact on fatty acid balance and outcomes using lipid emulsions, enteral nutrition, and enteral supplements are reviewed, including a summary of the most recent large clinical trials of enteral fatty acid supplementation for the preterm infant. Research gaps remain in successfully implementing nutritional strategies to optimize fatty acid status in preterm infants.

The psychosocial impact of coronavirus disease 2019 (COVID-19) on human life is well-known. Although vaccine protection represents an effective way to control the spread of the virus, vaccination hesitancy may decrease individuals’ willingness to get vaccinated, including among cancer patients. Therefore, the objective of the current study was to examine the predictors of cancer patients’ intentions to receive COVID-19 vaccinations and vaccine uptake, using and integrating the theory of planned behaviour (TPB) and the health belief model (HBM). A sample of 276 Italian cancer patients (54% female and 46% male) ranging from 19 to 85 years (M = 49.64, SD = 11.53) was recruited by administering an online questionnaire. The current study results showed that cancer patients with higher trust in health authorities tended to have vaccine-positive subjective norms, perceived that vaccination was under their control, and viewed COVID-19 vaccines positively. On the other hand, the perceived risk of COVID-19 was related to subjective norms but not to perceived behavioural control or attitudes towards COVID-19 vaccination. The current study reveals that TPB variables can function effectively as mediators between perceived risk, trust, and intention to vaccinate but at different levels. Together, these findings suggest that effective interventions (both public health messaging and personal medical communications) should focus on enhancing trust in health authorities, while at the same time endeavouring to highlight subjective norms that are vaccine-positive.

America's opioid epidemic has spawned an epidemic of neonatal abstinence syndrome (NAS). Studies have not tested approaches to promoting contraceptive services for women with opioid use disorder (OUD) along with treatment for this disorder. This pilot study examined the promotion of medication for OUD (MOUD) treatment and contraception use, primarily long-acting reversible contraception (LARC), for women with OUD.In Appalachia, a peer-delivered contraception and MOUD promotion intervention was delivered to a sample of 30 women with OUD. Primary outcomes were attendance of initial appointments to receive MOUD and counseling about contraceptive options. Peer recovery coaches also offered to help the women schedule appointments and attend the appointment with them or give them a ride if necessary and requested by the patients.Two-thirds experienced all seven symptoms of opioid dependence. Within 30 days of a brief counseling session, over one-half of the women (56.7%) were referred to MOUD, with all of them initiating treatment within 30 days. Just under one-half of the women (46.7%) were referred to a contraception consultation, with 85.7% of those receiving a LARC implant.Study findings indicate the potential efficacy of a single-session, peer-delivered counseling intervention for linking women with OUD and at high risk of unintended pregnancy to MOUD and to services that provide women with highly reliable contraceptives.This study is unique in exploring the efficacy of linking high-risk opioid-using women to contraceptive options and treatment for MOUD to prevent NAS.

Preventing postoperative complications is crucial for patients, surgeons, and health care facilities. We developed a risk stratification scoring system to optimize postoperative outcomes for patients undergoing foot and ankle surgery. A total of 35,580 patients who underwent foot and ankle procedures from 2005 to 2017 were identified as part of the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP). To assess the risk of a postoperative complication, we identified several independent risk factors associated with 30-day postoperative complications, then proceeded to develop a point-based risk scoring system. To validate our scoring system, we used it on a cohort of patients from the database who underwent foot and ankle surgery. Risk factors that correlated with postoperative complications included tobacco abuse, age (≥65 years), diabetes mellitus, hypertension, elevated creatinine level (≥1.3 mg/dL), hypoalbuminemia (Orthopedics . 2022;45(3):139–144.]

Metastatic disease affecting the proximal tibia is rarer than disease affecting the femur; however, it presents unique challenges that the orthopaedic surgeon must address to ensure successful outcomes and return the patient to an ambulatory status. The essential workup for evaluating and treating these patients is addressed briefly in this review as a summary of the information is provided in part 1 of this series. Part 2 of this series will focus on the surgical treatment of these lesions, which can be complex and is not as well described in the literature. Procedures ranging from open reduction internal fixation with cement augmentation to complex endoprosthetic reconstruction can be employed to address proximal tibia metastatic disease. An awareness of these various treatment modalities allows the orthopaedic surgeon to plan the most effective operation for the patients under their care.

Healthy ageing frameworks have been highly explored. Our objective was to assess existing frameworks for healthy ageing and to identify commonly described factors that can potentially act as determinants of healthy ageing.We carried out a systematic review by searching five electronic databases (EMBASE, MEDLINE, Cochrane, PsychINFO, and CINAHL) from January 2010 to November 2020 to capture contemporary evidence. Eligible studies needed to report a clear framework of healthy ageing in humans, within one or more of three domains (physical, mental/cognitive, social), in English. No restriction was placed on geographical location. Retrospective studies, studies that did not report a framework of healthy ageing, and studies with a focus on diagnostic measures were excluded.Of 3329 identified records, nine studies met our eligibility criteria and were included. Most of the studies were qualitative or cross sectional, and a majority were carried out in Asia, followed by North America, Australia, and Africa. The ten determinants identified for healthy ageing include physical activity, diet, self-awareness, outlook/attitude, life-long learning, faith, social support, financial security, community engagement, and independence.We identified ten determinants of healthy ageing proposed by the contemporary evidence base. There appears to be increasing acknowledgement of the instrumental role of social and mental/cognitive well-being as determinants of healthy ageing. The extent to which each determinant contributes to healthy ageing requires further evaluation.

Tay-Sachs disease (TSD) is an inherited neurological disorder caused by deficiency of hexosaminidase A (HexA). Here, we describe an adeno-associated virus (AAV) gene therapy expanded-access trial in two patients with infantile TSD (IND 18225) with safety as the primary endpoint and no secondary endpoints. Patient TSD-001 was treated at 30 months with an equimolar mix of AAVrh8-HEXA and AAVrh8-HEXB administered intrathecally (i.t.), with 75% of the total dose (1 × 10

As Earth's climate has varied strongly through geological time, studying the impacts of past climate change on biodiversity helps to understand the risks from future climate change. However, it remains unclear how paleo-climate shapes spatial variation in biodiversity. Here, we assessed the influence of Quaternary climate change on spatial dissimilarity in taxonomic, phylogenetic, and functional composition among neighboring 200-kilometer cells (beta-diversity) for angiosperm trees worldwide. We found that larger glacial-interglacial temperature change was strongly associated with lower spatial turnover (species replacements) and higher nestedness (rich-ness changes) components of beta-diversity across all three biodiversity facets. Moreover, phylogenetic and functional turnover was lower and nestedness higher than random expectations based on taxonomic beta -di-versity in regions that experienced large temperature change, reflecting phylogenetically and functionally se-lective processes in species replacement, extinction, and colonization during glacial-interglacial oscillations. Our results suggest that future human-driven climate change could cause local homogenization and reduction in taxonomic, phylogenetic, and functional diversity of angiosperm trees worldwide. W.-B.X. and A.O. acknowledge support from the Aarhus University Research Foundation (AUFF) Starting Grant (AUFF-F-2018-7-8). J.-C.S. acknowledges support from the Danish Council for Independent Research|Natural Sciences (grant 6108-00078B) to the TREECHANGE Project. J.-C.S. also considers this work a contribution to the Center for Ecological Dynamics in a Novel Biosphere (ECONOVO) funded by Danish National Research Foundation (grant DNRF173) and the VILLUM Investigator project “Biodiversity Dynamics in a Changing World” funded by VILLUM FONDEN (grant 16549). W.L.E. was supported by the VILLUM FONDEN (grant 00025354). M.A. was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) Discovery grants program. C.B. was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2022R1A2C1003504). A.G.G. was supported by the ANID PIA/BASAL (grant FB210006) and FONDECYT (grant 1200468). R.E.O. was supported by the German Research Foundation to German Centre for Integrative Biodiversity Research (iDiv) Halle-Jena-Leipzig (DFG-FZT 118, 202548816). J.Pe. was supported by the Fundación Ramón Areces project (CIVP20A6621) and Spanish Government project (PID2019-110521GB-I00). J.Pi. was supported by the Estonian Research Council Grants (PUT1355, PRG 1405) and Mobilitas Pluss (MOBERC11). V.D.P. was supported by the National Council of Scientific and Technological Development (CNPq) of Brazil (grant 307689/2014-0).

INTRODUCTION: Existing automated seizure detection algorithms report sensitivities between 43% and 77% and specificities between 56% and 90%. The algorithms suffer from false alarms when applied to neonatal EEG because of the high degree of nurse handling and rhythmic patting used to soothe neonates. Computer vision technology that quantifies movement in real time could distinguish artifactual motion and improve automated neonatal seizure detection algorithms. METHODS: The authors used video EEG recordings from 43 neonates undergoing monitoring for seizures as part of the NEOLEV2 clinical trial. The Persyst neonatal automated seizure detection algorithm ran in real time during study EEG acquisitions. Computer vision algorithms were applied to extract detailed accounts of artifactual movement of the neonate or people near the neonate though dense optical flow estimation. RESULTS: Using the methods mentioned above, 197 periods of patting activity were identified and quantified, of which 45 generated false-positive automated seizure detection events. A binary patting detection algorithm was trained with a subset of 470 event videos. This supervised detection algorithm was applied to a testing subset of 187 event videos with 8 false-positive events, which resulted in a 24% reduction in false-positive automated seizure detections and a 50% reduction in false-positive events caused by neonatal care patting, while maintaining 11 of 12 true-positive seizure detection events. CONCLUSIONS: This work presents a novel approach to improving automated seizure detection algorithms used during neonatal video EEG monitoring. This artifact detection mechanism can improve the ability of a seizure detector algorithm to distinguish between artifact and true seizure activity.

Acute respiratory distress syndrome (ARDS) is a heterogeneous clinical syndrome. Understanding of the complex pathways involved in lung injury pathogenesis, resolution, and repair has grown considerably in recent decades. Nevertheless, to date, only therapies targeting ventilation-induced lung injury have consistently proven beneficial, and despite these gains, ARDS morbidity and mortality remain high. Many candidate therapies with promise in preclinical studies have been ineffective in human trials, probably at least in part due to clinical and biological heterogeneity that modifies treatment responsiveness in human ARDS. A precision medicine approach to ARDS seeks to better account for this heterogeneity by matching therapies to subgroups of patients that are anticipated to be most likely to benefit, which initially might be identified in part by assessing for heterogeneity of treatment effect in clinical trials. In October 2019, the US National Heart, Lung, and Blood Institute convened a workshop of multidisciplinary experts to explore research opportunities and challenges for accelerating precision medicine in ARDS. Topics of discussion included the rationale and challenges for a precision medicine approach in ARDS, the roles of preclinical ARDS models in precision medicine, essential features of cohort studies to advance precision medicine, and novel approaches to clinical trials to support development and validation of a precision medicine strategy. In this Position Paper, we summarise workshop discussions, recommendations, and unresolved questions for advancing precision medicine in ARDS. Although the workshop took place before the COVID-19 pandemic began, the pandemic has highlighted the urgent need for precision therapies for ARDS as the global scientific community grapples with many of the key concepts, innovations, and challenges discussed at this workshop.

Introduction: The neonatal sequential organ failure assessment (nSOFA) score is a tool for calculating mortality risk of infants in the neonatal intensive care unit. The utility of the nSOFA in determining the risk of mortality or the association with surgical intervention among infants with necrotizing enterocolitis (NEC) has not been investigated. Methods: We performed a retrospective, cohort study of preterm (Results: Of the 259 infants, nSOFA scores for infants who died (n = 39) or had the composite outcome of surgery or death (n = 114) were significantly higher (p < 0.05) early in the NEC course compared to nSOFA scores for infants who survived medical NEC. Twelve hours after evaluation, the area under the receiver operating characteristic curve was 0.87 (95% confidence interval [CI], 0.80–0.93) to discriminate for mortality and 0.84 (95% CI, 0.79–0.90) for surgery or death (p < 0.001). A maximum nSOFA score of ≥4 at −6, 0, 6, or 12 h following evaluation was associated with a 20-fold increase in mortality and 19-fold increase in surgery or death compared with a score of p < 0.001). Conclusion: In this multicenter cohort, the nSOFA score was able to discriminate well for death as well as surgery or death among infants with NEC. The nSOFA is a clinical research tool that may be used in infants with NEC to improve classification by objective quantification of organ dysfunction.

PURPOSE/OBJECTIVES: To estimate the effects of interfractional anatomic changes on dose to organs-at-risk (OARs) and tumors, as measured with cone-beam computed tomography (CBCT) image guidance for pancreatic stereotactic body radiotherapy (SBRT). MATERIALS/METHODS: We evaluated 11 patients with pancreatic cancer, whom were treated with SBRT (33–40 Gy in 5 fractions) using daily CT-on-rails (CTOR) image guidance immediately before treatment with breath-hold motion management. CBCT alignment was simulated in the treatment planning software by aligning the original planning CT to each fractional CTOR image set via fiducial markers. CTOR datasets were used to calculate fractional doses after alignment by applying the rigid shift of the planning CT and CTOR image sets to the planning treatment isocenter and recalculating the fractional dose. Accumulated dose to the gross tumor volume (GTV), tumor vessel interface (TVI), duodenum, small bowel, and stomach were calculated by summing the 5 fractional absolute dose-volume histograms (DVHs) into a single DVH for comparison with the original planned dose. RESULTS: Four patients had a GTV D100% of at least 1.5 Gy less than the fractional planned value in several fractions; 4 patients had fractional underestimation of duodenum dose by 1.0 Gy per fraction. The D1.0 cm(3)

Measurement reliability is a fundamental concept in psychology. It is traditionally considered a stable property of a questionnaire, measurement device, or experimental task. Although intraclass correlation coefficients (ICC) are often used to assess reliability in repeated measure designs, their descriptive nature depends upon the assumption of a common within-person variance. This work focuses on the presumption that each individual is adequately described by the average within-person variance in hierarchical models. And thus whether reliability generalizes to the individual level, which leads directly into the notion of individually varying ICCs. In particular, we introduce a novel approach, using the Bayes factor, wherein a researcher can directly test for homogeneous within-person variance in hierarchical models. Additionally, we introduce a membership model that allows for classifying which (and how many) individuals belong to the common variance model. The utility of our methodology is demonstrated on cognitive inhibition tasks. We find that heterogeneous within-person variance is a defining feature of these tasks, and in one case, the ratio between the largest to smallest within-person variance exceeded 20. This translates into a tenfold difference in person-specific reliability! We also find that few individuals belong to the common variance model, and thus traditional reliability indices are potentially masking important individual variation. We discuss the implications of our findings and possible future directions. The methods are implemented in the R package vICC

Studies show that a woman's dissatisfaction with her birth experience may affect her well-being. This study aimed to examine: (1) the birth satisfaction in Croatian women and compare it with UK normative data ; (2) the association of different dimensions of birth satisfaction with posttraumatic stress disorder (PTSD) and depressive symptoms. In a cross-sectional online study, 603 postnatal Croatian women completed the Birth Satisfaction Scale-Revised (subscales: Stress experienced during labour (SL), Women's personal attributes (WA), and Quality of care provision (QC)) ; City Birth Trauma Scale (subscales: Birth-related symptoms and General symptoms) ; and Edinburgh Postnatal Depression Scale. Subscale and total scale scores were calculated. Path analysis tested the model of three aspects of birth satisfaction effect on PTSD dimensions and depressive symptoms. The average birth satisfaction score was significantly lower compared to the UK data on the total scale and all three subscale scores. Path analysis revealed that all three dimensions of birth satisfaction (SL, WA, and QC) had an effect on Birth-related symptoms. However, only Women's personal attributes (i.e., feeling anxiety or being in control during childbirth) had an effect on General symptoms and depressive symptoms, as well. Different aspects of birth satisfaction are important for maternal mental health following childbirth.

Background For children and adults, the standard treatment for obstructive sleep apnea is the delivery of continuous positive airway pressure (CPAP). Though effective, CPAP masks can be uncomfortable to patients, contributing to adherence concerns. Recently, nasal high flow (NHF) therapy has been investigated as an alternative, especially in CPAP-intolerant children. The present study aimed to compare and contrast the positive airway pressures and expired gas washout generated by NHF versus CPAP in child nasal airway replicas. Methods NHF therapy was investigated at a flow rate of 20 L/min and compared to CPAP at 5 cmH2O and 10 cmH2O for 10 nasal airway replicas, built from computed tomography scans of children aged 4–8 years. NHF was delivered with three different high flow nasal cannula models provided by the same manufacturer, and CPAP was delivered with a sealed nasal mask. Tidal breathing through each replica was imposed using a lung simulator, and airway pressure at the trachea was recorded over time. For expired gas washout measurements, carbon dioxide was injected at the lung simulator, and end-tidal carbon dioxide (EtCO2) was measured at the trachea. Changes in EtCO2 compared to baseline values (no intervention) were assessed. Results NHF therapy generated an average positive end-expiratory pressure (PEEP) of 5.17 ± 2.09 cmH2O (mean ± SD, n = 10), similar to PEEP of 4.95 ± 0.03 cmH2O generated by nominally 5 cmH2O CPAP. Variation in tracheal pressure was higher between airway replicas for NHF compared to CPAP. EtCO2 decreased from baseline during administration of NHF, whereas it increased during CPAP. No statistical difference in tracheal pressure nor EtCO2 was found between the three high flow nasal cannulas. Conclusion In child airway replicas, NHF at 20 L/min generated average PEEP similar to CPAP at 5 cm H2O. Variation in tracheal pressure was higher between airway replicas for NHF than for CPAP. The delivery of NHF yielded expired gas washout, whereas CPAP impeded expired gas washout due to the increased dead space of the sealed mask.

Prior studies have shown communication-related participation restrictions in patients with degenerative disease do not always match clinician judgment of symptom severity. Relatedly, there is a growing body of literature documenting discrepancies between patients with dementia and care partner perception of participation restrictions. However, it is not known how care partner perceptions of communication participation restrictions match or diverge from the patient's experience, which was the topic of this study. Toward that end, 28 patients with apraxia of speech and/or dysarthria associated with primary progressive apraxia of speech, nonfluent/agrammatic primary progressive aphasia, or progressive supranuclear palsy, all types of frontotemporal dementia, were seen for speech-language examinations. The patients and their care partners were asked to independently complete the Communication Participation Item Bank (CPIB), short form, which is a 10-question survey about communication in different contexts; higher scores reflect less interference from their condition on communication. Care partners were instructed to complete the form with their perception of the patient's restrictions. The total CPIB score (maximum 30) and difference scores were calculated and visualized. The data (Figure) suggest mismatches exist in care partner and patient ratings of communication participation restrictions. Of 28 patients, only 1 pair had identical scores, each rating severe interference in all communication contexts. 57% of patients rated communication as less impacted (higher scores) compared to their family member, leaving 39% of family members rating communication as less impacted than their loved one's perception. This study lays the foundation for future research to include patient and care partner ratings when examining the benefit of impairment-based therapy, utilization of compensatory speech strategies, effectiveness of such strategies, and impact of other augmentative or alternative means of communication. The CPIB may be useful to document reduced psychosocial impact of disease and diminished burden and burnout on care partners with different intervention options. Future studies will explore possible differences between FTD phenotypes and, more specifically, whether 1) the motor speech disorder (MSD) disorder is primary or secondary to other motor impairment, 2) the nature or severity of the MSD, or 3) concomitant cognitive-communication impairment predict the existence of and/or direction of a discrepancy.

Genetics play an important role in late-onset Alzheimer’s Disease (AD) etiology and dozens of genetic variants have been implicated in AD risk through large-scale GWAS meta-analyses. However, the precise mechanistic effects of most of these variants have yet to be determined. Deeply phenotyped cohort data can reveal physiological changes associated with genetic risk for AD across an age spectrum that may provide clues to the biology of the disease. We utilized over 2000 high-quality quantitative measurements obtained from blood of 2831 cognitively normal adult clients of a consumer-based scientific wellness company, each with CLIA-certified whole-genome sequencing data. Measurements included: clinical laboratory blood tests, targeted chip-based proteomics, and metabolomics. We performed a phenome-wide association study utilizing this diverse blood marker data and 25 known AD genetic variants and an AD-specific polygenic risk score (PGRS), adjusting for sex, age, vendor (for clinical labs), and the first four genetic principal components; sex-SNP interactions were also assessed. We observed statistically significant SNP-analyte associations for five genetic variants after correction for multiple testing (for SNPs in or near NYAP1, ABCA7, INPP5D, and APOE), with effects detectable from early adulthood. The ABCA7 SNP and the APOE2 and APOE4 encoding alleles were associated with lipid variability, as seen in previous studies; in addition, six novel proteins were associated with the e2 allele. The most statistically significant finding was between the NYAP1 variant and PILRA and PILRB protein levels, supporting previous functional genomic studies in the identification of a putative causal variant within the PILRA gene. We did not observe associations between the PGRS and any analyte. Sex modified the effects of four genetic variants, with multiple interrelated immune-modulating effects associated with the PICALM variant. In post-hoc analysis, sex-stratified GWAS results from an independent AD case–control meta-analysis supported sex-specific disease effects of the PICALM variant, highlighting the importance of sex as a biological variable. Known AD genetic variation influenced lipid metabolism and immune response systems in a population of non-AD individuals, with associations observed from early adulthood onward. Further research is needed to determine whether and how these effects are implicated in early-stage biological pathways to AD. These analyses aim to complement ongoing work on the functional interpretation of AD-associated genetic variants.

Introduction Progressive supranuclear palsy (PSP) variants other than PSP-Richardson Syndrome (PSP-RS) have been recognized, including PSP with speech and language problems (PSP-SL). Given the reported sleep disruptions in PSP-RS, we investigated sleep abnormalities in PSP-SL. Methods Four sleep-related screening questions were given to the caregivers of 90 patients with PSP-SL (59 suggestive of PSP-SL and 31 possible PSP-SL) and 71 probable PSP-RS (prob. PSP-RS) patients. Results At least one sleep-related disturbance was observed in 35.6% of suggestive of PSP-SL, 38.7% of possible PSP-SL, and 67.6% of prob. PSP-RS, the most common being “unable to fall or stay asleep”. Prob. PSP-RS showed higher frequency of “screaming or talking in sleep”, “acting out dreams”, and “unable to fall or stay asleep” compared to both PSP-SL groups, but did not differ from possible PSP-SL in “excessive daytime sleepiness”. Conclusion Sleep abnormalities are common in PSP-SL, but less frequent than prob.PSP-RS.

Male sexual orientation is influenced by environmental and complex genetic factors. Childhood gender nonconformity (CGN) is one of the strongest correlates of homosexuality with substantial familiality. We studied brothers in families with two or more homosexual brothers (409 concordant sibling pairs in 384 families, as well as their heterosexual brothers), who self-recalled their CGN. To map loci for CGN, we conducted a genome-wide linkage scan (GWLS) using SNP genotypes. The strongest linkage peaks, each with significant or suggestive two-point LOD scores and multipoint LOD score support, were on chromosomes 5q31 (maximum two-point LOD = 4.45), 6q12 (maximum two-point LOD = 3.64), 7q33 (maximum two-point LOD = 3.09), and 8q24 (maximum two-point LOD = 3.67), with the latter not overlapping with previously reported strongest linkage region for male sexual orientation on pericentromeric chromosome 8. Family-based association analyses were used to identify associated variants in the linkage regions, with a cluster of SNPs (minimum association p = 1.3 × 10–8) found at the 5q31 linkage peak. Genome-wide, clusters of multiple SNPs in the 10–6 to 10–8p-value range were found at chromosomes 5p13, 5q31, 7q32, 8p22, and 10q23, highlighting glutamate-related genes. This is the first reported GWLS and genome-wide association study on CGN. Further increasing genetic knowledge about CGN and its relationships to male sexual orientation should help advance our understanding of the biology of these associated traits.

Objective: Major postoperative adverse events (MPAEs) following head and neck surgery are not infrequent and lead to significant morbidity. The objective of this study was to ascertain which factors are most predictive of MPAEs in patients undergoing head and neck surgery. Methods: A cohort study was carried out based on data from patients registered in the National Surgical Quality Improvement Program (NSQIP) from 2006 to 2018. All patients undergoing non-ambulatory head and neck surgery based on Current Procedural Terminology codes were included. Perioperative factors were evaluated to predict MPAEs within 30-days of surgery. Age was classified as both a continuous and categorical variable. Retained factors were classified by attributable fraction and C-statistic. Multivariate regression and supervised machine learning models were used to quantify the contribution of age as a predictor of MPAEs. Results: A total of 43 701 operations were analyzed with 5106 (11.7%) MPAEs. The results of supervised machine learning indicated that prolonged surgeries, anemia, free tissue transfer, weight loss, wound classification, hypoalbuminemia, wound infection, tracheotomy (concurrent with index head and neck surgery), American Society of Anesthesia (ASA) class, and sex as most predictive of MPAEs. On multivariate regression, ASA class (21.3%), hypertension on medication (15.8%), prolonged operative time (15.3%), sex (13.1%), preoperative anemia (12.8%), and free tissue transfer (9%) had the largest attributable fractions associated with MPAEs. Age was independently associated with MPAEs with an attributable fraction ranging from 0.6% to 4.3% with poor predictive ability (C-statistic 0.60). Conclusion: Surgical, comorbid, and frailty-related factors were most predictive of short-term MPAEs following head and neck surgery. Age alone contributed a small attributable fraction and poor prediction of MPAEs. Level of evidence: 3

STUDY DESIGN Retrospective Cohort. OBJECTIVE Identify patient variables, injury characteristics, and costs associated with operative and non-operative treatment following inter-facility transfer of patients with isolated cervical spine fractures. SUMMARY OF BACKGROUND DATA Patients with isolated cervical spine fractures are subject to inter-facility transfer for surgical assessment, yet are often treated non-operatively. The American College of Surgeons' benchmark rate of "secondary over-triage" is < 50%. Identifying patient and injury characteristics as well as costs associated with treatment following transfer of patients with isolated cervical spine fractures may help reduce rates of secondary over-triage and healthcare expenditures. METHODS Patients transferred to a Level-1 trauma center with isolated cervical spine fractures between January 2015 and September 2020 were identified. Patient demographics, comorbidities, insurance data, injury characteristics, imaging workup, treatment, and financial data were collected for all patients. Multivariable logistic regression models were constructed to identify patient and injury characteristics associated with surgical treatment. RESULTS Nearly 75% of patients were treated non-operatively. Over 97% of transfers were accepted by the general surgery trauma service. Multivariable modeling found that higher BMI, presence of any neurologic deficit including spinal cord or isolated spinal nerve root injuries, current smoking status, or cervical spine MRI obtained post-transfer, were associated with surgical treatment for isolated cervical spine fractures. Among patients with type II dens fractures, increased fracture displacement was associated with surgical treatment. Median charges to patients treated operatively and non-operatively were $380,890 and $90,734, respectively. Median hospital expenditures for patients treated operatively and non-operatively were $55,115 and $12,131, respectively. CONCLUSION A large proportion of patients with isolated cervical spine fractures are subject to over-triage. Injury characteristics are important for determining need for surgical treatment, and therefore inter-facility transfer. Improving communication with spine surgeons when deciding to transfer patients may significantly reduce healthcare costs and resource use.Level of Evidence: 4.

Safeguarding Earth?s tree diversity is a conservation priority due to the importance of trees for biodiversity and ecosystem functions and services such as carbon sequestration. Here, we improve the foundation for effective conservation of global tree diversity by analyzing a recently developed database of tree species covering 46,752 species. We quantify range protection and anthropogenic pressures for each species and develop conservation priorities across taxonomic, phylogenetic, and functional diversity dimensions. We also assess the effectiveness of several influential proposed conservation prioritization frameworks to protect the top 17% and top 50% of tree priority areas. We find that an average of 50.2% of a tree species? range occurs in 110-km grid cells without any protected areas (PAs), with 6,377 small-range tree species fully unprotected, and that 83% of tree species experience nonnegligible human pressure across their range on average. Protecting highpriority areas for the top 17% and 50% priority thresholds would increase the average protected proportion of each tree species? range to 65.5% and 82.6%, respectively, leaving many fewer species (2,151 and 2,010) completely unprotected. The priority areas identified for trees match well to the Global 200 Ecoregions framework, revealing that priority areas for trees would in large part also optimize protection for terrestrial biodiversity overall. Based on range estimates for >46,000 tree species, our findings show that a large proportion of tree species receive limited protection by current PAs and are under substantial human pressure. Improved protection of biodiversity overall would also strongly benefit global tree diversity. Made available in DSpace on 2022-06-21T15:23:55Z (GMT). No. of bitstreams: 1 Guo-et-al.-2022-PNAS-High-exposure-of-global-tree-diversity-to-human-pressure.pdf: 2523289 bytes, checksum: 245be3df3fb487ed152d25bf50f4e984 (MD5) Previous issue date: 2022 Proceedings of the National Academy of Sciences of the United States of America.

Objective:To characterize and compare the neuropsychological profiles of patients with primary progressive apraxia of speech (PPAOS) and apraxia of speech with progressive agrammatic aphasia (AOS-PAA).Method:Thirty-nine patients with PPAOS and 49 patients with AOS-PAA underwent formal neurological, speech, language, and neuropsychological evaluations. Cognitive domains assessed included immediate and delayed episodic memory (Wechsler Memory Scale-Third edition; Logical Memory; Visual Reproduction; Rey Auditory Verbal Learning Test), processing speed (Trail Making Test A), executive functioning (Trail Making Test B; Delis-Kaplan Executive Functioning Scale – Sorting), and visuospatial ability (Rey-Osterrieth Complex Figure copy).Results:The PPAOS patients were cognitively average or higher in the domains of immediate and delayed episodic memory, processing speed, executive functioning, and visuospatial ability. Patients with AOS-PAA performed more poorly on tests of immediate and delayed episodic memory and executive functioning compared to those with PPAOS. For every 1 unit increase in aphasia severity (e.g. mild to moderate), performance declined by 1/3 to 1/2 a standard deviation depending on cognitive domain. The degree of decline was stronger within the more verbally mediated domains, but was also notable in less verbally mediated domains.Conclusion:The study provides neuropsychological evidence further supporting the distinction of PPAOS from primary progressive aphasia and should be used to inform future diagnostic criteria. More immediately, it informs prognostication and treatment planning.

Background T2 mapping is of great interest in abdominal imaging but current methods are limited by low resolution, slice coverage, motion sensitivity, or lengthy acquisitions. Purpose Develop a radial turbo spin-echo technique with refocusing variable flip angles (RADTSE-VFA) for high spatiotemporal T2 mapping and efficient slice coverage within a breath-hold and compare to the constant flip angle counterpart (RADTSE-CFA). Study type Prospective technical efficacy. Subjects Testing performed on agarose phantoms and 12 patients. Focal liver lesion classification tested on malignant (N = 24) and benign (N = 11) lesions. Field strength/sequence 1.5 T/RADTSE-VFA, RADTSE-CFA. Assessment A constrained objective function was used to optimize the refocusing flip angles. Phantom and/or in vivo data were used to assess relative contrast, T2 estimation, specific absorption rate (SAR), and focal liver lesion classification. STATISTICAL TESTS: t-Tests or Mann-Whitney Rank Sum tests were used. Results Phantom data did not show significant differences in mean relative contrast (P = 0.10) and T2 accuracy (P = 0.99) between RADTSE-VFA and RADTSE-CFA. Adding noise caused T2 overestimation predominantly for RADTSE-CFA and low T2 values. In vivo results did not show significant differences in mean spleen-to-liver (P = 0.62) and kidney-to-liver (P = 0.49) relative contrast between RADTSE-VFA and RADTSE-CFA. Mean T2 values were not significantly different between the two techniques for spleen (T2VFA = 109.2 ± 12.3 msec; T2CFA = 110.7 ± 11.1 msec; P = 0.78) and kidney-medulla (T2VFA = 113.0 ± 8.7 msec; T2CFA = 114.0 ± 8.6 msec; P = 0.79). Liver T2 was significantly higher for RADTSE-CFA (T2VFA = 52.6 ± 6.6 msec; T2CFA = 60.4 ± 8.0 msec) consistent with T2 overestimation in the phantom study. Focal liver lesion classification had comparable T2 distributions for RADTSE-VFA and RADTSE-CFA for malignancies (P = 1.0) and benign lesions (P = 0.39). RADTSE-VFA had significantly lower SAR than RADTSE-CFA increasing slice coverage by 1.5. Data conclusion RADTSE-VFA provided noise-robust T2 estimation compared to the constant flip angle counterpart while generating T2-weighted images with comparable contrast. The VFA scheme minimized SAR improving slice efficiency for breath-hold imaging. Level of evidence 2 TECHNICAL EFFICACY STAGE: 1.

To examine the measurement model of the Tokophobia Severity Scale and consider issues of statistical power and sample size from the original instrument development study.Fear of childbirth (FoC) and tokophobia represents an area of increasing concern within perinatal mental health research and clinical practice. Existing measures of the FoC have been criticised due to either measurement inconsistencies, difficulties in scoring or practical clinical application. Attempting to address these limitations, researchers developed the Tokophobia Severity Scale (TSS). A fundamental assumption underpinning the use of the TSS is unidimensionality, however this assertion may have been based on sub-optimal sample size and approach taken to factor structure determination.Parallel analysis (PA), principal components analysis (PCA), exploratory factor analysis (EFA), power analysis and sample size calculation using a reconstruction of the original dataset from published summary data.Following replication of the original PCA, a three-factor model was found to offer a significantly better fit to data than a unidimensional model. Power analysis suggested the original study was underpowered.The TSS remains a promising tool but assumptions regarding its measurement model are based on an inadequate sample size. Sample sizes for a sufficiently powered study indicated.

Male sexual orientation is a scientifically and socially important trait shown by family and twin studies to be influenced by environmental and complex genetic factors. Individual genome-wide linkage studies (GWLS) have been conducted, but not jointly analyzed. Two main datasets account for > 90% of the published GWLS concordant sibling pairs on the trait and are jointly analyzed here: MGSOSO (Molecular Genetic Study of Sexual Orientation; 409 concordant sibling pairs in 384 families, Sanders et al. (2015)) and Hamer (155 concordant sibling pairs in 145 families, Mustanski et al. (2005)). We conducted multipoint linkage analyses with Merlin on the datasets separately since they were genotyped differently, integrated genetic marker positions, and combined the resultant LOD (logarithm of the odds) scores at each 1 cM grid position. We continue to find the strongest linkage support at pericentromeric chromosome 8 and chromosome Xq28. We also incorporated the remaining published GWLS dataset (on 55 families) by using meta-analytic approaches on published summary statistics. The meta-analysis has maximized the positional information from GWLS of currently available family resources and can help prioritize findings from genome-wide association studies (GWAS) and other approaches. Although increasing evidence highlights genetic contributions to male sexual orientation, our current understanding of contributory loci is still limited, consistent with the complexity of the trait. Further increasing genetic knowledge about male sexual orientation, especially via large GWAS, should help advance our understanding of the biology of this important trait. Supplementary Information The online version contains supplementary material available at 10.1007/s10508-021-02035-3.

Progressive apraxia of speech is a neurodegenerative syndrome affecting spoken communication. Molecular pathology, biochemistry, genetics, and longitudinal imaging were investigated in 32 autopsy-confirmed patients with progressive apraxia of speech who were followed over 10 years. Corticobasal degeneration and progressive supranuclear palsy (4R-tauopathies) were the most common underlying pathologies. Perceptually distinct speech characteristics, combined with age-at-onset, predicted specific 4R-tauopathy; phonetic subtype and younger age predicted corticobasal degeneration, and prosodic subtype and older age predicted progressive supranuclear palsy. Phonetic and prosodic subtypes showed differing relationships within the cortico-striato-pallido-nigro-luysial network. Biochemical analysis revealed no distinct differences in aggregated 4R-tau while tau H1 haplotype frequency (69%) was lower compared to 1000+ autopsy-confirmed 4R-tauopathies. Corticobasal degeneration patients had faster rates of decline, greater cortical degeneration, and shorter illness duration than progressive supranuclear palsy. These findings help define the pathobiology of progressive apraxia of speech and may have consequences for development of 4R-tau targeting treatment., Progressive apraxia of speech (PAOS) is a neurodegenerative syndrome of multiple etiologies which affects spoken communication. Here, the authors characterized the molecular pathology, biochemistry, genetics and longitudinal neuroimaging of 32 autopsy-confirmed patients with PAOS who were followed over 10 years.

Persistent immune activation is a hallmark of human immunodeficiency virus (HIV) infection and thought to play a role on chronic diseases in people with HIV (PWH). Food insecurity is disproportionately prevalent in PWH and is associated with adverse health outcomes. We determined whether food insecurity was associated with increased plasma levels of soluble CD14, CD27, and CD163 in 323 antiretroviral-treated PWH from the Miami Adult Studies on HIV cohort. Nearly half (42.7%) of participants were food insecure, and 85.5% were virally suppressed (

Diffuse intrinsic pontine glioma (DIPG), a rare pediatric brain tumor, afflicts approximately 350 new patients each year in the United States. DIPG is noted for its lethality, as fewer than 1% of patients survive to five years. Multiple clinical trials involving chemotherapy, radiotherapy, and/or targeted therapy have all failed to improve clinical outcomes. Recently, high-throughput sequencing of a cohort of DIPG samples identified potential therapeutic targets, including interleukin 13 receptor subunit alpha 2 (IL13Rα2) which was expressed in multiple tumor samples and comparably absent in normal brain tissue, identifying IL13Rα2 as a potential therapeutic target in DIPG. In this work, we investigated the role of IL13Rα2 signaling in progression and invasion of DIPG and viability of IL13Rα2 as a therapeutic target through the use of immunoconjugate agents. We discovered that IL13Rα2 stimulation via canonical ligands demonstrates minimal impact on both the cellular proliferation and cellular invasion of DIPG cells, suggesting IL13Rα2 signaling is non-essential for DIPG progression in vitro. However, exposure to an anti-IL13Rα2 antibody–drug conjugate demonstrated potent pharmacological response in DIPG cell models both in vitro and ex ovo in a manner strongly associated with IL13Rα2 expression, supporting the potential use of targeting IL13Rα2 as a DIPG therapy. However, the tested ADC was effective in most but not all cell models, thus selection of the optimal payload will be essential for clinical translation of an anti-IL13Rα2 ADC for DIPG. Supplementary Information The online version contains supplementary material available at 10.1186/s40478-021-01184-9.

Context.— Pathology studies using convolutional neural networks (CNNs) have focused on neoplasms, while studies in inflammatory pathology are rare. We previously demonstrated a CNN that differentiates reactive gastropathy, Helicobacter pylori gastritis (HPG), and normal gastric mucosa. Objective.— To determine whether a CNN can differentiate the following 2 gastric inflammatory patterns: autoimmune gastritis (AG) and HPG. Design.— Gold standard diagnoses were blindly established by 2 gastrointestinal (GI) pathologists. One hundred eighty-seven cases were scanned for analysis by HALO-AI. All levels and tissue fragments per slide were included for analysis. The cases were randomized, 112 (60%; 60 HPG, 52 AG) in the training set and 75 (40%; 40 HPG, 35 AG) in the test set. A HALO-AI correct area distribution (AD) cutoff of 50% or more was required to credit the CNN with the correct diagnosis. The test set was blindly reviewed by pathologists with different levels of GI pathology expertise as follows: 2 GI pathologists, 2 general surgical pathologists, and 2 residents. Each pathologist rendered their preferred diagnosis, HPG or AG. Results.— At the HALO-AI AD percentage cutoff of 50% or more, the CNN results were 100% concordant with the gold standard diagnoses. On average, autoimmune gastritis cases had 84.7% HALO-AI autoimmune gastritis AD and HP cases had 87.3% HALO-AI HP AD. The GI pathologists, general anatomic pathologists, and residents were on average, 100%, 86%, and 57% concordant with the gold standard diagnoses, respectively. Conclusions.— A CNN can distinguish between cases of HPG and autoimmune gastritis with accuracy equal to GI pathologists.

BACKGROUND: A variety of shared care models have been developed, which aim to stratify glaucoma patients according to risk of disease progression. However, there is limited published data on the rate of glaucoma progression in the hospital vs community setting. Here we aimed to compare rates of glaucomatous visual field progression in the Cambridge Community Optometrist Glaucoma Scheme (COGS) and Addenbrooke's Hospital Glaucoma Clinic (AGC). METHODS: A retrospective comparative cohort review was performed. Patients with five or more visual field tests were included. Zeiss Forum software was used to calculate the MD progression rate (dB/year). Loss of sight years (LSY) were also calculated for both COGS and AGC. RESULTS: Overall, 8465 visual field tests from 854 patients were reviewed. In all, 362 eyes from the AGC group and 210 eyes from COGS were included. The MD deterioration rate was significantly lower in the COGS patients compared with the AGC group (-0.1 vs -0.3 dB/year; p

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the US. Understanding the mechanisms of CRC progression is essential to improve treatment. Mitochondria is the powerhouse for healthy cells. However, in tumor cells, less energy is produced by the mitochondria and metabolic reprogramming is an early hallmark of cancer. The metabolic differences between normal and cancer cells are being interrogated to uncover new therapeutic approaches. Mitochondria targeting PTEN-induced kinase 1 (PINK1) is a key regulator of mitophagy, the selective elimination of damaged mitochondria by autophagy. Defective mitophagy is increasingly associated with various diseases including CRC. However, a significant gap exists in our understanding of how PINK1-dependent mitophagy participates in the metabolic regulation of CRC. By mining Oncomine, we found that PINK1 expression was downregulated in human CRC tissues compared to normal colons. Moreover, disruption of PINK1 increased colon tumorigenesis in two colitis-associated CRC mouse models, suggesting that PINK1 functions as a tumor suppressor in CRC. PINK1 overexpression in murine colon tumor cells promoted mitophagy, decreased glycolysis and increased mitochondrial respiration potentially via activation of p53 signaling pathways. In contrast, PINK1 deletion decreased apoptosis, increased glycolysis, and reduced mitochondrial respiration and p53 signaling. Interestingly, PINK1 overexpression in vivo increased apoptotic cell death and suppressed colon tumor xenograft growth. Metabolomic analysis revealed that acetyl-CoA was significantly reduced in tumors with PINK1 overexpression, which was partly due to activation of the HIF-1α-pyruvate dehydrogenase (PDH) kinase 1 (PDHK1)-PDHE1α axis. Strikingly, treating mice with acetate increased acetyl-CoA levels and rescued PINK1-suppressed tumor growth. Importantly, PINK1 disruption simultaneously increased xenografted tumor growth and acetyl-CoA production. In conclusion, mitophagy protein PINK1 suppresses colon tumor growth by metabolic reprogramming and reducing acetyl-CoA production.

The ongoing global health crisis caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the virus which leads to Coronavirus Disease 2019 (COVID-19) has impacted not only the health of people everywhere, but the economy in nations across the world. While vaccine candidates and therapeutics are currently undergoing clinical trials, there is yet to be a proven effective treatment or cure for COVID-19. In this study, we have presented a synergistic computational platform, including molecular dynamics simulations and immunoinformatics techniques, to rationally design a multi-epitope vaccine candidate for COVID-19. This platform combines epitopes across Linear B Lymphocytes (LBL), Cytotoxic T Lymphocytes (CTL) and Helper T Lymphocytes (HTL) derived from both mutant and wild-type spike glycoproteins from SARS-CoV-2 with diverse protein conformations. In addition, this vaccine construct also takes the considerable glycan shield of the spike glycoprotein into account, which protects it from immune response. We have identified a vaccine candidate (a 35.9 kDa protein), named COVCCF, which is composed of 5 LBL, 6 HTL, and 6 CTL epitopes from the spike glycoprotein of SARS-CoV-2. Using multi-dose immune simulations, COVCCF induces elevated levels of immunoglobulin activity (IgM, IgG1, IgG2), and induces strong responses from B lymphocytes, CD4 T-helper lymphocytes, and CD8 T-cytotoxic lymphocytes. COVCCF induces cytokines important to innate immunity, including IFN-γ, IL4, and IL10. Additionally, COVCCF has ideal pharmacokinetic properties and low immune-related toxicities. In summary, this study provides a powerful, computational vaccine design platform for rapid development of vaccine candidates (including COVCCF) for effective prevention of COVID-19.

OBJECTIVE To demonstrate the feasibility of implementing a competency-based education (CBE) curriculum within a general surgery residency program and to evaluate its effectiveness in improving resident skill. SUMMARY BACKGROUND DATA Operative skill variability affects residents and practicing surgeons and directly impacts patient outcomes. CBE can decrease this variability by ensuring uniform skill acquisition. We implemented a CBE laparoscopic cholecystectomy (LC) curriculum to improve resident performance and decrease skill variability. METHODS PGY-2 residents completed the curriculum during monthly rotations starting in July 2017. Once simulator proficiency was reached, residents performed elective LCs with a select group of faculty at three hospitals. Performance at curriculum completion was assessed using LC simulation metrics and intraoperative OPRS scores and compared to both baseline and historical controls, comprised of rising PGY-3 s, using a two-sample Wilcoxon rank-sum test. PGY-2 group's performance variability was compared with PGY-3 s using Levene's Robust Test of Equality of Variances; p < 0.05 was considered significant. RESULTS 21 residents each performed 17.52 ± 4.15 consecutive LCs during the monthly rotation. Resident simulated and operative performance increased significantly with dedicated training and reached that of more experienced rising PGY-3 s (n = 7) but with significantly decreased variability in performance (p = 0.04). CONCLUSIONS Completion of a CBE rotation led to significant improvements in PGY-2 residents' LC performance that reached that of PGY-3 s and decreased performance variability. These results support wider implementation of CBE in resident training.

Multinational organizations are increasingly looking to deploy assessments on a global basis. However, the social desirability of different personality characteristics may vary as a function of culture, yet limited research has explored this idea. Based on the GLOBE cultural dimensions and the theory of purposeful behavior, we examined potential connections between cultural practice dimensions and the desirability of personality aspects with a large personality item bank, utilizing raters across 34 countries. Findings indicated few connections of societal level cultural practices and social desirability perceptions for particular aspects. An exception to this was the finding that higher social desirability ratings were given for cooperativeness, sensitivity, and assertiveness in Confucian Asian, South Asian, and Sub-Saharan contexts compared with Germanic Europe, Eastern Europe, Latin America, and Latin Europe contexts. Limitations of the study as well as implications for development and use of personality assessments globally in high stakes contexts are discussed. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Background: Socioeconomic disadvantages and potential immunocompromise raise particular concerns for people living with HIV (PLWH) and other marginalized communities during the COVID-19 pandemic. In this study, we explored COVID-19 testing and the impact of the pandemic among participants from the Miami Adult Studies on HIV cohort, predominantly composed of lowincome minorities living with and without HIV. Methods: Between July and August 2020, a telephone survey was administered to 299 Miami Adult Studies on HIV participants to assess COVID-19 testing, prevention behaviors, and psychosocial stressors. Health care utilization, antiretroviral adherence, food insecurity, and substance use during the pandemic were compared with those of their last cohort visit (7.8 6 2.9 months earlier). Results: Half of surveyed participants had been tested for COVID-19, 8 had tested positive and 2 had been hospitalized. PLWH (n = 183) were 42% times less likely than HIV-uninfected participants to have been tested. However, after adjustment for age, employment, COVID-19 symptoms, mental health care, and substance use, the effect of HIV status was no longer significant. PLWH were more likely to have seen a health care provider, use face coverings, and avoid public transportation and less likely to be food insecure and drink hazardously. There were significant changes in substance use patterns during the pandemic when compared with those before. Conclusion: PLWH, compared with their HIV-uninfected peers, were more likely to engage in preventive measures and health care during the pandemic, potentially reducing their exposure to COVID-19. There were no reported changes in antiretroviral adherence or health care utilization, but there were changes in substance use;these need to be monitored as this crisis progresses. [ABSTRACT FROM AUTHOR] Copyright of JAIDS: Journal of Acquired Immune Deficiency Syndromes is the property of Lippincott Williams & Wilkins 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 abstract 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 abstract. (Copyright applies to all Abstracts.)

The gut microbiota of preterm infants develops predictably1–7, with pioneer species colonizing the gut after birth, followed by an ordered succession of microorganisms. The gut microbiota is vital to the health of preterm infants8,9, but the forces that shape these predictable dynamics of microbiome assembly are unknown. The environment, the host and interactions between microorganisms all potentially shape the dynamics of the microbiota, but in such a complex ecosystem, identifying the specific role of any individual factor is challenging10–14. Here we use multi-kingdom absolute abundance quantification, ecological modelling and experimental validation to address this challenge. We quantify the absolute dynamics of bacteria, fungi and archaea in a longitudinal cohort of 178 preterm infants. We uncover microbial blooms and extinctions, and show that there is an inverse correlation between bacterial and fungal loads in the infant gut. We infer computationally and demonstrate experimentally in vitro and in vivo that predictable assembly dynamics may be driven by directed, context-dependent interactions between specific microorganisms. Mirroring the dynamics of macroscopic ecosystems15–17, a late-arriving member of the microbiome, Klebsiella, exploits the pioneer microorganism, Staphylococcus, to gain a foothold within the gut. Notably, we find that interactions between different kingdoms can influence assembly, with a single fungal species—Candida albicans—inhibiting multiple dominant genera of gut bacteria. Our work reveals the centrality of simple microbe–microbe interactions in shaping host-associated microbiota, which is critical both for our understanding of microbiota ecology and for targeted microbiota interventions. Absolute microbial abundances delineate longitudinal dynamics of bacteria, fungi and archaea in the infant gut microbiome, uncovering drivers of microbiome development masked by relative abundances and revealing notable parallels to macroscopic ecosystem assemblies.

Technological and computational advances in genomics and interactomics have made it possible to identify how disease mutations perturb protein–protein interaction (PPI) networks within human cells. Here, we show that disease-associated germline variants are significantly enriched in sequences encoding PPI interfaces compared to variants identified in healthy participants from the projects 1000 Genomes and ExAC. Somatic missense mutations are also significantly enriched in PPI interfaces compared to noninterfaces in 10,861 tumor exomes. We computationally identified 470 putative oncoPPIs in a pan-cancer analysis and demonstrate that oncoPPIs are highly correlated with patient survival and drug resistance/sensitivity. We experimentally validate the network effects of 13 oncoPPIs using a systematic binary interaction assay, and also demonstrate the functional consequences of two of these on tumor cell growth. In summary, this human interactome network framework provides a powerful tool for prioritization of alleles with PPI-perturbing mutations to inform pathobiological mechanism- and genotype-based therapeutic discovery. Human disease mutations affect protein–protein interfaces in a three-dimensional structurally resolved interaction network. Predicted oncoPPIs in cancer correlate with survival and drug sensitivity, and affect growth in vitro, supporting their relevance to disease pathogenesis.

Context Human milk contains hormones that regulate metabolism. Extrauterine growth restriction remains common among preterm infants, but the effect of ingesting milk hormones on preterm infant growth is poorly understood. Objective To quantify associations of longitudinal exposure to leptin, adiponectin, and insulin in milk with physical growth of preterm infants. Design/Methods In 50 preterm neonates (median gestational age 29.4 weeks), we sampled maternal milk on day-of-life 7, 14, 21, and 28 and measured hormone levels in whole milk by ELISA. Milk leptin levels were available for a subset of 18 infants. We calculated milk hormone doses by multiplying the hormone level by the milk volume ingested on each day and estimated the area under the curve (AUC) to reflect longitudinal exposure. We analyzed associations of milk hormone exposure with growth outcomes in generalized estimated equations. Main Outcome Measures Weight gain velocity and z-scores in weight, length, head circumference, and body mass index at 36 weeks’ postmenstrual age (PMA). Results Higher leptin intake was associated with greater weight gain (2.17g/kg/day [95% CI, 1.31, 3.02]) and weight z-score at 36 weeks’ PMA (0.30 [0.08, 0.53] higher z-score per tertile). Higher adiponectin intake was associated with greater length z-score (0.41 [0.13, 0.69]), however, this association was nullified after adjustment of protein and calorie intake. Higher adiponectin was associated with smaller head circumference z-score (−0.36 [−0.64, −0.07]). Insulin was not associated with growth outcomes. Conclusions Milk leptin and adiponectin exposures may affect growth of preterm infants. The long-term effects of milk hormones warrant further investigation.

In primates, the retinal ganglion cells contributing to high acuity spatial vision (midget cells and parasol cells), and blue-yellow color vision (small bistratified cells) are well understood. Many other ganglion cell types with large dendritic fields (named wide-field ganglion cells) have been identified, but their spatial density and distribution are largely unknown. Here we took advantage of the recently established molecular diversity of ganglion cells to study wide-field ganglion cell populations in three primate species. We used antibodies against the transcription factor Special AT-rich binding protein 2 (Satb2) to explore its expression in macaque (Macaca fascicularis, M. nemestrina), human and marmoset (Callithrix jacchus) retinas. In all three species, Satb2 cells make up a low proportion (1.5-4%) of the ganglion cell population, with a slight increase from central to peripheral retina. Intracellular dye injections revealed that in macaque and human retinas, the large majority (over 80%) of Satb2 cells are inner and outer stratifying large sparse cells. By contrast, in marmoset retina the majority (over 60%) of Satb2 expressing cells were broad thorny cells, with smaller proportions of recursive bistratified (putative direction-selective), large bistratified, and outer stratifying narrow thorny cells. Our findings imply that Satb2 expression has undergone rapid species specific adaptations during primate evolution, because expression is not conserved across Old World (macaque, human) and New World (marmoset) suborders.

Necrotizing enterocolitis (NEC) is a manifestation of maladaptive intestinal responses in preterm infants centrally medicated by unattenuated inflammation. Early in the postnatal period, preterm infants develop a deficit in arachidonic and docosahexaenoic acid, both potent regulators of inflammation. We hypothesized that the fatty acid composition of parenteral lipid emulsions uniquely induces blood and intestinal fatty acid profiles which, in turn, modifies the risk of NEC development. Forty-two preterm pigs were randomized to receive one of three lipid emulsions containing 100% soybean oil (SO), 15% fish oil (MO15), or 100% fish oil (FO100) with enteral feedings over an 8-day protocol. Blood and distal ileum tissue were collected for fatty acid analysis. The distal ileum underwent histologic, proteomic, and metabolomic analyses. Eight pigs [3/14 SO (21%), 3/14 MO15 (21%), and 2/14 FO100 (14%)] developed NEC. No differences in NEC risk were evident between groups despite differences in induced fatty acid profiles in blood and ileal tissue. Metabolomic analysis of NEC versus no NEC tissue revealed differences in tryptophan metabolism and arachidonic acid-containing glycerophospholipids. Proteomic analysis demonstrated no differences by lipid group; however, 15 proteins differentiated NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling. Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC development. Metabolomic and proteomic analyses of NEC versus no NEC intestinal tissue provide mechanistic insights into the pathogenesis of NEC in preterm infants. NEW & NOTEWORTHY Exposure to parenteral lipid emulsions induces unique intestinal fatty acid and metabolomic profiles; however, these profiles are not linked to a difference in NEC risk in preterm pigs. Metabolomic and proteomic analyses provide mechanistic insights into NEC pathogenesis. Compared with healthy ileal tissue, metabolites in tryptophan metabolism and arachidonic acid-containing glycerophospholipids are increased in NEC tissue. Proteomic analysis differentiates NEC versus no NEC in the domains of tissue injury, glucose uptake, and chemokine signaling.

Background: Smoking has been associated with mental disorders (MD). People who smoke are at a higher risk of contracting COVID-19 and experiencing more severe symptoms of the illness. This study aimed to investigate the relationship between cigarette smoking and MD before and during the COVID-19 pandemic and whether it was influenced by COVID-19-related stress in the MASH cohort. Methods: An ambispective design was used with data collected during the pandemic (July/August 2020) by the COVID-19-Related Worry Scale, a parameter for stress, and data collected at the participants’ last cohort visit before the pandemic (December 2019). Results: In our sample of 314 participants, 58.6% were living with HIV, 39.2% had MD, 52.5% smoked before, and 47.8% smoked during the pandemic. Participants with MD were twice as likely to smoke cigarettes both before (aOR = 2.02, 95% CI: 1.21–3.37, p = 0.007) and during the pandemic (aOR = 2.10, 95% CI: 1.24–3.56, p = 0.006); and experienced higher levels of stress measured by the COVID-19-Related Worry Scale (8.59 [5.0–10.0] vs. 7.65 [5.0–10.0]; p = 0.026) compared to those without MD. Participants with MD and high levels of stress smoked more days per month (20.1 [0–30] days) than those with lower levels of stress (9.2 [0–30] days, p = 0.021), and more than those with high levels of stress, but no MD (2.6 [0–30] days, p < 0.001). Conclusions: Cigarette smoking decreased in the MASH cohort during the pandemic, but increased in participants with MD and higher levels of stress.

Clinical and molecular heterogeneity are common features of human disease. Understanding the basis for heterogeneity has led to major advances in therapy for many cancers and pulmonary diseases such as cystic fibrosis and asthma. Although heterogeneity of risk factors, disease severity, and outcomes in survivors are common features of the acute respiratory distress syndrome (ARDS), many challenges exist in understanding the clinical and molecular basis for disease heterogeneity and using heterogeneity to tailor therapy for individual patients. This report summarizes the proceedings of the 2021 Aspen Lung Conference, which was organized to review key issues related to understanding clinical and molecular heterogeneity in ARDS. The goals were to review new information about ARDS phenotypes, to explore multicellular and multisystem mechanisms responsible for heterogeneity, and to review how best to account for clinical and molecular heterogeneity in clinical trial design and assessment of outcomes. The report concludes with recommendations for future research to understand the clinical and basic mechanisms underlying heterogeneity in ARDS to advance the development of new treatments for this life-threatening critical illness.

Amebiasis, a disease caused by the parasite Entamoeba histolytica, is estimated to cause millions of infections and at least 55,000 deaths globally each year. With no vaccine currently available, there is an urgent need for an accessible means of stimulating protective mucosal immunity. The objective of this study was to characterize the nasal spray of a novel amebiasis vaccine candidate from a syringe-based liquid atomization device, the Teleflex MAD Nasal™, in both adult and infant nasal airways. Human ergonomic testing was completed to determine realistic actuation parameters. Spray pattern, plume geometry, and droplet size distribution were measured to evaluate reproducibility of free plume characteristics. The Alberta Idealized Nasal Inlet (AINI) and three realistic infant nasal airways were used to determine the in vitro deposition profile in adult and infant airways, respectively. Collectively, in vitro results demonstrated the feasibility of delivering the vaccine candidate to target sites within the nasal airways. Penetration through the nasal airways that could lead to deposition in the lungs was below the limit of quantification for both adult and infant geometries, indicating a low likelihood of adverse events due to lung exposure. These results support continued investigation of intranasal delivery of the synthetic Entamoeba histolytica vaccine.

Polygenic risk scores (PRS) estimate an individual's genetic likelihood of complex traits and diseases by aggregating information across multiple genetic variants identified from genome-wide association studies. PRS can predict a broad spectrum of diseases and have therefore been widely used in research settings. Some work has investigated their potential applications as biomarkers in preventative medicine, but significant work is still needed to definitively establish and communicate absolute risk to patients for genetic and modifiable risk factors across demographic groups. However, the biggest limitation of PRS currently is that they show poor generalizability across diverse ancestries and cohorts. Major efforts are underway through methodological development and data generation initiatives to improve their generalizability. This review aims to comprehensively discuss current progress on the development of PRS, the factors that affect their generalizability, and promising areas for improving their accuracy, portability, and implementation.