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Rural residence has been identified as a risk factor for suicide, especially for men. Little qualitative research exists on rural suicide, which might help deepen understandings of prevention strategies within rural places. Therefore, virtual focus groups were held across six Canadian provinces to give voice to rural community members and service workers about suicide prevention. Barriers to accessing services and the need to strengthen rural support networks were discussed. Enhancing peer support was highlighted as a strategy to better address the needs of rural Canadians.

Posttraumatic stress disorder (PTSD) and traumatic brain injury (TBI) demonstrate high prevalence and comorbidity among post-9/11 veterans. Veterans with this comorbidity often present with multiple co-occurring healthcare needs and increased clinical complexity. The current case report describes the clinical presentation of a veteran with mild TBI and PTSD, both before, during, and after treatment within a multidisciplinary 2-week intensive outpatient program involving prolonged exposure, evidence-based PTSD treatment, and Cognitive Symptom Management and Rehabilitation Therapy, evidence-based treatment for postconcussive symptoms. Mr. A was a 25-year-old White, transgender male who presented with a complex mental health history. At intake, presenting complaints included anxiety, panic attacks, nightmares, and depression secondary to military sexual trauma, as well as reported cognitive difficulties secondary to a concussion. He met current criteria for PTSD as well as panic disorder with agoraphobia. Head injury history consisted of a motor vehicle collision with less than 30 seconds loss of consciousness, brief posttraumatic amnesia, and alterations of consciousness. Mr. A demonstrated habituation during individual exposure sessions as assessed via skin conductance during imaginal exposures and decreased subjective ratings during in vivo exposures, as well as a decrease in trauma-potentiated startle response to trauma cues. Posttreatment data indicates significant reduction in neurobehavioral, posttraumatic stress, and depression symptoms and significant improvement in subjective cognitive functioning. The current findings support the feasibility and efficacy of short-term integrated treatment for complex clinical presentations and the need for larger scale research investigating combined PTSD and TBI intervention.

A scoping review of research about suicidality in rural and remote Canadian communities, published between 2009 and July 2020 was conducted by searching Embase, Medline, CINAHL, PsychInfo, SocIndex, Geobase, and PsycArticles databases. Included articles were reviewed and charted using data extraction. Thirty-nine Canadian, non-Indigenous articles met inclusion. Most publications were based on quantitative research (23). Apart from one intervention study, articles were prevention focused, with suicidality risk and protective factors noted to be of particular interests. The most frequently referenced suicidality risk factor was rural residence. It is anticipated that results of this review will inform future research, particularly the need to include qualitative and mixed methodologies, protocol, and evaluations of interventions as well as postvention research, with further consideration of different Canadian settings and populations.

Die systematische Auswertung („Review“) und Metaanalyse der Ergebnisse kontrollierter klinischer Studien gilt als „Goldstandard“ der evidenzbasierten Medizin und kann dennoch zu unterschiedlichen und sogar vermeintlich widersprüchlichen Ergebnissen führen. Die folgenden Ausführungen sollen helfen, systematische Reviews zur multidisziplinären Rehabilitation korrekt zu interpretieren, um kritische Schlussfolgerungen für die klinische Praxis zu ermöglichen.

The blood-brain barrier (BBB) is an essential gatekeeper for the central nervous system and incidence of neurodevelopmental disorders (NDDs) is higher in infants with a history of intracerebral hemorrhage (ICH). We discovered a rare disease trait in thirteen individuals, including four fetuses, from eight unrelated families associated with homozygous loss-of-function variant alleles of ESAM which encodes an endothelial cell adhesion molecule. The c.115del (p.Arg39Glyfs∗33) variant, identified in six individuals from four independent families of Southeastern Anatolia, severely impaired the in vitro tubulogenic process of endothelial colony-forming cells, recapitulating previous evidence in null mice, and caused lack of ESAM expression in the capillary endothelial cells of damaged brain. Affected individuals with bi-allelic ESAM variants showed profound global developmental delay/unspecified intellectual disability, epilepsy, absent or severely delayed speech, varying degrees of spasticity, ventriculomegaly, and ICH/cerebral calcifications, the latter being also observed in the fetuses. Phenotypic traits observed in individuals with bi-allelic ESAM variants overlap very closely with other known conditions characterized by endothelial dysfunction due to mutation of genes encoding tight junction molecules. Our findings emphasize the role of brain endothelial dysfunction in NDDs and contribute to the expansion of an emerging group of diseases that we propose to rename as “tightjunctionopathies.”

INTRODUCTION Swiss national recommendations advise, since end of 2018, supporting women with HIV who wish to breastfeed. Our objective is to describe the motivational factors and the outcome of these women and of their infants. METHODS mothers included in MoCHiV with a delivery between January 2019 and February 2021 who fulfilled the criteria of the "optimal scenario" (adherence to cART, regular clinical care, and suppressed HIV plasma viral load (pVL) of

von Willebrand factor (VWF) is a multimeric protein, the size of which is regulated via ADAMTS13-mediated proteolysis within the A2 domain. We aimed to isolate nanobodies distinguishing between proteolyzed and non-proteolyzed VWF, leading to the identification of a nanobody (designated KB-VWF-D3.1) targeting the A3 domain, the epitope of which overlaps the collagen-binding site. Although KB-VWF-D3.1 binds with similar efficiency to dimeric and multimeric derivatives of VWF, binding to VWF was lost upon proteolysis by ADAMTS13, suggesting that proteolysis in the A2 domain modulates exposure of its epitope in the A3 domain. We therefore used KB-VWF-D3.1 to monitor VWF degradation in plasma samples. Spiking experiments showed that a loss of 10% intact VWF could be detected using this nanobody. By comparing plasma from volunteers to that from congenital von Willebrand disease (VWD) patients, intact-VWF levels were significantly reduced for all VWD types, and most severely in VWD type 2A–group 2, in which mutations promote ADAMTS13-mediated proteolysis. Unexpectedly, we also observed increased proteolysis in some patients with VWD type 1 and VWD type 2M. A significant correlation (r = 0.51, P < .0001) between the relative amount of high–molecular weight multimers and levels of intact VWF was observed. Reduced levels of intact VWF were further found in plasmas from patients with severe aortic stenosis and patients receiving mechanical circulatory support. KB-VWF-D3.1 is thus a nanobody that detects changes in the exposure of its epitope within the collagen-binding site of the A3 domain. In view of its unique characteristics, it has the potential to be used as a diagnostic tool to investigate whether a loss of larger multimers is due to ADAMTS13-mediated proteolysis.

We investigate the state complexity of languages resulting from the cascade product of two minimal deterministic finite automata with [Formula: see text] and [Formula: see text] states, respectively. More precisely we study the magic number problem of the cascade product operation and show what range of complexities can be produced in case the left automaton is unary, that is, has only a singleton letter alphabet. Here we distinguish the cases when the involved automata are reset automata, permutation automata, permutation-reset automata, or do not have any restriction on their structure. It turns out that the picture on the obtained state complexities of the cascade product is diverse, and for all cases, except where the left automaton is a unary permutation(-reset) or a deterministic finite automaton without structural restrictions, and the right one is a reset automaton or a deterministic finite automaton without structural restrictions, we are able to identify state sizes that cannot be reached — these numbers are called “magic.”

BACKGROUND AND OBJECTIVES Inequities in pediatric illness include unequal treatment and outcomes for children of historically marginalized races/ethnicities. Length of stay (LOS) is used to assess health care quality and is associated with higher costs/complications. Studies show LOS disparities for Black and Hispanic children in specific diagnoses, but it is unclear how broadly they exist or how they change over time. We examined the association between race/ethnicity and LOS longitudinally for the most common pediatric inpatient diagnoses. METHODS We used the 2016 and 2019 Kids’ Inpatient Databases. The 10 most frequent diagnoses in 2016 were determined. For each diagnosis in each year, we assessed the association between race and LOS by fitting a generalized linear mixed effects model with a negative binomial distribution, accounting for clustering and confounding. Using descriptive statistics, we compared associations between the 2 years for trends over time. RESULTS Our analysis included >450 000 admissions and revealed significantly longer LOS for Black, Hispanic, and/or Asian American or Pacific Islander, Native American, and other children in 8 of the 10 diagnoses in 2016, with mixed changes over time. Three new disparities emerged in 2019. The largest disparities were for Black children in most diagnoses. CONCLUSIONS Kids’ Inpatient Database data showed longer LOS for children of historically marginalized race/ethnicity with common pediatric inpatient diagnoses, which largely persisted from 2016 to 2019. There is no plausible biological explanation for these findings, and inequities in social needs, access to care, and quality of care likely contribute. Future directions include further study to understand and address contributing factors.

Background In the context of the ongoing COVID-19 pandemic, rapid transitions have been made towards telehealth. Optimal use of telehealth in elderly patients remains poorly understood and adaptation challenges persist. Our study aimed at identifying perceptions, barriers, and possible facilitators to telehealth use amongst elderly patients with comorbidities, their caregivers, and health-care providers (HCPs). Methods Health-care providers, patients 65 years and older with multiple comorbidities, and caregivers were recruited from outpatient clinics and invited to complete an electronic self-administered or telephone-administered survey on their perceptions of telehealth and of barriers to its implementation. Results A total of 39 health-care providers, 40 patients, and 22 care-givers responded to the survey. Most patients (90%), caregivers (82%), and HCPs (97%) had experienced telephone visits, but few were conducted via videoconference platforms. Patients and caregivers showed interest in pursuing some future telehealth visits (68%, 86%, respectively), but felt they lacked access to technology and skills (n=8, 20%), and some felt that telehealth visits may be inferior to in-person visits (n=9, 23%). HCPs showed interest in incorporating telehealth visits into practice (n=32, 82%), but identified challenges in lack of administrative support (n=37), lack of HCP (n=28) and patient (n=37) technological skills, and limited infrastructure (n=37)/internet access (n=33). Conclusions Older patients, caregivers, and HCPs show interest in pursuing future telehealth visits but elucidate similar barriers. Facilitating access to technology, as well as to administrative and technology support guides, could promote high quality and equal access to virtual care for the older adult.

This paper presents a method for integrating industrial consumers owning compensation systems as alternative reactive power sources into grid operating processes. In remuneration, they receive a market-based provision of reactive power. The aim is to analyze the potential of reactive power compensation systems of industrial companies connected to medium-voltage (10 kV–30 kV) AC grids in order to increase the reactive power ability of distribution grids. Measurement methods and reactive power potential results of six industrial companies are presented to characterize the amount and temporal availability of their reactive power potential. The presented approach for using the decentralized reactive power potential is a centralized reactive power control method and is based on optimal power flow (OPF) calculations. An optimization algorithm based on linear programming is used to coordinate a reactive power retrieval tuned to the actual demand. The influencing quantities are the current grid status (voltage and load flow capacity reserves at grid nodes and power lines) and the current reactive power potential of the reactive power sources. The compensation impact of six measured industrial companies on an exemplary medium-voltage grid is shown by an application example.

PURPOSE Triple-negative breast cancer (TNBC) is a heterogeneous disease with variable response to neoadjuvant therapy (NAT). Pathologic complete response (pCR) has become a prognostic marker for overall and disease-free survival. The aim of this study was to determine if dynamic contrast-enhanced (DCE)-MRI after 2 and/or 4 cycles of NAT can identify patients with a high likelihood of achieving pCR, triaging them to standard of care (SOC), or, when appropriate, to de-escalation trials. Conversely, we aimed to identify chemoresistant tumors that are unlikely to achieve pCR and may benefit from escalated targeted trials. METHOD AND MATERIALS 309 patients with stage I-III TNBC underwent DCE-MRI (temporal resolution: 9-12 sec) at baseline (BL), 2 cycles (C2), and 4 cycles (C4) of SOC doxorubicin/cyclophosphamide (AC) NAT as part of a prospective IRB-approved study (NCT02276443). Tumor volumes of the index lesion were calculated using 3 axis measurements during the early phase of the DCE-MRI (60s). Percent tumor volume reduction (TVR) between BL, C2, and C4 was calculated. Patients were randomly assigned to a training or a validation cohort in a 1:1 ratio. pCR was assessed at surgery after completion of SOC NAT. Correlation between pCR and TVR was evaluated using ROC analysis. RESULTS Of 309 TNBC patients, 136 (44%) achieved pCR. Following 2 cycles of NAT, TVR >80% was predictive of pCR (chemosensitivity), while TVR ≤ 55% was predictive of non-pCR (chemoresistance) with PPV 80%, NPV 89%, AUC 0.811 (0.73~0.893, p< 0.0001) in the training cohort, and PPV 82%, NPV 85%, AUC 0.815 (CI:0.736~0.894, p< 0.0001) in the validation cohort. Following 4 cycles of NAT, TVR >90% was predictive of pCR, while TVR ≤80% was predictive of non-pCR with PPV 80%, NPV 84%, AUC 0.827 (0.756~0.898, p< 0.0001) in the training cohort and with PPV 73%, NPV 82%, AUC 0.785 (CI:0.709~0.862, p< 0.001) in the validation cohort. Using this model, the pCR status was correctly classified in 50% of TNBC patients using C2 DCE-MRI in the training cohort, and 54% in the validation cohort. Only 8% were misclassified in the training cohort, and 10% in the validation cohort. Using C4 DCE-MRI, the pCR status of 61% and 57% of TNBC was correctly classified in the validation and the testing cohorts, respectively. 12% were misclassified in the validation cohort, and 21% in the testing cohort. CONCLUSION DCE-MRI after 2 and 4 cycles of AC-based NAT correctly predicted the pCR status of 54% and 57% of TNBC patients, respectively, as either excellent responders or nonresponders with high AUC 0.811 and 0.827. This may allow patients to be triaged to SOC NAT with option of de-escalation or early targeted therapies for non-responders. Citation Format: Mary S. Guirguis, Beatriz Adrada, Miral Patel, Frances Perez, Rosalind Candelaria, Wei Yang, Jia Sun, Rania M. Mohamed, Medine Boge, H. T. Carisa Le-Petross, Jessica Leung, Gary J. Whitman, Deanna L. Lane, Marion E. Scoggins, Tanya Moseley, Benjamin Musall, Jason White, Sanaz Pashapoor, Peng Wei, Jong Bum Son, Ken-Pin Hwang, Bikash Panthi, Mark Pagel, Lei Huo, Kelly K. Hunt, Elizabeth Ravenberg, Alastair M. Thompson, Jennifer K. Litton, Vicente Valero, Debu Tripathy, Stacy Moulder, Clinton Yam, Jingfei Ma, Gaiane Rauch. DCE-MRI for early prediction of excellent response versus chemoresistance in triple negative breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-05-15.

To derive and initially validate a brief bedside clinical decision support tool that identifies emergency department patients at high risk of substantial, persistent posttraumatic stress symptoms after a motor vehicle collision.Derivation (n=1,282, 19 ED sites) and validation (n=282, 11 separate ED sites) data were obtained from adults prospectively enrolled in the Advancing Understanding of RecOvery afteR traumA study who were discharged from the ED after motor vehicle collision-related trauma. The primary outcome was substantial posttraumatic stress symptoms at 3 months (Posttraumatic Stress Disorder Checklist for Diagnostic and Statistical Manual of Mental Disorders-5 ≥38). Logistic regression derivation models were evaluated for discriminative ability using the area under the curve and the accuracy of predicted risk probabilities (Brier score). Candidate posttraumatic stress predictors assessed in these models (n=265) spanned a range of sociodemographic, baseline health, peritraumatic, and mechanistic domains. The final model selection was based on performance and ease of administration.Significant 3-month posttraumatic stress symptoms were common in the derivation (27%) and validation (26%) cohort. The area under the curve and Brier score of the final 8-question tool were 0.82 and 0.14 in the derivation cohort and 0.76 and 0.17 in the validation cohort.This simple 8-question tool demonstrates promise to risk-stratify individuals with substantial posttraumatic stress symptoms who are discharged to home after a motor vehicle collision. Both external validation of this instrument, and work to further develop more accurate tools, are needed. Such tools might benefit public health by enabling the conduct of preventive intervention trials and assisting the growing number of EDs that provide services to trauma survivors aimed at promoting psychological recovery.

Background: In breast cancer patients, neoadjuvant chemotherapy (NAC) allows to obtain pathological complete response (pCR). In case of initially involved node before NAC, pCR after NAC could make it possible to avoid axillary surgery. The aim of our study was to address parameters to build a tool able to accurately select patients at a high probability of axillary pCR after NAC. Method: GANEA 3 was a French prospective multi institutional cohorts of breast cancer patients with a proven axillary involved node treated with NAC (NCT03630913). Initially involved node was clipped before treatment. Each patient received, before and after NAC, a bilateral mammography, a Magnetic Resonance Imaging (MRI), an axillary sonography. After NAC breast, conservative or radical, and axillary surgery, were performed. Breast surgery allowed to measure breast tumor residual and to perform a Sataloff classification. Targeted axillary detection (TAD) was defined as the combination of the resection of the clipped node and SLN dissection. Axillary clipped node, sentinel lymph node (SLN) and axillary lymph node dissection (ALND) were always performed. ALND allowed to assess the false negative rate (FNR) of axillary clipped node and SLN dissection. A total of 500 included patients is planned to close this still ongoing trial. Results : From January 2019 to March 2022, 405 patients were included from 18 institutions. We present here the results of the 260 first patients, who experienced a complete treatment with NAC courses and post NAC breast and axillary surgery. Among these patients, SBR grade was III in 52%, OR and PR were positive in 59% and 46% respectively, HER2 was overexpressed in 40%, 26% were triple negative and pCR was present in 28%. FNR of the SLN detection was 21.1%, 9% for the clipped node alone and 6% for the TAD. Histopronostic grading, progesteron receptors, HER2 expression, MRI results and Sataloff grading of breast residual tumor were indepently linked with global pCR (breast and axilla) in multivariate analysis. The Area Under the Curve (AUC) model was 0.91 with 82% correctly patients classified. The false negative rate of no pCR classified patients was 14%. Conclusion : Intermediate results of Ganea 3 trial showed that operable breast cancer patients with an initially involved axillary node treated with NAC, showed that TAD allows to reduce the FNR of axillary surgery. Patients with histopronostic grade 3, negative progesteron receptors, HER2 overexpression, a normal MRI after NAC and a breast Sataloff A, have a low risk of axillary tumour residual burden and could be safely spare from any axillary surgery. Large prospective trials are needed to confirm the safety of this surgical de-escalation. Citation Format: Céline Renaudeau, Pierre Gimbergues, Eugénie Guillot, Marie-Pierre Chauvet, Marian Gutowski, Eva Jouve, Philippe Rauch, Monique Cohen, Christelle Faure, Marie-Martine Padeano, Vivien Ceccato, Catherine Uzan, Anne-Sophie Bats, Hélène Charitansky, Pierre-François Dupré, Augustin Reynard, Séverine Alran, Cécile Bendavid-Athias, Loïc Campion, Isabelle Doutriaux, Jean-Marc Classe. Axillary surgery de-escalation after neoadjuvant chemotherapy in breast cancer patients with initially involved node: the GANEA 3 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT1-09-01.

Osteocytes act as bone mechanosensors, regulators of osteoblast/osteoclast activity and mineral homeostasis, however, knowledge about their functional/morphological changes throughout life is limited. We used quantitative backscattered electron imaging (qBEI) to investigate osteocyte lacunae sections (OLS) as a 2D-surrogate characterizing the osteocytes. OLS characteristics, the density of mineralized osteocyte lacunae (i.e., micropetrotic osteocytes, md.OLS-Density in nb/mm

While intravascular imaging guidance during percutaneous coronary intervention (PCI) improves outcomes, routine intravascular imaging usage remains low, in part due to perceived inefficiency and safety concerns.The LightLab (LL) Initiative was designed to evaluate whether implementing a standardised optical coherence tomography (OCT) workflow impacts PCI safety metrics and procedural efficiency.In this multicentre, prospective, observational study, PCI procedural data were collected over 2 years from 45 physicians at 17 US centres. OCT-guided PCI incorporating the LL workflow (N=264), a structured algorithm using routine pre- and post-PCI OCT imaging, was compared with baseline angiography-only PCI (angio) (N=428). Propensity score analysis identified 207 matched procedures. Outcomes included procedure time, radiation exposure, contrast volume, device utilisation, and treatment strategy.Compared with angiography alone, LL workflow OCT-guided PCI increased the median procedural time by 9 minutes but reduced vessel preparation time (2 min LL workflow vs 3 min angio; p0.001) and resulted in less unplanned additional treatment (4% LL workflow vs 10% angio; p=0.01). With LL workflow OCT guidance, fewer cineangiography views were needed compared to angiography guidance, leading to decreased radiation exposure (1,133 mGy LL workflow vs 1,269 mGy angio; p=0.02), with no difference in contrast utilisation between groups (p=0.28). Furthermore, LL workflow OCT guidance resulted in fewer predilatation balloons and stents being used, more direct stent placement, and greater stent post-dilatation than angiography-guided PCI.The incorporation of a standardised pre- and post-PCI OCT imaging workflow improves procedural efficiency and safety metrics, at a cost of a modestly longer procedure time.

Coronavirus disease-19 (COVID-19) is still affecting the lives of people round the globe and remains a major public health threat. The emergence of new variants more efficiently transmitted, more virulent and more capable of escaping naturally acquired and vaccine-induced immunity creates a long-term negative outlook for the management of the pandemic. The development of effective and viable prevention and treatment options to reduce viral transmission is of the utmost importance. The fruits of the European black elderberry and extracts thereof have been traditionally used to treat viral infections such as coughs, cold and flu. Specifically, its efficacy against the Influenza A virus has been shown in vitro as well as in human clinical trials. In the current project, we investigated the antiviral activity of a black elderberry extract, mainly containing anthocyanins and phenolic compounds, against SARS-CoV-2 and its variants of concern and explored the possible mode of action by performing time of addition experiments. The results revealed that the extract displayed a strong anti-SARS-CoV-2 activity against the Wuhan type as well as the variants of concern Alpha, Beta, Gamma, Delta and Omicron with a comparable antiviral activity. Based on cytotoxicity data, a 2-log theoretical therapeutic window was established. The data accumulated so far suggest that the viral replication cycle is inhibited at later stages, inasmuch as the replication process was affected after virus entry. Therefore, it would be legitimate to assume that black elderberry extract might have the potential to be an effective treatment option for SARS-CoV-2 infections.

Embedded validity indicators (EVIs) derived from motor tests have received less empirical attention than those derived from tests of other neuropsychological abilities, particularly memory. Preliminary evidence suggests that the Grooved Pegboard Test (GPB) may function as an EVI, but existing studies were largely conducted using simulators and population samples without cognitive impairment. In this study we aimed to evaluate the GPB’s classification accuracy as an EVI among a mixed clinical neuropsychiatric sample with and without cognitive impairment. This cross-sectional study comprised 223 patients clinically referred for neuropsychological testing. GPB raw and T-scores for both dominant and nondominant hands were examined as EVIs. A known-groups design, based on ≤1 failure on a battery of validated, independent criterion PVTs, showed that GPB performance differed significantly by validity group. Within the valid group, receiver operating characteristic curve analyses revealed that only the dominant hand raw score displayed acceptable classification accuracy for detecting invalid performance (area under curve [AUC] = .72), with an optimal cut-score of ≥106 seconds (33% sensitivity/88% specificity). All other scores had marginally lower classification accuracy (AUCs = .65–.68) for differentiating valid from invalid performers. Therefore, the GPB demonstrated limited utility as an EVI in a clinical sample containing patients with bona fide cognitive impairment.

There is a bidirectional relationship between poor sleep and both mood- and anxiety-related disorders, which are among leading global health concerns. Additionally, both disordered sleep and these psychiatric disorders appear to be independently associated with altered autonomic nervous system (ANS) function. We hypothesise that ANS dysregulation during sleep may explain part of the relationship between poor sleep and mood- and anxiety-related disorders. Heart rate variability (HRV) is a frequently used marker of ANS function and gives an indication of ANS input to the heart - in particular, of the relative contributions of sympathetic and parasympathetic activity. A systematic review of PubMed, Scopus and Web of Science yielded 41 studies dealing with sleep, mood- and anxiety-related disorders and sleep-related HRV. Hyperarousal during sleep, reflecting a predominance of sympathetic activation and indicative of ANS dysregulation, may be an important factor in the association between poor sleep and mood-related disorders. Longitudinal studies and mediation analyses are necessary to further understand the potential mediating role of ANS dysregulation on the relationship between poor sleep and mood- and anxiety-related disorders.

This paper reports on a demonstration of YAMZ (Yet Another Metadata Zoo) as a mechanism for building community consensus around metadata terms. The demonstration is motivated by the complexity of the metadata standards environment and the need for more user-friendly approaches for researchers to achieve vocabulary consensus. The paper reviews a series of metadata standardization challenges, explores crowdsourcing factors that offer possible solutions, and introduces the YAMZ system. A YAMZ demonstration is presented with members of the Toberer materials science laboratory at the Colorado School of Mines, where there is a need to confirm and maintain a shared understanding for the vocabulary supporting research documentation, data management, and their larger metadata infrastructure. The demonstration involves three key steps: 1) Sampling terms for the demonstration, 2) Engaging graduate student researchers in the demonstration, and 3) Reflecting on the demonstration. The results of these steps, including examples of the dialog provenance among lab members and voting, show the ease with YAMZ can facilitate building metadata vocabulary consensus. The conclusion discusses implications and highlights next steps.

The study aimed to determine the effects of two differing amino acid beverage interventions on biomarkers of intestinal epithelial integrity and systemic inflammation in response to an exertional-heat stress challenge. One week after the initial assessment, participants (n = 20) were randomly allocated to complete two exertional-heat stress trials, with at least 1 week washout. Trials included a water control trial (CON), and one of two possible amino acid beverage intervention trials (VS001 or VS006). On VS001 (4.5 g/L) and VS006 (6.4 g/L), participants were asked to consume two 237-ml prefabricated doses daily for 7 days before the exertional-heat stress, and one 237-ml dose immediately before, and every 20 min during 2-hr running at 60% maximal oxygen uptake in 35 °C ambient conditions. A water volume equivalent was provided on CON. Whole blood samples were collected pre-, immediately post-, 1 and 2 hr postexercise, and analyzed for plasma concentrations of cortisol, intestinal fatty acid protein, soluble CD14, and immunoglobulin M (IgM) by ELISA, and systemic inflammatory cytokines by multiplex. Preexercise resting biomarker concentrations for all variables did not significantly differ between trials (p > .05). A lower response magnitude for intestinal fatty acid protein (mean [95% CI]: 249 [60, 437] pg/ml, 900 [464, 1,336] pg/ml), soluble CD14 (−93 [−458, 272] ng/ml, 12 [−174, 197] ng/ml), and IgM (−6.5 [−23.0, 9.9] MMU/ml, −10.4 [−16.2, 4.7] MMU/ml) were observed on VS001 and V006 compared with CON (p p

Short stature is common in osteogenesis imperfecta (OI) and is usually severe in OI types III and IV. The characteristics of pubertal growth in OI have not been studied in detail.We assessed 82 individuals with OI caused by pathogenic variants in COL1A1 or COL1A2 who had annual height data between 6 and 16 years of age at a minimum. Height velocity curves were fitted to each individual's height data to describe the pubertal growth spurt.Curve fitting was successful in 30 of the 33 individuals with OI type I (91%), in 23 of the 32 individuals with OI type IV (72%), and in 4 of the 17 participants with OI type III (24%). Pubertal growth spurt could be identified in most individuals with OI types I and IV, but rarely in OI type III. The timing of the pubertal growth spurt was similar between OI types I and IV in both sexes. However, height velocity was consistently higher in OI type I, leading to a widening height gap between OI types I and IV.A pubertal growth spurt was present in most individuals with OI types I and IV, but rarely in OI type III.

RAF kinases play major roles in cancer. BRAFV600E mutants drive ~6% of human cancers. Potent kinase inhibitors exist but show variable effects in different cancer types, sometimes even inducing paradoxical RAF kinase activation. Both paradoxical activation and drug resistance are frequently due to enhanced dimerization between RAF1 and BRAF, which maintains or restores the activity of the downstream MEK-ERK pathway. Here, using quantitative proteomics we mapped the interactomes of RAF1 monomers, RAF1-BRAF and RAF1-BRAFV600E dimers identifying and quantifying >1,000 proteins. In addition, we examined the effects of vemurafenib and sorafenib, two different types of clinically used RAF inhibitors. Using regression analysis to compare different conditions we found a large overlapping core interactome but also distinct condition specific differences. Given that RAF proteins have kinase independent functions such dynamic interactome changes could contribute to their functional diversification. Analysing this dataset may provide a deeper understanding of RAF signalling and mechanisms of resistance to RAF inhibitors.

Dissociation, a disruption or discontinuity in psychological functioning, is often linked with worse psychiatric symptoms; however, the prognostic value of dissociation after trauma is inconsistent. Determining whether trauma-related dissociation is uniquely predictive of later outcomes would enable early identification of at-risk trauma populations. The authors conducted the largest prospective longitudinal biomarker study of persistent dissociation to date to determine its predictive capacity for adverse psychiatric outcomes following acute trauma.All data were part of the Freeze 2 data release from the Advancing Understanding of Recovery After Trauma (AURORA) study. Study participants provided self-report data about persistent derealization (N=1,464), a severe type of dissociation, and completed a functional MRI emotion reactivity task and resting-state scan 2 weeks posttrauma (N=145). Three-month follow-up reports were collected of posttraumatic stress, depression, pain, anxiety symptoms, and functional impairment.Derealization was associated with increased ventromedial prefrontal cortex (vmPFC) activation in the emotion reactivity task and decreased resting-state vmPFC connectivity with the cerebellum and orbitofrontal cortex. In separate analyses, brain-based and self-report measures of persistent derealization at 2 weeks predicted worse 3-month posttraumatic stress symptoms, distinct from the effects of childhood maltreatment history and current posttraumatic stress symptoms.The findings suggest that persistent derealization is both an early psychological and biological marker of worse later psychiatric outcomes. The neural correlates of trauma-related dissociation may serve as potential targets for treatment engagement to prevent posttraumatic stress disorder. These results underscore dissociation assessment as crucial following trauma exposure to identify at-risk individuals, and they highlight an unmet clinical need for tailored early interventions.

PurposeYouth are vulnerable to poor mental health outcomes during emerging adulthood. This study examined COVID-19 pandemic effects among young Latino adults and changes in anxiety and depressive symptoms.MethodsUsing data from 309 individuals, predominantly of Mexican origin, we examined anxiety and depressive symptoms (before and during COVID) to determine whether mental health worsened during this period. We also examined associations between specific pandemic-related stressors and mental health. Analyses used paired T-tests and linear regressions. Participant sex was included as a moderator. We corrected for multiple comparisons using the Benjamini-Hochberg method.ResultsDuring the 2-year time period, depressive symptoms increased while anxiety symptoms decreased. There were no significant stressor by sex interactions; however, exploratory analyses signaled that pandemic-related stressors had stronger mental health effects for young women.DiscussionYoung adults' depressive and anxiety symptoms changed during the pandemic, and pandemic-related stressors were associated with increases in mental health symptoms.

BACKGROUND: Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear-induced proteolysis of von Willebrand factor (VWF) by ADAMTS13 (A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired haemostasis which could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti-ADAMTS13 monoclonal antibody (mAb) that inhibits the shear-induced proteolysis of VWF by ADAMTS13. METHODS: Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti-ADAMTS13 mAb 3H9 or 17C7 (20 μg/mL) or control anti-ADAMTS13 mAb 5C11 or PBS. VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella® pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13 and blood parameters were determined. RESULTS: We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella®-induced aVWS calf model. CONCLUSION: Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients.

A third vaccine dose is often required to achieve potent, long-lasting immune responses. We investigated the effect of three 8-μg doses of CVnCoV, CureVac's severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine candidate containing sequence-optimized unmodified mRNA encoding the spike (S) glycoprotein, administered at 0, 4, and 28 weeks, on immune responses in rhesus macaques. After the third dose, S-specific binding and neutralizing antibodies increased 50-fold compared with post-dose 2 levels, with increased responses also evident in the lower airways and against the SARS-CoV-2 B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), and B.1.617.2 (Delta) variants. Enhanced binding affinity of serum antibodies after the third dose correlated with higher somatic hypermutation in S-specific B cells, corresponding with improved binding properties of monoclonal antibodies expressed from isolated B cells. Administration of low-dose mRNA led to fewer cells expressing antigen

Trauma-informed beliefs often decrease during posttraumatic stress disorder (PTSD) treatment. This may also extend to anxiety sensitivity (AS), defined as a fear of anxiety-related sensations and beliefs that anxiety is dangerous and/or intolerable. However, little is known about how AS changes during exposure-based and psychopharmacological PTSD treatments. Further, high AS may be a risk factor for diminished PTSD symptom improvement and increased treatment dropout. To better understand how AS impacts and is impacted by PTSD treatment, we conducted a secondary analysis of a randomized clinical trial with a sample of 223 veterans (87.0% male, 57.5% White) with PTSD from four U.S. sites. Veterans were randomized to receive prolonged exposure (PE) plus placebo (n = 74), sertraline plus enhanced medication management (n = 74), or PE plus sertraline (n = 75). Veterans answered questions about PTSD symptoms and AS at baseline and 6-, 12-, 24-, 36-, and 52-week follow-ups. High baseline AS was related to high levels of PTSD severity at 24 weeks across all conditions, β = .244, p = .013, but did not predict dropout from exposure-based, β = .077, p = .374, or psychopharmacological therapy, β = .009, p = .893. AS also significantly decreased across all three treatment arms, with no between-group differences; these reductions were maintained at the 52-week follow-up. These findings suggest that high AS is a risk factor for attenuated PTSD treatment response but also provide evidence that AS can be improved by both PE and an enhanced psychopharmacological intervention for PTSD.

Background Despite effective prevention approaches, ongoing human immunodeficiency virus 1 (HIV-1) transmission remains a public health concern indicating a need for identifying its drivers. Methods We combined a network-based clustering method using evolutionary distances between viral sequences with statistical learning approaches to investigate the dynamics of HIV transmission in the Swiss HIV Cohort Study and to predict the drivers of ongoing transmission. Results We found that only a minority of clusters and patients acquired links to new infections between 2007 and 2020. While the growth of clusters and the probability of individual patients acquiring new links in the transmission network was associated with epidemiological, behavioral, and virological predictors, the strength of these associations decreased substantially when adjusting for network characteristics. Thus, these network characteristics can capture major heterogeneities beyond classical epidemiological parameters. When modeling the probability of a newly diagnosed patient being linked with future infections, we found that the best predictive performance (median area under the curve receiver operating characteristic AUCROC = 0.77) was achieved by models including characteristics of the network as predictors and that models excluding them performed substantially worse (median AUCROC = 0.54). Conclusions These results highlight the utility of molecular epidemiology-based network approaches for analyzing and predicting ongoing HIV transmission dynamics. This approach may serve for real-time prospective assessment of HIV transmission.