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Conservation programs worldwide pursue social equity alongside environmental benefits and economic efficiency. When the spatial patterning of human diversity differs from the patterning of biological diversity, conservation planners face complex tradeoffs between social and biological objectives. Here, we quantify how these tradeoffs depend on the correlation between the spatial distributions of social and biological diversity. We used empirical patterns in the commonness and rarity of species to generate simulated landscapes with pre-defined correlations between biological diversity and human social diversity. Our analysis shows how tradeoffs between social equity and environmental benefits are unavoidable when human and biological diversity are negatively correlated. However, when human and biological diversity are strongly positively correlated, then biological and social priorities are congruent. In these settings, well-designed conservation programs may engender positive feedbacks between social equity and ecosystem services, enhancing both. Our analysis focused on distributional equity, but similar dynamics are likely to occur with procedural, recognitional and contextual equity. Given growing evidence that socially equitable conservation programs are more likely to be successful, our findings underscore the importance of carefully assessing the potential for conflicts and synergies between the social and biological goals of conservation programs.

ABSTRACT Medical modulation of sex hormone levels is a cornerstone of treatment for many conditions that impact well-being, including cancer, fertility/infertility, gender dysphoria, and chronic metabolic diseases such as diabetes and obesity. The microbial residents of the intestine, known as the microbiota, interact with sex hormones in the intestine, and there is correlative evidence that this interaction is bidirectional. Based on these published findings, we hypothesized that transgender individuals receiving exogenous testosterone as part of their gender-affirming medical treatment might undergo changes in their intestinal microbiome. To test this, we collected 26 stool samples from nine individuals before and up to 8 months after initiation of treatment with exogenous testosterone and subjected these samples to metagenomic analysis. While no species were significantly associated with the duration of testosterone therapy, pathways that generate glutamate increased in abundance, while those that consume glutamate decreased. Glutamate is a precursor of arginine, and testosterone is known to increase levels of arginine and its metabolites in the plasma. We hypothesize that testosterone increases the uptake of glutamate by enterocytes, thus decreasing access of the microbiota to this amino acid. While this pilot study establishes the impact of testosterone therapy on the intestinal microbiome, a more comprehensive study is necessary to establish the impact of testosterone-driven metagenomic shifts on the stool metatranscriptome, the stool metabolome, and the plasma metabolome.IMPORTANCEThe human intestine is inhabited by a large community of microbes known as the microbiome. Members of the microbiome consume the diet along with their human host. Thus, the metabolomes of the host and microbe are intricately linked. Testosterone alters the plasma metabolome. In particular, plasma levels of arginine and its metabolites and testosterone are positively correlated. To investigate the impact of exogenous testosterone on the microbiome, we analyzed the stool metagenomes of transgender individuals before and after the initiation of testosterone treatment. In this pilot project, we found a modest impact on the microbiome community structure but an increase in the abundance of metabolic pathways that generate glutamate and spare glutamate consumption. We propose that the host uses glutamate to generate arginine, decreasing the amount available for the microbiome.

Flooding poses a severe global threat, necessitating advanced methodologies to assess and manage its risks effectively. This study introduces a novel approach that integrates Geographic Information System (GIS) with hydrologic-hydraulic modeling to evaluate the combined drivers of current and future flood risks. The method is applied to the development Bonita Bay in southwest Florida. It occurs in a region highly susceptible to flooding due to its low elevation and proximity to tidal waters. The innovative integration of GIS with hydrologic-hydraulic models enables detailed assessment and visualization of flood inundation areas under multiple flood drivers including design storms, land use changes, groundwater rise, and sea-level rise. This allows for the seamless simulation of complex flood interactions with only minor adjustments to the model for the identified drivers. The results indicate significant increases in initial water storage caused by sea and groundwater level rise and amplified storm runoff from land use changes. A 2% increase in flooded areas is projected with stronger design storms, and a 5% increase by 2,100 compared to 2024. This approach provides a robust framework for developing tailored flood mitigation strategies and can be adapted to various coastal regions globally.

Introduction Inadequate treatment of enlarged lateral lymph nodes (LLNs) in rectal cancer patients is associated with an increased lateral local recurrence (LLR) risk, despite neoadjuvant treatment and total mesorectal excision (TME) surgery. There is a promising role for LLN dissection (LLND) to lower this risk, but this challenging procedure requires appropriate training. This study protocol describes a prospective evaluation of oncological outcomes after standardised treatment based on multidisciplinary training, thereby aiming for a 50% reduction in LLR rate.Methods and analysis A prospective registration study will be opened in hospitals in which the involved multidisciplinary team members (radiologists, radiation oncologists, surgeons and pathologists) have received dedicated training to enhance knowledge and awareness of LLNs and in which standardised treatment including LLND has been implemented. Patients with rectal cancer and at least one enlarged LLN (short-axis ≥7.0 mm), or intermediate LLN (short-axis 5.0–6.9 mm) with at least one malignant feature on primary MRI, evaluated by a trained radiologist, are eligible. Patients will undergo neoadjuvant treatment by trained radiation oncologists, followed by TME surgery in combination with a minimally invasive, nerve-sparing LLND performed by trained surgeons. LLND specimens are evaluated by trained pathologists or grossing assistants. The primary outcome is LLR rate 3 years postoperatively. Secondary outcomes are morbidity, disease-free survival, overall survival and quality of life. To demonstrate a significant reduction in LLR rate from 13% (based on historical control data) to 6% after optimised treatment, 200 patients with enlarged LLNs are required.Ethics and dissemination The medical ethics board of the Vrije Universiteit Medical Centre (VUMC), the Netherlands, approved the study on 23 November 2022 (reference: 2021.0524). Participating centres must obtain local approval and participants are required to provide written informed consent. Results obtained from this study will be communicated via peer-reviewed medical journals and presentations at conferences.Trail registration number NCT04486131, 24 July 2020, https://clinicaltrials.gov/ct2/show/NCT04486131.

Intensified chemoimmunotherapy regimens are often used in young patients with double hit and triple hit lymphoma (DHL/THL) despite no survival benefit compared to R-CHOP. Favorable retrospective reports on the application of CODOX-M/IVAC-R are subject to selection bias as only young fit patients can tolerate this treatment. We conducted a retrospective analysis to investigate outcome differences between CODOX-M/IVAC-R and DA-EPOCH-R in DHL/THL patients aged 60 years or younger. 113 patients were identified; CODOX-M/IVAC-R (N=49) and DA-EPOCH-R (N=64). 80% (39/49) achieved complete (CR) after completing CODOX-M/IVAC-R compared to 58% (37/64) with DA-EPOCH-R. The median follow-up was 5.3 years and 3.3 years for the CODOX-M/IVAC-R and DA-EPOCH-R group respectively. CODOX-M/IVAC-R demonstrated superior EFS on univariate (HR=0.54, 95%CI=0.31-0.97) and multivariable analysis adjusted for age, BCL translocation (BCL2 vs BCL6 vs both), IPI score and receipt of ASCT (aHR=0.52, 95%CI=0.29-0.93); however there was no significant influence on OS (aHR=0.92, 95%CI=0.46-1.84). The 1, 2 and 5 years EFS in the CODOX-M/IVAC-R group was 68.3%, 64.1% and 61.5% respectively compared to 52.4%, 48.9% and 39.5% respectively in the DA-EPOCH-R group. Primary refractory disease or relapse occurred in 33% (16/49) of CODOX-M/IVAC-R and 54% (35/64) of DA-EPOCH-R recipients, and produced median OS of 10.3 months and 33.7 months, respectively, indicating poor outcomes in the CODOX-M/IVAC-R subgroup with R/R disease. More patients were able to receive subsequent salvage therapies in the DA-EPOCH-R group. No patients died of regimen toxicity and the rates of CNS relapse and therapy related hematologic neoplasms were similar in both groups.

Metastatic lung cancer remains a leading cause of death worldwide, with its intricate metastatic cascade posing significant challenges to researchers and clinicians. Despite substantial progress in understanding this cascade, many aspects remain elusive. Microfluidic-based vasculature-on-chip models have emerged as powerful tools in cancer research, enabling the simulation of specific stages of tumor progression. In this study, we investigate the extravasation behaviors of A549 lung cancer cell subpopulations, revealing distinct differences based on their phenotypes. Our results show that holoclones, which exhibit an epithelial phenotype, do not undergo extravasation. In contrast, paraclones, characterized by a mesenchymal phenotype, demonstrate a notable capacity for extravasation. Furthermore, we observed that paraclones migrate significantly faster than holoclones within the microfluidic model. Importantly, we found that the depletion of vascular endothelial growth factor (VEGF) effectively inhibits the extravasation of paraclones. These findings highlight the utility of microfluidic-based models in replicating key aspects of the metastatic cascade. The insights gained from this study underscore the potential of these models to advance precision medicine by facilitating the assessment of patient-specific cancer cell dynamics and drug responses. This approach could lead to improved strategies for predicting metastatic risk and tailoring personalized cancer therapies, potentially involving the sampling of cancer cells from patients during tumor resection or biopsies.

Purpose: To investigate the impact of smartphone viewing distance and angle on reaction times. Design: A prospective, self-controlled, single-center study. Methods: Participants engaged in a driving simulation facing a large screen with a simulated brake pedal. They were tasked to stop the simulation once recognizing the deceleration of upcoming traffic. Tests were conducted without distraction and with a standardized distraction simulating texting while driving (TWD). Smartphone positions varied at distances of 30 cm and 60 cm, and at angles parallel to and 30° below the road plane. Reaction times were measured from the onset of simulated closure to detection. Stopping distances were extrapolated using data from the National Highway Traffic Safety Administration. Results: Ninety-four participants were included with a mean age of 24 ± 2.7 years. The control reaction time was 11.5 ± 4.1 s. Reaction times significantly decreased with smartphone placement at a closer distance of 30 cm parallel (17.0 ± 3.3 s) vs 60 cm parallel (15.4 ± 3.8 s), P

Introduction It remains uncertain whether Descemet membrane endothelial keratoplasty (DMEK) or Descemet stripping only (DSO) yields better outcomes in patients with symptomatic Fuchs endothelial corneal dystrophy (FECD). This paper presents the protocol for the Descemet Endothelial Thickness Comparison Trial II (DETECT II), a multicentre, outcome-masked, randomised, placebo-controlled, clinical trial comparing DMEK to DSO with ripasudil (DSO-R) for this patient population.Methods and analysis A total of 60 patients with endothelial dysfunction due to symptomatic FECD will be enrolled from seven participating sites in the USA. The patients will be randomly assigned in a 1:1 ratio to one of the following treatment groups: group 1—DMEK plus topical placebo and group 2—DSO plus topical ripasudil 0.4%. The enrolment period is 24 months. The primary outcome is best spectacle-corrected visual acuity at 12 months. Secondary outcomes include peripheral and central endothelial cell density, visual acuity, vision-related quality of life and Pentacam Scheimpflug tomography. Study outcomes will be analysed using mixed effects linear regression. Adverse events, including rebubble procedures, endothelial failure and graft rejection, will be documented and analysed using appropriate statistical methods. DETECT II aims to provide evidence on the comparative effectiveness of DMEK and DSO-R. The results of this trial will contribute to optimising the treatment of FECD, while also exploring the cost-effectiveness of these interventions. Dissemination of findings through peer-reviewed publications and national/international meetings will facilitate knowledge translation and guide clinical practice in the field of corneal transplantation.Ethics and dissemination A data and safety monitoring committee has been empanelled by the National Eye Institute. All study protocols will be subject to review and approval by WCG IRB as the single IRB of record. This study will comply with the National Institute of Health (NIH) Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. Data from the trial will be made available on reasonable request.Trial registration number NCT05275972.

ABSTRACT The introduction of non‐native species across the world represents a major global challenge. Retracing invasion origin is an important first step in understanding the invasion process, often requiring detailed sampling within the native range. Insect species frequently host Wolbachia, a widespread endosymbiotic bacterium that manipulates host reproduction to increase infected female fitness. Here, we draw on the spatial variation in infection frequencies of an actively spreading Wolbachia strain wCer2 to investigate the invasion origin of the European cherry fruit fly, Rhagoletis cerasi. This pest of cherries was introduced from Europe to North America within the last decade. First, we screen the introduced fly population for the presence of Wolbachia. The introduced populations lack the wCer2 strain and the strongly associated mitochondrial haplotype, suggesting strain absence due to founder effects with invading individuals originating from wCer2‐uninfected native population(s). To narrow down geographic regions of invasion origin, we perform spatial interpolation of the wCer2 infection frequency across the native range and predict the infection frequency in unsampled regions. For this, we use an extensive dataset of R. cerasi infection covering 238 populations across Europe over 25 years, complemented with 14 additional populations analyzed for this study. We find that R. cerasi was unlikely introduced from wCer2‐infected populations in Central and Western Europe. We propose wCer2‐uninfected populations from Eastern Europe and the Mediterranean region as the most likely candidates for the invasion origin. This work utilizes Wolbachia as an indirect instrument to provide insights into the invasion source of R. cerasi in North America, revealing yet another application for this multifaceted heritable endosymbiont. Given the prevalence of biological invasions, rapidly uncovering invasion origins gives fundamental insights into how invasive species adapt to new environments.

Despite general agreement that science outreach is important, the effectiveness of science outreach programs on participants' learning often is not assessed. Brain Explorers is a neuroscience outreach program that allows medical students to partner with Biomedical Sciences faculty to develop lesson plans with learning objectives, interactive experiments for middle schoolers, and assessments of learning. These lessons are then implemented through a community-level intervention in which medical students teach their lesson plans to middle schoolers and assist them in performing activities to reinforce the concepts. Importantly, the efficacy of these active learning interventions is assessed. Throughout the program's evolution, a variety of different forms of assessment have been utilized to examine student understanding. While the goals of outreach programs are varied, here we have focused on the evaluation of content knowledge gains laying out three unique evaluation methods including post-event, immediate pre- and post-event, and spaced pre- and post-event evaluation. Specifically, using Brain Explorers lessons as examples we explore the practicality and feasibility of various learning assessments in outreach programs, begin to examine the impacts of participation in these programs on the medical school instructors and encourage others in the field to implement assessment of their programs.

Reproducible and standardised neurological assessment scales are important in quantifying research outcomes. These scales are often performed by non-neurologists and/or non-clinicians and must be robust, quantifiable, reproducible and comparable to a neurologist's assessment. COVID-CNS is a multi-centre study which utilised the Neurological Impairment Scale (NIS) as a core assessment tool in studying neurological outcomes following COVID-19 infection. We investigated the strengths and weaknesses of the NIS when used by non-neurology clinicians and non-clinicians, and compared performance to a structured neurological examination performed by a neurology clinician. Through our findings, we provide practical advice on how non-clinicians can be readily trained in conducting reproducible and standardised neurological assessments in a multi-centre study, as well as illustrating potential pitfalls of these tools.

Decentralized clinical trials (DCTs) are becoming increasingly popular. Digital clinical trial platforms are software environments where users complete designated clinical trial tasks, providing investigators and trial participants with efficient tools to support trial activities and streamline trial processes. In particular, digital platforms with a modular architecture lend themselves to DCTs, where individual trial activities can correspond to specific platform modules. While design features can allow users to customize their platform experience, the real strengths of digital platforms for DCTs are enabling centralized data capture and remote monitoring of trial participants and in using digital technologies to streamline workflows and improve trial management. When selecting a platform for use in a DCT, sponsors and investigators must consider the specific trial requirements. All digital platforms are limited in their functionality and technical capabilities. Integrating additional functional modules into a central platform may solve these challenges, but few commercial platforms are open to integrating third-party components. The lack of common data standardization protocols for clinical trials will likely limit the development of one-size-fits-all digital platforms for DCTs. This viewpoint summarizes the current role of digital platforms in supporting decentralized trial activities, including a discussion of the potential benefits and challenges of digital platforms for investigators and participants. We will highlight the role of the digital platform in the development of DCTs and emphasize where existing technology is functionally limiting. Finally, we will discuss the concept of the ideal fully integrated and unified DCT and the obstacles developers must address before it can be realized.

Species of the cleptoparasitic bee genus Triepeolus Robertson, 1901 (Hymenoptera: Apidae: Nomadinae) of which the female has a trapezoidal or triangular pseudopygidial area with bright, reflective setae and a concave apical margin are revised. This entirely New World group includes the widely known species T. simplex Robertson, 1903 and is thus termed the simplex species group. A total of 18 species in the T. simplex group are recognized as valid, of which seven are newly named and described—T. apache sp. nov., T. eumeniformis sp. nov., T. hirsutus sp. nov., T. oblongimacula sp. nov., T. parahirsutus sp. nov., T. paucipunctatus sp. nov., and T. shoshone sp. nov., all from North America. Eleven redundant names are newly synonymized under three valid ones as follows: Epeolus rugulosus Cockerell, 1917 syn. nov., E. metatarsalis Friese, 1921 syn. nov., and T. bilunatus Cockerell, 1949 syn. nov. under Triepeolus mexicanus (Cresson, 1878); E. lectiformis Cockerell, 1925 syn. nov., T. lusor Cockerell, 1925 syn. nov., and T. junctus Mitchell, 1962 syn. nov. under T. rhododontus Cockerell, 1921; and E. permixtus Cockerell, 1923 syn. nov., T. brunnescens Cockerell & Sandhouse, 1924 syn. nov., T. pacis Cockerell, 1925 syn. nov., E. sarothrinus Cockerell, 1929 syn. nov., and E. sarothrinus var. confluens Cockerell, 1929 syn. nov. under T. segregatus (Cockerell, 1900). Species limits were established using an integrative systematics approach, namely considering morphological and biogeographic evidence as well as DNA barcode data. Taxon concepts are revised for all species in the T. simplex group, with morphological diagnoses and keys presented to enable their identification. Known information on the ranges and ecology of the treated species is summarized.

Summary: Motivated by the cellular heterogeneity in complex tissues, particularly in brain and induced pluripotent stem cell (iPSC)-derived brain models, we developed a complete workflow to reproducibly characterize cell types in complex tissues. Our approach combines a flow cytometry (FC) antibody panel with our computational pipeline CelltypeR, enabling dataset aligning, unsupervised clustering optimization, cell type annotating, and statistical comparisons. Applied to human iPSC derived midbrain organoids, it successfully identified the major brain cell types. We performed fluorescence-activated cell sorting of CelltypeR-defined astrocytes, radial glia, and neurons, exploring transcriptional states by single-cell RNA sequencing. Among the sorted neurons, we identified subgroups of dopamine neurons: one reminiscent of substantia nigra cells most vulnerable in Parkinson’s disease. Finally, we used our workflow to track cell types across a time course of organoid differentiation. Overall, our adaptable analysis framework provides a generalizable method for reproducibly identifying cell types across FC datasets in complex tissues.

Faster and more accurate analytical methods are needed to support the advancement of recombinant adeno-associated virus (rAAV) production systems. Recently, biolayer interferometry (BLI) has been developed for high-throughput AAV capsid titer measurement by functionalizing the AAVX ligand onto biosensor probes (AAVX-BLI). In this work, an AAVX-BLI method was evaluated using Octet AAVX biosensors across four rAAV serotypes (rAAV2, -5, -8, and -9) and applied in an upstream and downstream processing context. AAVX-BLI measured the capsid titer across a wide concentration range (1 × 1010–1 × 1012 capsids/mL) for different rAAV serotypes and sample backgrounds with reduced measurement variance and error compared to an enzyme-linked immunosorbent assay (ELISA) method. Biosensors were regenerated for repeated use, with lysate samples showing reduced regeneration capacity compared to purified and supernatant samples. The AAVX-BLI method was applied in a transfection optimization study where direct capsid titer measurement of culture supernatants generated a representative response surface for the total vector genome (VG) titer. For rAAV purification, AAVX-BLI was used to measure dynamic binding capacity with POROS CaptureSelect AAVX affinity chromatography, showing resin breakthrough dependence on the operating flow rate. Measurement accuracy, serotype and sample background flexibility, and high sample throughput make AAVX-BLI an attractive alternative to other capsid titer measurement techniques.

Abstract. Objectives:. The aim of this study was to determine the variations in effect for predictors of mortality over time and risk of in-hospital complications in geriatric patients with a hip fracture. Many studies have investigated risk factors of short-term and long-term mortality separately. In current literature, little is known about the variations in effect of risk factors over time and no comparison with the general population is made. Methods:. All patients with a hip fracture aged 70 years or older admitted to our hospital between January 1, 2016, and May 1, 2018, were included in this retrospective study. Patients who had undergone total hip arthroplasty (THA) were not included. The primary outcome was mortality after 1 year. Secondary outcomes were mortality after 30 days, 90 days, 2 years, and complications. Kaplan–Meier (KM) curves for risk factors were generated to visualize survival over time. Data were compared with data extracted from the national health records. Results:. A total of 685 geriatric patients with hip fractures were included with a 1-year mortality of 27%. The adjusted odds ratios (AOR) found differed over time. Five risk factors for mortality were investigated in this study using KM curves: age, prefracture living situation, dementia, sex, and ASA classification. Conclusions:. Over time, the variation of 5 risk factors for mortality were visualized in geriatric patients with a hip fracture: age, prefracture living situation, dementia, sex, and ASA classification. An elevated risk of mortality was discovered compared with the general population. The variation in effect observed in risk factors plays a vital role in prognosis. This insight will help guide accurate medical decision-making for a tailored treatment plan for geriatric patients with a hip fracture.

Objectives: To determine the associated pathogen during the 2023 conjunctivitis outbreak in Vietnam Methods: RNA-sequencing was used to identify pathogens before and during the outbreak. Results: 24 patients with infectious conjunctivitis between March and October 2023 from Hai Yen Vision Institute in Vietnam were swabbed. Coxsackievirus A24v was the most common pathogen identified. Phylogenetic analysis of these strains demonstrates similarities to the Coxsackievirus identified in the 2022 India outbreak. Human adenovirus D was also circulating. Ocular findings of tearing, purulence, and itching were common in this outbreak. Conclusions: Multiple viruses can co-circulate during conjunctivitis outbreaks. Hemorrhagic conjunctivitis, commonly associated with coxsackievirus conjunctivitis, was not a common clinical sign in this outbreak. Repeat genetic surveillance, with the notable inclusion of RNA virus detection strategies, is important for outbreak detection.

Abstract Solitons are nonlinear solitary waves which maintain their shape over time and through collisions, occurring in a variety of nonlinear media from plasmas to optics. We present an experimental and theoretical study of hydrodynamic phenomena in a two-component atomic Bose-Einstein condensate where a soliton array emerges from the imprinting of a periodic spin pattern by a microwave pulse-based winding technique. We observe the ensuing dynamics which include shape deformations, the emergence of dark-antidark solitons, apparent spatial frequency tripling, and decay and revival of contrast related to soliton collisions. For the densest arrays, we obtain soliton complexes where solitons undergo continued collisions for long evolution times providing an avenue towards the investigation of soliton gases in atomic condensates.

Abstract Background Post-acute sequelae of SARS-CoV-2 infection (PASC) symptoms have broad impact, and may affect individuals regardless of COVID-19 severity, socioeconomic status, race, ethnicity, or age. A prominent PASC symptom is cognitive dysfunction, colloquially referred to as “brain fog” and characterized by declines in short-term memory, attention, and concentration. Cognitive dysfunction can severely impair quality of life by impairing daily functional skills and preventing timely return to work. Methods RECOVER-NEURO is a prospective, multi-center, multi-arm, phase 2, randomized, active-comparator design investigating 3 interventions: (1) BrainHQ is an interactive, online cognitive training program; (2) PASC-Cognitive Recovery is a cognitive rehabilitation program specifically designed to target frequently reported challenges among individuals with brain fog; (3) transcranial direct current stimulation (tDCS) is a noninvasive form of mild electrical brain stimulation. The interventions will be combined to establish 5 arms: (1) BrainHQ; (2) BrainHQ + PASC-Cognitive Recovery; (3) BrainHQ + tDCS-active; (4) BrainHQ + tDCS-sham; and (5) Active Comparator. The interventions will occur for 10 weeks. Assessments will be completed at baseline and at the end of intervention and will include cognitive testing and patient-reported surveys. All study activities can be delivered in Spanish and English. Discussion This study is designed to test whether cognitive dysfunction symptoms can be alleviated by the use of pragmatic and established interventions with different mechanisms of action and with prior evidence of improving cognitive function in patients with neurocognitive disorder. If successful, results will provide beneficial treatments for PASC-related cognitive dysfunction. Trial registration ClinicalTrials.gov NCT05965739. Registered on July 25, 2023.

Abstract Background An elevated neutrophil–lymphocyte ratio (NLR) in blood has been associated with Alzheimer’s disease (AD). However, an elevated NLR has also been implicated in many other conditions that are risk factors for AD, prompting investigation into whether the NLR is directly linked with AD pathology or a result of underlying comorbidities. Herein, we explored the relationship between the NLR and AD biomarkers in the cerebrospinal fluid (CSF) of cognitively unimpaired (CU) subjects. Adjusting for sociodemographics, APOE4, and common comorbidities, we investigated these associations in two cohorts: the Alzheimer’s Disease Neuroimaging Initiative (ADNI) and the M.J. de Leon CSF repository at NYU. Specifically, we examined associations between the NLR and cross-sectional measures of amyloid-β42 (Aβ42), total tau (t-tau), and phosphorylated tau181 (p-tau), as well as the trajectories of these CSF measures obtained longitudinally. Results A total of 111 ADNI and 190 NYU participants classified as CU with available NLR, CSF, and covariate data were included. Compared to NYU, ADNI participants were older (73.79 vs. 61.53, p

Abstract Schizophrenia is a complex neuropsychiatric disorder with sexually dimorphic features, including differential symptomatology, drug responsiveness, and male incidence rate. Prior large-scale transcriptome analyses for sex differences in schizophrenia have focused on the prefrontal cortex. Analyzing BrainSeq Consortium data (caudate nucleus: n = 399, dorsolateral prefrontal cortex: n = 377, and hippocampus: n = 394), we identified 831 unique genes that exhibit sex differences across brain regions, enriched for immune-related pathways. We observed X-chromosome dosage reduction in the hippocampus of male individuals with schizophrenia. Our sex interaction model revealed 148 junctions dysregulated in a sex-specific manner in schizophrenia. Sex-specific schizophrenia analysis identified dozens of differentially expressed genes, notably enriched in immune-related pathways. Finally, our sex-interacting expression quantitative trait loci analysis revealed 704 unique genes, nine associated with schizophrenia risk. These findings emphasize the importance of sex-informed analysis of sexually dimorphic traits, inform personalized therapeutic strategies in schizophrenia, and highlight the need for increased female samples for schizophrenia analyses.

Abstract Background Hyaluronan (HA) is an extracellular glycosaminoglycan polysaccharide with widespread roles throughout development and in healthy and neoplastic tissues. In pluripotent stem cell culture it can support both stem cell renewal and differentiation. However, responses to HA in culture are influenced by interaction with a range of cognate factors and receptors including components of blood serum supplements, which alter results. These may contribute to variation in cell batch production yield and phenotype as well as heighten the risks of adventitious pathogen transmission in the course of cell processing for therapeutic applications. Main Here we characterise differentiation of a human embryo/pluripotent stem cell derived Mesenchymal Stromal Cell (hESC/PSC-MSC)-like cell population by culture on a planar surface coated with HA in serum-free media qualified for cell production for therapy. Resulting cells met minimum criteria of the International Society for Cellular Therapy for identification as MSC by expression of. CD90, CD73, CD105, and lack of expression for CD34, CD45, CD14 and HLA-II. They were positive for other MSC associated markers (i.e.CD166, CD56, CD44, HLA 1-A) whilst negative for others (e.g. CD271, CD71, CD146). In vitro co-culture assessment of MSC associated functionality confirmed support of growth of hematopoietic progenitors and inhibition of mitogen activated proliferation of lymphocytes from umbilical cord and adult peripheral blood mononuclear cells, respectively. Co-culture with immortalized THP-1 monocyte derived macrophages (Mɸ) concurrently stimulated with lipopolysaccharide as a pro-inflammatory stimulus, resulted in a dose dependent increase in pro-inflammatory IL6 but negligible effect on TNFα. To further investigate these functionalities, a bulk cell RNA sequence comparison with adult human bone marrow derived MSC and hESC substantiated a distinctive genetic signature more proximate to the former. Conclusion Cultivation of human pluripotent stem cells on a planar substrate of HA in serum-free culture media systems is sufficient to yield a distinctive developmental mesenchymal stromal cell lineage with potential to modify the function of haematopoietic lineages in therapeutic applications.

The Bali myna Leucopsar rothschildi has long suffered heavy trapping, leading to its near extinction in the wild and categorization as Critically Endangered on the IUCN Red List. Decades of conservation breeding, release of birds and post-release management at Bali Barat National Park have, until recently, failed to secure a viable wild population. However, over the past decade, population increases, expansion into new areas of the National Park and beyond, and successful breeding in both artificial and natural nest sites have occurred. These recent successes are associated with a change in approach by the National Park authority from concentrating efforts on the last refugium of the species (an area protected from trapping but with potentially suboptimal habitat) and towards the human-dominated landscapes around the main road through the National Park. Bali mynas tended to favour areas with extensive shorter grass cover and open canopies and to shun denser woodland. Anthropogenic landscapes such as farmland and plantations presumably mimic the original savannah habitat of the species, but nestbox provision has probably been crucial in these areas in the absence of natural cavities. A potential further factor in the increases in myna numbers and range has been a scheme involving local people in commercial breeding of the species, thereby reducing its market price, and working with communities to reduce trapping pressure. We encourage continuing operation of this management strategy inside the National Park and its further extension into adjacent tourist areas, which appear to have myna-friendly socio-ecological conditions.

The potential benefits of epidural anesthesia on mortality, atrial fibrillation, and pulmonary complications must be weighed against the risk of epidural hematoma associated with intraoperative heparinization. This study aims to provide an updated assessment of the clinical risks of epidural anesthesia in cardiac surgery, focusing on the occurrence of epidural hematomas and subsequent paralysis. A systematic search of Embase, Medline, Ovid Central, Web of Science, and PubMed was conducted to identify relevant publications between 1966 and 2022. Two independent reviewers assessed the eligibility of the retrieved manuscripts. Studies reporting adult patients undergoing cardiac surgery with epidural catheterization were included. The incidence of hematomas was calculated by dividing the number of hematomas by the total number of patients in the included studies. Risk calculations utilized various denominators based on the rigor of trial designs, and the risks of hematoma and paralysis were compared to other commonly encountered risks. The analysis included a total of 33,089 patients who underwent cardiac surgery with epidural catheterization. No epidural hematomas were reported across all published RCTs, prospective, and retrospective trials. Four case reports associated epidural hematoma with epidural catheterization and perioperative heparinization. The risks of epidural hematoma and subsequent paralysis were estimated at 1:7643 (95% CI 1:3860 to 380,916) and 1:10,190 (95% CI 1:4781 to 0:1), respectively. The risk of hematoma is similar to the non-obstetric population (1:5405; 95% CI 1:4784 to 6134). The risk of hematoma in cardiac surgery patients receiving epidural anesthesia is therefore similar to that observed in some other surgical non-obstetric populations commonly exposed to epidural catheterization.

Abstract The polygenic architecture of schizophrenia implicates several molecular pathways involved in synaptic function. However, it is unclear how polygenic risk funnels through these pathways to translate into syndromic illness. Using tensor decomposition, we analyze gene co-expression in the caudate nucleus, hippocampus, and dorsolateral prefrontal cortex of post-mortem brain samples from 358 individuals. We identify a set of genes predominantly expressed in the caudate nucleus and associated with both clinical state and genetic risk for schizophrenia that shows dopaminergic selectivity. A higher polygenic risk score for schizophrenia parsed by this set of genes predicts greater dopamine synthesis in the striatum and greater striatal activation during reward anticipation. These results translate dopamine-linked genetic risk variation into in vivo neurochemical and hemodynamic phenotypes in the striatum that have long been implicated in the pathophysiology of schizophrenia.

Abstract Background Obesity influences the development of osteoarthritis via low-grade inflammation. Progression of local inflammation (= synovitis) increased with weight gain in overweight and obese women compared to stable weight. Synovitis could be associated with subcutaneous fat (SCF) around the knee. Purpose of the study was to investigate the effect of weight loss on synovitis progression and to assess whether SCF around the knee mediates the relationship between weight loss and synovitis progression. Methods We included 234 overweight and obese participants (body mass index [BMI] ≥ 25 kg/m2) from the Osteoarthritis Initiative (OAI) with > 10% weight loss (n = 117) or stable overweight (

Abstract Background To tag large marine vertebrates, without the need to catch them, avoiding using barbs for tag retention, and precisely controlling tag location, the remote Tag Attachment Device on a pole (TADpole) was developed. This allows single-pin tags (Finmount, Wildlife Computers) to be attached to the dorsal fins of free-swimming large marine vertebrates. Results TADpole comprises a pole-mounted holster that carries a tag. It uses compressed air, and a micro-controller, to rapidly insert a stainless-steel pin through a corrodible metal retaining ring in the first tag attachment wing, the animal’s dorsal fin, and then a press fit Delrin retaining ring in the tag wing on the other side of the fin. Tagging only occurs when the trailing edge of the dorsal fin touches a trigger bar in the holster, ensuring optimal pin placement. It was developed using fins from cadavers, then trialed on briefly restrained coastal dolphins that could be followed in successive days and weeks, and then on free-swimming animals in the field. The latter showed very short touch/response intervals and highlighted the need for several iterative revisions of the pneumatic system. This resulted in reducing the total time from triggering to tag application to ~ 20 ms. Subsequent efforts expanded the TADpole’s applicability to sharks. One free-swimming Atlantic spotted dolphin, two white sharks, and one whale shark were then tagged using the TADpole. Conclusions Being able to tag free-swimming dolphins and sharks remotely and precisely with satellite-linked telemetry devices may contribute to solving conservation challenges. Sharks were easier to tag than dolphins. Dolphin touch-to-response times were 28 ms or less. Delphinid skin has unique polymodal axon bundles that project into the epidermis, perhaps a factor in their uniquely fast response, which is 10 × faster than humans. Their primary reaction to tagging is to abduct the flippers and roll the fin out of the TADpole holster. This device has the potential to deliver high-quality tag data from large vertebrates with dorsal fins without the stress and logistics associated with catch-and-release, and without the trauma of tags that use barbs for retention. It also collects a dorsal fin biopsy core.

Abstract Advancements in cytometry technologies have enabled quantification of up to 50 proteins across millions of cells at single cell resolution. Analysis of cytometry data routinely involves tasks such as data integration, clustering, and dimensionality reduction. While numerous tools exist, many require extensive run times when processing large cytometry data containing millions of cells. Existing solutions, such as random subsampling, are inadequate as they risk excluding rare cell subsets. To address this, we propose SuperCellCyto, an R package that builds on the SuperCell tool which groups highly similar cells into supercells. SuperCellCyto is available on GitHub ( https://github.com/phipsonlab/SuperCellCyto ) and Zenodo ( https://doi.org/10.5281/zenodo.10521294 ).

Abstract One of the main burdens in the treatment of diseases is imputable to the delay between the appearance of molecular dysfunctions in the first affected disease cells and their presence in sufficient number for detection in specific tissues or organs. This delay obviously plays in favor of disease progression to an extent that makes efficient treatments difficult, as they arrive too late. The development of a novel medical strategy, termed cell-based interception and precision medicine, seeks to identify dysfunctional cells early, when tissue damages are not apparent and symptoms not yet present, and develop therapies to treat diseases early. Central to this strategy is the use of single-cell technologies that allow detection of molecular changes in cells at the time of phenotypical bifurcation from health to disease. In this article we describe a general procedure to support such an approach applied to neurodegenerative disorders. This procedure combines four components directed towards highly complementary objectives: 1) a high-performance single-cell proteomics (SCP) method (Detect), 2) the development of disease experimental cell models and predictive computational models of cell trajectories (Understand), 3) the discovery of specific targets and personalized therapies (Cure), and 4) the creation of a community of collaborating laboratories to accelerate the development of this novel medical paradigm (Collaborate). A global initiative named 37TrillionCells (37TC) was launched to advance the development of cell-based interception and precision medicine.

Abstract Background Induced pluripotent stem cell-derived microglia (iMGL) represent an excellent tool in studying microglial function in health and disease. Yet, since differentiation and survival of iMGL are highly reliant on colony-stimulating factor 1 receptor (CSF1R) signaling, it is difficult to use iMGL to study microglial dysfunction associated with pathogenic defects in CSF1R. Methods Serial modifications to an existing iMGL protocol were made, including but not limited to changes in growth factor combination to drive microglial differentiation, until successful derivation of microglia-like cells from an adult-onset leukoencephalopathy with axonal spheroids and pigmented glia (ALSP) patient carrying a c.2350G > A (p.V784M) CSF1R variant. Using healthy control lines, the quality of the new iMGL protocol was validated through cell yield assessment, measurement of microglia marker expression, transcriptomic comparison to primary microglia, and evaluation of inflammatory and phagocytic activities. Similarly, molecular and functional characterization of the ALSP patient-derived iMGL was carried out in comparison to healthy control iMGL. Results The newly devised protocol allowed the generation of iMGL with enhanced transcriptomic similarity to cultured primary human microglia and with higher scavenging and inflammatory competence at ~ threefold greater yield compared to the original protocol. Using this protocol, decreased CSF1R autophosphorylation and cell surface expression was observed in iMGL derived from the ALSP patient compared to those derived from healthy controls. Additionally, ALSP patient-derived iMGL presented a migratory defect accompanying a temporal reduction in purinergic receptor P2Y12 (P2RY12) expression, a heightened capacity to internalize myelin, as well as heightened inflammatory response to Pam3CSK4. Poor P2RY12 expression was confirmed to be a consequence of CSF1R haploinsufficiency, as this feature was also observed following CSF1R knockdown or inhibition in mature control iMGL, and in CSF1R WT/KO and CSF1R WT/E633K iMGL compared to their respective isogenic controls. Conclusions We optimized a pre-existing iMGL protocol, generating a powerful tool to study microglial involvement in human neurological diseases. Using the optimized protocol, we have generated for the first time iMGL from an ALSP patient carrying a pathogenic CSF1R variant, with preliminary characterization pointing toward functional alterations in migratory, phagocytic and inflammatory activities. Graphical Abstract

Calcific tendinopathy in the gluteus medius is uncommon and sporadically reported. It may be asymptomatic or present with acute or chronic pain. Pain is usually isolated to the lateral hip overlying the gluteal muscles or greater trochanter. We present a rare case of gluteus medius calcific tendonitis as a cause of severe anterior hip pain. Given the atypical local and clinical presentation these can be often misdiagnosed as septic arthritis or fracture which may lead to overtreatment and even unnecessary surgery. This article will detail the clinical presentation, imaging findings, and clinical course following treatment. This will facilitate the clinician in making a timely diagnosis and establishing an effective treatment course.

Lateral patellar dislocations are the second most common type of traumatic knee injury, accounting for approximately 2-3% of cases, the most common being anterior cruciate ligament (ACL) injury. There are several well-documented anatomical risk factors predisposing to patellofemoral instability for example: patella alta, trochlear dysplasia, ligamentous laxity, and genu valgum. Co-existing medial collateral ligament injury in cases of patellar dislocations in the absence of ACL injury is uncommon and infrequently reported in the literature. The authors present a case of a 14-year-old boy presenting with a left knee injury while playing football who was diagnosed on magnetic resonance imaging (MRI) with a transient lateral patellar dislocation, high-grade medial patellofemoral ligament (MPFL) injury and a full thickness (grade III) injury to the distal medial collateral ligament.

Abstract High levels of proinflammatory cytokines induce neurotoxicity and catalyze inflammation-driven neurodegeneration, but the specific release mechanisms from microglia remain elusive. Here we show that secretory autophagy (SA), a non-lytic modality of autophagy for secretion of vesicular cargo, regulates neuroinflammation-mediated neurodegeneration via SKA2 and FKBP5 signaling. SKA2 inhibits SA-dependent IL-1β release by counteracting FKBP5 function. Hippocampal Ska2 knockdown in male mice hyperactivates SA resulting in neuroinflammation, subsequent neurodegeneration and complete hippocampal atrophy within six weeks. The hyperactivation of SA increases IL-1β release, contributing to an inflammatory feed-forward vicious cycle including NLRP3-inflammasome activation and Gasdermin D-mediated neurotoxicity, which ultimately drives neurodegeneration. Results from protein expression and co-immunoprecipitation analyses of male and female postmortem human brains demonstrate that SA is hyperactivated in Alzheimer’s disease. Overall, our findings suggest that SKA2-regulated, hyperactive SA facilitates neuroinflammation and is linked to Alzheimer’s disease, providing mechanistic insight into the biology of neuroinflammation.

Abstract A key hallmark of Parkinson’s disease (PD) is Lewy pathology. Composed of α-synuclein, Lewy pathology is found both in dopaminergic neurons that modulate motor function, and cortical regions that control cognitive function. Recent work has established the molecular identity of dopaminergic neurons susceptible to death, but little is known about cortical neurons susceptible to Lewy pathology or molecular changes induced by aggregates. In the current study, we use spatial transcriptomics to capture whole transcriptome signatures from cortical neurons with α-synuclein pathology compared to neurons without pathology. We find, both in PD and related PD dementia, dementia with Lewy bodies and in the pre-formed fibril α-synucleinopathy mouse model, that specific classes of excitatory neurons are vulnerable to developing Lewy pathology. Further, we identify conserved gene expression changes in aggregate-bearing neurons that we designate the Lewy-associated molecular dysfunction from aggregates (LAMDA) signature. Neurons with aggregates downregulate synaptic, mitochondrial, ubiquitin-proteasome, endo-lysosomal, and cytoskeletal genes and upregulate DNA repair and complement/cytokine genes. Our results identify neurons vulnerable to Lewy pathology in the PD cortex and describe a conserved signature of molecular dysfunction in both mice and humans.

Abstract Declining Arctic sea ice over recent decades has been linked to growth in coastal hazards affecting the Alaskan Arctic. In this study, climate model projections of sea ice are utilized in the simulation of an extratropical cyclone to quantify how future changes in seasonal ice coverage could affect coastal waves caused by this extreme event. All future scenarios and decades show an increase in coastal wave heights, demonstrating how an extended season of open water in the Chukchi and Beaufort Seas could expose Alaskan Arctic shorelines to wave hazards resulting from such a storm event for an additional winter month by 2050 and up to three additional months by 2070 depending on climate pathway. Additionally, for the Beaufort coastal region, future scenarios agree that a coastal wave saturation limit is reached during the sea ice minimum, where historically sea ice would provide a degree of protection throughout the year.

Abstract Background Meniscal root tears can lead to early knee osteoarthritis and pain. This study aimed (1) to compare clinical and radiological outcomes between patients who underwent arthroscopic meniscal root repair after meniscal root tears and those who received non-surgical treatment, and (2) to identify whether baseline MRI findings could be potential predictors for future treatment strategies. Methods Patients with meniscal root tears were identified from our picture archiving and communication system from 2016 to 2020. Two radiologists reviewed radiographs and MRI studies using Kellgren-Lawrence (KL) grading and a modified Whole Organ MRI Scoring (WORMS) at baseline and follow-up. The median (interquartile range [IQR]) of follow-up radiographs and MRI studies were 134 (44–443) days and 502 (260–1176) days, respectively. MR images were assessed for root tear-related findings. Pain scores using visual analogue scale (VAS) and management strategies (non-surgical vs. arthroscopic root repair) were also collected. Chi-squared tests and independent t-tests were used to assess differences regarding clinical and imaging variables between treatment groups. Logistic regression analyses were performed to evaluate the associations between baseline MRI findings and each future treatment. Results Ninety patients were included. VAS pain scores were significantly (p

Abstract Oral drug absorption kinetics are usually established in populations with a properly functioning gastrointestinal tract. However, many diseases and therapeutics can alter gastrointestinal physiology and cause diarrhea. The extent of diarrhea‐associated impact on drug pharmacokinetics has not been quantitatively described. To address this knowledge gap, we used a population pharmacokinetic modeling approach with data collected in a phase IIa study of matched human immunodeficiency virus (HIV)–infected adults with/without cryptosporidiosis and diarrhea to examine diarrhea‐associated impact on oral clofazimine pharmacokinetics. A population pharmacokinetic model was developed with 428 plasma samples from 23 HIV‐infected adults with/without Cryptosporidium infection using nonlinear mixed‐effects modeling. Covariates describing cryptosporidiosis‐associated diarrhea severity (e.g., number of diarrhea episodes, diarrhea grade) or HIV infection (e.g., viral load, CD4+ T cell count) were evaluated. A two‐compartment model with lag time and first‐order absorption and elimination best fit the data. Maximum diarrhea grade over the study duration was found to be associated with a more than sixfold reduction in clofazimine bioavailability. Apparent clofazimine clearance, intercompartmental clearance, central volume of distribution, and peripheral volume of distribution were 3.71 L/h, 18.2 L/h (interindividual variability [IIV] 45.0%), 473 L (IIV 3.46%), and 3434 L, respectively. The absorption rate constant was 0.625 h−1 (IIV 149%) and absorption lag time was 1.83 h. In conclusion, the maximum diarrhea grade observed for the duration of oral clofazimine administration was associated with a significant reduction in clofazimine bioavailability. Our results highlight the importance of studying disease impacts on oral therapeutic pharmacokinetics to inform dose optimization and maximize the chance of treatment success.

Abstract Model‐informed precision dosing using virtual twins (MIPD‐VTs) is an emerging strategy to predict target drug concentrations in clinical practice. Using a high virtualization MIPD‐VT approach (Simcyp version 21), we predicted the steady‐state clozapine concentration and clozapine dosage range to achieve a target concentration of 350 to 600 ng/mL in hospitalized patients with treatment‐resistant schizophrenia (N = 11). We confirmed that high virtualization MIPD‐VT can reasonably predict clozapine concentrations in individual patients with a coefficient of determination (R2) ranging between 0.29 and 0.60. Importantly, our approach predicted the final dosage range to achieve the desired target clozapine concentrations in 73% of patients. In two thirds of patients treated with fluvoxamine augmentation, steady‐state clozapine concentrations were overpredicted two to four‐fold. This work supports the application of a high virtualization MIPD‐VT approach to inform the titration of clozapine doses in clinical practice. However, refinement is required to improve the prediction of pharmacokinetic drug–drug interactions, particularly with fluvoxamine augmentation.

Abstract Rivers are the natural drainage system, transporting anthropogenic wastes and pollution, including microplastics (plastic 1; PLIzone = 1.87 and 1.68 for water and sediment samples respectively), with risk categories between Levels I and IV (“minor” to “danger”). Overall, the river stands in a “considerable” risk category (PRIzone = 134 and 113 for water and sediment samples respectively). The overall objective of this pilot study was to evaluate our hypothesis and advance our understanding of microplastic dynamics in rural river systems, elucidating their introduction from a point source (wastewater treatment plant), transit through an impediment (hydro-dam), and release into a vital transboundary river (confluence of Raquette-St. Lawrence Rivers).

Abstract Yeast Cadmium Factor 1 (Ycf1) sequesters glutathione and glutathione-heavy metal conjugates into yeast vacuoles as a cellular detoxification mechanism. Ycf1 belongs to the C subfamily of ATP Binding Cassette (ABC) transporters characterized by long flexible linkers, notably the regulatory domain (R-domain). R-domain phosphorylation is necessary for activity, whereas dephosphorylation induces autoinhibition through an undefined mechanism. Because of its transient and dynamic nature, no structure of the dephosphorylated Ycf1 exists, limiting understanding of this R-domain regulation. Here, we capture the dephosphorylated Ycf1 using cryo-EM and show that the unphosphorylated R-domain indeed forms an ordered structure with an unexpected hairpin topology bound within the Ycf1 substrate cavity. This architecture and binding mode resemble that of a viral peptide inhibitor of an ABC transporter and the secreted bacterial WXG peptide toxins. We further reveal the subset of phosphorylation sites within the hairpin turn that drive the reorganization of the R-domain conformation, suggesting a mechanism for Ycf1 activation by phosphorylation-dependent release of R-domain mediated autoinhibition.

Abstract Mobile Health (mHealth) has the potential to be transformative in the management of chronic conditions. Machine learning can leverage self-reported data collected with apps to predict periods of increased health risk, alert users, and signpost interventions. Despite this, mHealth must balance the treatment burden of frequent self-reporting and predictive performance and safety. Here we report how user engagement with a widely used and clinically validated mHealth app, myCOPD (designed for the self-management of Chronic Obstructive Pulmonary Disease), directly impacts the performance of a machine learning model predicting an acute worsening of condition (i.e., exacerbations). We classify how users typically engage with myCOPD, finding that 60.3% of users engage frequently, however, less frequent users can show transitional engagement (18.4%), becoming more engaged immediately (

Abstract Despite remarkable scientific progress over the past six decades within the medical arts and in radiobiology in general, limited radiation medical countermeasures (MCMs) have been approved by the United States Food and Drug Administration for the acute radiation syndrome (ARS). Additional effort is needed to develop large animal models for improving the prediction of clinical safety and effectiveness of MCMs for acute and delayed effects of radiation in humans. Nonhuman primates (NHPs) are considered the animal models that reproduce the most appropriate representation of human disease and are considered the gold standard for drug development and regulatory approval. The clinical and histopathological effects of supralethal, total- or partial-body irradiations (12 Gy) of NHPs were assessed, along with possible protective actions of a promising radiation MCM, gamma-tocotrienol (GT3). Results show that these supralethal radiation exposures induce severe injuries that manifest both clinically as well as pathologically, as evidenced by the noted functionally crippling lesions within various major organ systems of experimental NHPs. The MCM, GT3, has limited radioprotective efficacy against such supralethal radiation doses.

Abstract Directed evolution of computationally designed enzymes has provided new insights into the emergence of sophisticated catalytic sites in proteins. In this regard, we have recently shown that a histidine nucleophile and a flexible arginine can work in synergy to accelerate the Morita-Baylis-Hillman (MBH) reaction with unrivalled efficiency. Here, we show that replacing the catalytic histidine with a non-canonical N δ-methylhistidine (MeHis23) nucleophile leads to a substantially altered evolutionary outcome in which the catalytic Arg124 has been abandoned. Instead, Glu26 has emerged, which mediates a rate-limiting proton transfer step to deliver an enzyme (BHMeHis1.8) that is more than an order of magnitude more active than our earlier MBHase. Interestingly, although MeHis23 to His substitution in BHMeHis1.8 reduces activity by 4-fold, the resulting His containing variant is still a potent MBH biocatalyst. However, analysis of the BHMeHis1.8 evolutionary trajectory reveals that the MeHis nucleophile was crucial in the early stages of engineering to unlock the new mechanistic pathway. This study demonstrates how even subtle perturbations to key catalytic elements of designed enzymes can lead to vastly different evolutionary outcomes, resulting in new mechanistic solutions to complex chemical transformations.

Background: Brachial plexus catheter placement at the interscalene level is beneficial for shoulder analgesia but presents logistical challenges due to the superficial nature of the plexus at this level, increased patient movement in the neck, and therefore higher likelihood for catheter dislodgement. Methods: Patients requiring shoulder arthroscopy and suprascapular nerve decompression were identified. Under arthroscopic guidance, a catheter was placed percutaneously into the scalene medius muscle next to the suprascapular nerve and the upper trunk of the brachial plexus. Patients were followed postoperatively for perioperative analgesic outcomes. Results: Ten patients were identified and consented for intraoperative brachial plexus catheter placement. Patient demographics and surgical details were determined. Postoperative adjunctive pain management and pain scores were variable. Two patients required catheter replacement using ultrasound guidance in the perioperative anesthesia care unit due to poorly controlled pain. There were no incidents of catheter failure due to dislodgement. Discussion: This study presents the first description of arthroscopically-assisted brachial plexus catheter placement. This method may present an alternative to traditional ultrasound guided interscalene catheter placement. Further study is needed to determine if analgesic outcomes, block success, and dislodgement rates are improved with this method.

3,3‘,5,5‘-Tetranitro-4,4‘-bipyrazole monohydrate (TNBPz, 1⋅H2O) is an excellent precursor for the synthesis of new energetic materials (2–12). Several nitrogen-rich salts (e.g. guanidinium, aminoguanidinium, hydrazinium, ammonium and hydroxylammonium) were prepared from 1⋅H2O by neutralization reactions. In addition, the N-methylation and N-amination of compound TNBPz was investigated and is reported. All new synthesized energetic materials were fully characterized by NMR (1H, 13C, 14N, and 15N) spectroscopy, infrared spectroscopy, differential thermal analysis (DTA) and elemental analysis. Compounds 2, 4–8 and 10 were characterized with single crystal X-ray diffraction. The heats of formation for compounds 2, 4–6, 8, 11 and 12 were calculated using the atomization method based on CBS-4 M enthalpies. Several detonation parameters, such as detonation pressure, velocity and energy, were calculated by using the X-ray densities and the calculated standard molar enthalpies of formation. The sensitivities of all energetic materials toward external stimuli were tested according to the BAM standards. In addition, the toxicity toward vibrio fischeri bacteria of few energetic salts (3 and 4) is reported.

Summary: Antibody–drug conjugates (ADCs) have become an important class of anticancer drugs in solid tumors including drug-resistant gynecologic malignancies. TROP2 is a cell surface antigen that is highly expressed in ovarian carcinoma (OC) but minimally expressed in normal ovarian tissues. In this study, we aimed to identify how TROP2-specific ADC, sacituzumab govitecan (SG), modulates DNA damage response pathways in drug-resistant OC. We found that SG induces G2/M arrest, increases RPA1 foci, and decreases replication fork speed, resulting in replication stress in TROP2-positive cells while these were less evident in TROP2-negative cells. In OC in vitro and in vivo models, SN-38 sensitivity and TROP2 expression play key roles in response to either ATR inhibitor or SG alone, or in combination. Additionally, inhibition of translesion DNA synthesis enhances SG and PARP inhibitor (PARPi) sensitivity in PARPi-resistant OC cells. These findings provide mechanistic insights for clinical development of SG in drug-resistant OC.

Background: A recent international consensus conference called for the development of risk prediction models to identify ICU survivors at increased risk of each of the post-ICU syndrome domains. We previously developed and validated a risk prediction tool for functional impairment after ICU admission among older adults. Research Question: In this pilot study, we assessed the feasibility of administering the risk prediction tool in the hospital to older adults who had just survived critical illness. An exploratory objective was to evaluate whether augmentation of the model with additional hospital-related factors improved discrimination. Study Design and Methods: Between January and October 2020, 50 adults aged 65 years and older underwent in-hospital administration of the risk prediction tool. Survivors were called monthly for 6 months after discharge. Feasibility was defined as completion of all tool components by ≥ 70% of enrolled participants. Persistent functional impairment was defined as failure to return to the functional baseline from before the ICU stay at the 6-month interview based on seven daily activities. The model was sequentially refit after adding three in-hospital factors as predictors, one at a time and then all together. Model discrimination was assessed with receiver operating characteristic curves. Results: The tool met the a priori feasibility threshold, with 92.0% of enrolled participants completing all eight components. In the exploratory analysis, the addition of Acute Physiology and Chronic Health Evaluation II score, presence of delirium, and maximum in-hospital mobility resulted in a 5% gain in discrimination that did not achieve statistical significance (area under the receiver operating characteristic curve, 0.75; 95% CI, 0.68-0.82; P = .09). Interpretation: Our results indicate that the risk prediction tool is feasible for use in the hospital setting, enabling the identification of ICU survivors at high risk of persistent functional impairment at 6 months after discharge. Augmentation with hospital-related factors improved model discrimination, but did not achieve statistical significance in this pilot study. Future studies should evaluate the augmented model in larger cohorts.