Search

Abstract Many studies have explored different loading and rehabilitation strategies, yet rehabilitation intensity and its impact on the local strain environment and bone healing have largely not been investigated. This study combined implantable strain sensors and subject-specific finite element models in a 2 mm rodent segmental bone defect model. After injury animals were underwent high or low intensity rehabilitation. High intensity rehabilitation increased local strains within the regenerative niche by an average of 44% compared to the low intensity rehabilitation. Finite element modeling demonstrated that resistance rehabilitation significantly increased compressive strain by a factor of 2.0 at week 2 and 4.45 after 4 weeks of rehabilitation. Animals that underwent resistance running had the greatest bone volume and improved functional recovery with regenerated femurs that matched intact failure torque and torsional stiffness values. These results demonstrate the potential for early resistance rehabilitation to improve bone healing.

Abstract Background The primary objective of this study was to assess the frequency of body composition increases and their relationships to changes in body weight in two cohorts of real world, treatment‐naïve, advanced non‐small cell lung cancer (NSCLC) patients. One cohort received the current standard of care (CSOC), which consisted of immunotherapy and newer chemotherapy regimens, and the other cohort was treated with the former standard of care (FSOC), consisting only of older platinum‐containing regimens. Methods CSOC (n = 106) and FSOC (n = 88) cohorts of advanced NSCLC patients were included in this study. Weights were collected at each clinical visit, and body composition analysis from routine chest computed tomography via automated segmentation software assessed at baseline and at 6 and 12 weeks. Standard statistical methods were used to calculate relationships between changes in weight and in body composition. Results The CSOC cohort contained 106 stage IV NSCLC patients treated between 16/12/2014 and 22/10/2020 while the FSOC cohort contained 88 stage III/IV NSCLC patients treated between 16/6/2006 and 18/11/2014. While each cohort exhibited decreases in median weight, body mass index (BMI), mean skeletal muscle index (SMI) and subcutaneous adipose tissue index (SATI) at the 6 and 12 week time points, a subset of patients experienced increases in these parameters. Using a threshold of ≥2.5% increase for weight, BMI, SMI, and SATI at the 12 week time point, both cohorts showed similar (20.5% and 27.3%) increases in these parameters. With a cut point of ≥5% increase at 12 weeks follow‐up, 8.0% to 25.0% of the patients gained ≥5% in weight, BMI, SMI and SATI. Comparing these results in each cohort showed no significant differences. Pearson coefficients for weight change related to changes in SMI and SATI at 6 and 12 weeks ranged from 0.31 to 0.58 with all P values

Abstract Additional and refurbished pumping stations are required to mitigate the intensifying occurrence of droughts and floodings. These installations negatively impact threatened freshwater fish populations due to the increased risk of injury and mortality when fish pass through them. Fish-friendly pumping installations have been proposed as a potential solution to reduce these risks. However, published assessments of these new types of pumps remains lacking, and the few available studies do not enable a cross-comparison with conventional pump types. The promising, yet understudied, Fairbank Nijhuis ‘fish-friendly’ axial flow pump has been assessed in previous works, however the results remain ambiguous due to low recapture rates, unconsidered parameters, fixed operating conditions, and the inability to identify the likely sources of injury and mortality. In this study, we address the limitations of previous works by implementing a standardized protocol for live fish in conjunction with passive barotrauma detection sensors. The major finding of this work is that safe passage of eel (100% survival) is confirmed, but that bream and roach had a much lower survival probability (24% and 70% survival respectively) than expected, albeit higher than for a conventional axial flow pump (roach survival: 13%). Furthermore, roach and bream passing at higher rpm suffered significantly higher mortalities. The impact of the impeller was found to be the most common source of severe injury for both pumps. These results are significant because they conclusively show that fish-friendly pumps may be considered safe for eel, but not for other endemic European fish species such as roach and bream.

Abstract The RNA-binding protein Hu antigen R (HuR) plays a pivotal role in cancer progression, and previous studies have demonstrated its involvement in suppressing cell death in cancer. However, the precise mechanisms underlying HuR inhibition-induced cell death remain elusive. Here, we investigated the impacts of HuR functional inhibition via the small molecule inhibitor KH-3 on cell proliferation, colony formation, and cell death across multiple cancer cell lines, with an emphasis on breast and prostate cancers. KH-3 treatment induced apoptotic cell death of various cancer cell lines, as well as autophagy-associated cell death and ferroptosis. Remarkably, KH-3-induced cell death was partially rescued by an autophagy inhibitor and a ferroptosis inhibitor. The anti-tumor effects of KH-3 were further validated in two mouse xenograft models of human prostate cancer. Mechanistically, KH-3 reduced the expression of HuR targets involved in apoptosis and ferroptosis suppression, including cFLIP and SLC7A11, respectively. Moreover, cFLIP silencing enhanced Caspase-8 activation as well as PARP cleavage in both breast cancer and prostate cancer cells. Both KH-3-induced pharmacological HuR inhibition and RNA interference-mediated HuR knockdown reduced the expression of SLC7A11. Additionally, KH-3 also reduced XIAP and Survivin, enhancing the activation of multiple caspases and leading to apoptosis. This study highlights the critical roles of HuR in programmed cell death regulation, advocating HuR inhibition as a promising anti-tumor strategy for cell-death-inducing cancer therapy.

Abstract Background Mobile health (mHealth) applications have been utilized in chronic diseases to improve medication adherence, though factors driving engagement remain understudied. We previously demonstrated the benefits of mHealth app utilization in increasing adherence to hydroxyurea. In the “Integration of mHealth into Sickle Cell Disease (SCD) Care to Increase Hydroxyurea Utilization” (meSH) study, greater engagement with the InCharge Health app increased the percentage of days covered (PDC) for hydroxyurea. However, factors influencing app engagement were not investigated. This study aimed to identify patient-level factors associated with mHealth engagement during and post-study among adolescents and adults with SCD. Methods All meSH participants were included. The InCharge Health app use was measured for 24 weeks (study period) and 12 weeks (post-study period). Baseline demographics and validated measures of self-efficacy, financial hardship, and pain severity, impact, and frequency were evaluated as predictors of app engagement during the study period and post-study using linear models. Results Complete app use data were obtained from 284 of 293 participants, including 150 (52.8%) females and 240 (84.8%) who were HbSS/HbSβ0-thalassemia with a median age of 27 years. During the study period, 232 (81.7%) used InCharge Health at least once (median use excluding zeros: 26 days; IQR: 7–72 days). During the post-study period, 132 (46.5%) participants used the app at least once (median use excluding zeros: 16 days; IQR: 3–44 days). During the study period, the HbSS genotype, age > 25 years, higher education, higher self-efficacy score, and lower pain severity were associated with greater app engagement. Only age (p = 0.0032) and financial hardship (p = 0.0125) were significant in a multivariable model after backward elimination. During the post-study period, older age (p = 0.035), lower pain severity (p = 0.021) and lower frequency of pain (p = 0.033) predicted mHealth engagement. All three remained significant in a multivariable model after backward elimination. Conclusions Older age, lower financial hardship, lower pain severity, and greater self-efficacy were associated with increased engagement with a mHealth intervention for improving medication adherence among people living with SCD. This research can shift future app development from focusing on factors that drive patient interaction with mHealth targeting modifiable factors influencing app engagement. Trial registration The trial was registered with ClinicalTrials.gov. Registration Identifier: NCT04080167. Registration date: November 11, 2019.

Generation of cardiomyocytes from human pluripotent stem cells (hPSCs) is of high interest for disease modelling and regenerative medicine. hPSCs can provide an unlimited source of patient-specific cardiomyocytes that are otherwise difficult to obtain from individuals. Moreover, the low proliferation rate of adult cardiomyocytes and low viability ex vivo limits the quantity of study material. Most protocols for the differentiation of cardiomyocytes from hPSCs are based on the temporal modulation of the Wnt pathway. However, during the initial stage of GSK-3 inhibition, a substantial number of cells are lost due to detachment. In this study, we aimed to increase the efficiency of generating cardiomyocytes from hPSCs. We identified cell death as a detrimental factor during this initial stage of in vitro cardiomyocyte differentiation. Through pharmacological targeting of different types of cell death, we discovered that ferroptosis was the main cell death type during the first 48 h of the in vitro differentiation procedure. Inhibiting ferroptosis using ferrostatin-1 during cardiomyocyte differentiation resulted in increased robustness and cell yield.

Abstract Plasmodium vivax transmission occurs throughout the tropics and is an emerging threat in areas of Plasmodium falciparum decline, causing relapse infections that complicate treatment and control. Targeted sequencing for P. falciparum has been widely deployed to detect population structure and the geographic spread of antimalarial and diagnostic resistance. However, there are fewer such tools for P. vivax. Leveraging global variation data, we designed four molecular inversion probe (MIP) genotyping panels targeting geographically differentiating SNPs, neutral SNPs, putative antimalarial resistance genes, and vaccine candidate genes. We deployed these MIP panels on 866 infections from the Peruvian Amazon and identified transmission networks with clonality (IBD[identity by descent]>0.99), copy number variation in Pvdbp and multiple Pvrbps, mutations in antimalarial resistance orthologs, and balancing selection in 13 vaccine candidate genes. Our MIP panels are the broadest genotyping panel currently available and are poised for successful deployment in other regions of P. vivax transmission.

Abstract Plasmodium ovale curtisi (Poc) and Plasmodium ovale wallikeri (Pow) are relapsing malaria parasites endemic to Africa and Asia that were previously thought to represent a single species. Amid increasing detection of ovale malaria in sub-Saharan Africa, we present a population genomic study of both species across the continent. We conducted whole-genome sequencing of 25 isolates from Central and East Africa and analyzed them alongside 20 previously published African genomes. Isolates are predominantly monoclonal (43/45), with their genetic similarity aligning with geography. Pow shows lower average nucleotide diversity (1.8×10−4) across the genome compared to Poc (3.0×10−4) (p

Abstract Background Immune checkpoint inhibitors (ICIs) have revolutionized the treatment landscape for non-small cell lung cancer (NSCLC). The variability in patient responses necessitates a blood-based, multi-cohort gene signature to predict ICI response in NSCLC. Methods We performed transcriptomic profiling of peripheral blood mononuclear cell (PBMC) and buffy coat (BC) samples from three independent cohorts of NSCLC patients treated with ICIs: a retrospective cohort (PMBCR, n = 59), a retrospective validation cohort (BC, n = 44), and a prospective validation cohort (PBMCP, n = 42). We identified a 5-gene signature (UQCRB, NDUFA3, CDKN2D, FMNL1-DT, and APOL3) predictive of ICI response and validated its clinical utility in the prospective PBMCP cohort. Response was evaluated using RECIST criteria, and patients were followed up for progression-free survival (PFS) and overall survival (OS). Results In the prospective PBMCP cohort, the 5-gene signature demonstrated high accuracy in stratifying patients into responders and non-responders (AUC = 0.89, 95% CI: 0.80–0.99). Predicted responders exhibited significantly longer PFS compared to predicted non-responders (median: 13.8 months vs. 4.2 months, HR = 0.21, 95% CI: 0.07–0.58, p = 0.005). Conclusion Our study confirms a 5-gene signature as a key biomarker for ICI response in NSCLC, enhancing treatment precision.

Abstract The emergence of antimalarial drug resistance is an impediment to malaria control and elimination in Africa. Analysis of temporal trends in molecular markers of resistance is critical to inform policy makers and guide malaria treatment guidelines. In a low and seasonal transmission region of southern Zambia, we successfully genotyped 85.5% (389/455) of Plasmodium falciparum samples collected between 2013 and 2018 from 8 spatially clustered health centres using molecular inversion probes (MIPs) targeting key drug resistance genes. Aside from one sample from 2016 carrying K13 622I, no other World Health Organization-validated or candidate artemisinin partial resistance (ART-R) mutations were observed. However, in the more recent years (2016–2017) five novel K13-propeller-domain mutations, C532S, A578S, Q613E, D680N and G718S were identified at low prevalence. Moreover, 13% (CI, 9.6–17.2) of isolates had the AP2MU 160N mutation, which has been associated with delayed clearance following artemisinin combination therapy in Africa. This mutation increased in prevalence between 2015 and 2018 and bears a genomic signature of selection. During this time period, there was an increase in the MDR1 NFD haplotype that is associated with reduced susceptibility to lumefantrine. Sulfadoxine-pyrimethamine polymorphisms were near fixation. While validated ART-R mutations are rare, a mutation associated with slow parasite clearance in Africa appears to be under selection in southern Zambia.

Introduction: Immune checkpoint inhibitors (ICIs) have substantially advanced the treatment of patients with malignant melanoma. However, improving therapeutic efficacy requires identifying drug combinations that elicit durable responses without inducing intolerable toxicity. Within that context, selinexor emerges as a possible combination option that has been shown in preclinical studies to enhance the efficacy of ICI therapy. Methods: In this phase 1b study, we investigated selinexor in combination with pembrolizumab in 25 patients with advanced non-uveal melanoma. Patients received selinexor at a dosage of 60 mg taken orally twice weekly, and pembrolizumab intravenously at a dosage of 200 mg every 3 weeks. Results: Despite the high incidence of adverse events (96%), most treatment-related toxicities were manageable with supportive care and dose reductions. The most common adverse events of any grade were nausea (n = 20; 80%), decreased white blood cell count (n = 15; 60%), vomiting (n = 14; 56%), anemia (n = 12; 48%), fatigue (n = 12; 48%), and decreased platelet count (n = 12; 48%). The 10 patients with treatment-naïve evaluable disease had an objective response rate (ORR) of 70% (n = 7, including three patients with complete response), which was significantly higher than that of the 14 patients with prior anti–programmed cell death protein 1 (anti-PD-1) therapy, whose ORR was 7% (n = 1; p = 0.002). Stable disease was observed in two patients (20%) with treatment-naïve disease and seven patients (50%) with prior anti-PD-1 therapy. Conclusion: Selinexor combined with pembrolizumab showed promising antitumor activity in patients with treatment-naïve metastatic melanoma. The toxicity profile of the combination was consistent with that reported for individual agents, with no additional safety concerns.

Position statement The International Society of Sports Nutrition (ISSN) provides an objective and critical review of the use of a ketogenic diet in healthy exercising adults, with a focus on exercise performance and body composition. However, this review does not address the use of exogenous ketone supplements. The following points summarize the position of the ISSN:1. A ketogenic diet induces a state of nutritional ketosis, which is generally defined as serum ketone levels above 0.5 mM. While many factors can impact what amount of daily carbohydrate intake will result in these levels, a broad guideline is a daily dietary carbohydrate intake of less than 50 grams per day.2. Nutritional ketosis achieved through carbohydrate restriction and a high dietary fat intake is not intrinsically harmful and should not be confused with ketoacidosis, a life-threatening condition most commonly seen in clinical populations and metabolic dysregulation.3. A ketogenic diet has largely neutral or detrimental effects on athletic performance compared to a diet higher in carbohydrates and lower in fat, despite achieving significantly elevated levels of fat oxidation during exercise (~1.5 g/min).4. The endurance effects of a ketogenic diet may be influenced by both training status and duration of the dietary intervention, but further research is necessary to elucidate these possibilities. All studies involving elite athletes showed a performance decrement from a ketogenic diet, all lasting six weeks or less. Of the two studies lasting more than six weeks, only one reported a statistically significant benefit of a ketogenic diet.5. A ketogenic diet tends to have similar effects on maximal strength or strength gains from a resistance training program compared to a diet higher in carbohydrates. However, a minority of studies show superior effects of non-ketogenic comparators.6. When compared to a diet higher in carbohydrates and lower in fat, a ketogenic diet may cause greater losses in body weight, fat mass, and fat-free mass, but may also heighten losses of lean tissue. However, this is likely due to differences in calorie and protein intake, as well as shifts in fluid balance.7. There is insufficient evidence to determine if a ketogenic diet affects males and females differently. However, there is a strong mechanistic basis for sex differences to exist in response to a ketogenic diet.

Over the past two decades, therapeutic antibodies have emerged as a rapidly expanding domain within the field of biologics. In silico tools that can streamline the process of antibody discovery and optimization are critical to support a pipeline that is growing more numerous and complex every year. High-quality structural information remains critical for the antibody optimization process, but antibody-antigen complex structures are often unavailable and in silico antibody docking methods are still unreliable. In this study, DeepAb, a deep learning model for predicting antibody Fv structure directly from sequence, was used in conjunction with single-point experimental deep mutational scanning (DMS) enrichment data to design 200 potentially optimized variants of an anti-hen egg lysozyme (HEL) antibody. We sought to determine whether DeepAb-designed variants containing combinations of beneficial mutations from the DMS exhibit enhanced thermostability and whether this optimization affected their developability profile. The 200 variants were produced through a robust high-throughput method and tested for thermal and colloidal stability (Tonset, Tm, Tagg), affinity (KD) relative to the parental antibody, and for developability parameters (nonspecific binding, aggregation propensity, self-association). Of the designed clones, 91% and 94% exhibited increased thermal and colloidal stability and affinity, respectively. Of these, 10% showed a significantly increased affinity for HEL (5- to 21-fold increase) and thermostability (>2.5C increase in Tm1), with most clones retaining the favorable developability profile of the parental antibody. Additional in silico tests suggest that these methods would enrich for binding affinity even without first collecting experimental DMS measurements. These data open the possibility of in silico antibody optimization without the need to predict the antibody–antigen interface, which is notoriously difficult in the absence of crystal structures.

Abstract Recent findings suggest that adding a visual depiction of a nose to virtual reality displays (virtual nose) can reduce motion sickness. If so, this would be a simple intervention that could improve the experience of a variety of VR applications. However, only one peer-reviewed study has reported a benefit from a virtual nose, and the effect was observed in a single low-powered experiment. To further test the effectiveness of a virtual nose for mitigating motion sickness in VR, we performed a preregistered experiment with higher power and better control. Subjects were presented with simulated movement in a virtual environment using a head-mounted display, and the resulting motion sickness was measured using the Fast Motion Sickness Scale (FMS) and the Simulator Sickness Questionnaire (SSQ). Conditions with and without a virtual nose were tested in separate sessions on different days, and the mean habituation effects were removed analytically. Awareness of the manipulation was assessed with a funnel debriefing procedure. The sample size (n = 32) was chosen to have over 90% power to detect the estimated effect size based on previous data (d z = 0.6). We found no significant difference between motion sickness in conditions with and without the virtual nose. The estimated effect size was close to zero, d z = − 0.02, with a 95% credible interval [− 0.37, 0.33]. Results from a Bayesian analysis imply that any benefit from a virtual nose is unlikely to be more than a 26% reduction in FMS scores, and any cost is unlikely to be more than a 23% increase. Our results do not support the hypothesis that a virtual nose is a general and effective way to relieve motion sickness in virtual reality.

Abstract Background INCbase is an international, multicenter prospective observational study using a customizable web-based modular registry to study the clinical, biological and electrophysiological variation and boundaries of chronic inflammatory demyelinating polyneuropathy (CIDP). The primary objective of INCbase is to develop and validate a clinical prediction model for treatment response. Methods All patients meeting clinical criteria for CIDP can be included in INCbase. Collected data include demographics, clinical history, diagnostics and various domains of clinical outcomes. Data is collected at a minimum of every 6 months for two years, and more frequently at the discretion of the investigational site to allow for assessment of unexpected changes in treatment response or clinical status. Participants can be enrolled in various sub-studies designed to capture data relevant to specific groups of interest. Data is entered directly into the web-based data entry system by local investigators and/or participants. Collection and local storage of biomaterial is optional. To develop a clinical prediction model for treatment response, newly diagnosed patients with active disease warranting start of first-line treatment will be included. The study population will be split into a development and validation cohort. Univariate and multivariate logistic regression analysis will be used to identify and combine predictors at start of treatment for treatment response at six months. Model performance will be assessed through discrimination and calibration in an external validation cohort. The externally validated prediction model will be made available to researchers and clinicians on the INCbase website. Discussion With this study, we aim to create a clinically relevant and implementable prediction model for treatment response to first line treatments in CIDP. INCbase enrollment started in April 2021, with 29 centers across 8 countries and 303 patients participating to date. This collaborative effort between academia, patient advocacy organizations and pharmaceutical industry will deepen our understanding of how to diagnose and treat CIDP.

Abstract During the 2022 mpox outbreak, our study conducted 30 interviews with a recruited sample of Chicago gay men (age 18+) during June-September to investigate their experiences of mpox, HIV/AIDS, and COVID-19. Participants were interviewed with a semi-structured guide about gay sexual identity and social experiences; HIV/AIDS, ART, and PrEP; and COVID-19 behaviors and vaccination. All 30 interview respondents had been fully vaccinated for COVID-19 and expressed minimal COVID-19 vaccine hesitancy. All the men living with HIV in our study were on ART with HIV well controlled. A majority of HIV- participants (70%) were on PrEP, with participants universally aware of PrEP benefits. Additionally, most participants had already received at least one shot of the Jynneos mpox vaccine, with many interviewees enduring long lines, sometimes at multiple locations, before vaccination in primarily gay social spaces. These Chicago gay men demonstrated widespread enthusiasm for mpox vaccination as a disease prevention strategy and most of them had already been vaccinated despite significant barriers. The enthusiasm of the participants in our study emerged within a medical landscape shaped by both COVID-19 vaccination and HIV/AIDS-related health interventions including ART and PrEP, which may have helped instill increased medical trust among this population. Our study suggests that out urban gay men may comprise a distinctive minority population with increased medical trust due to specific social, sexual, and historical experiences.

Abstract In this review, we discuss current research on forest carbon risk from natural disturbance under climate change for the United States, with emphasis on advancements in analytical mapping and modeling tools that have potential to drive research for managing future long-term stability of forest carbon. As a natural mechanism for carbon storage, forests are a critical component of meeting climate mitigation strategies designed to combat anthropogenic emissions. Forests consist of long-lived organisms (trees) that can store carbon for centuries or more. However, trees have finite lifespans, and disturbances such as wildfire, insect and disease outbreaks, and drought can hasten tree mortality or reduce tree growth, thereby slowing carbon sequestration, driving carbon emissions, and reducing forest carbon storage in stable pools, particularly the live and standing dead portions that are counted in many carbon offset programs. Many forests have natural disturbance regimes, but climate change and human activities disrupt the frequency and severity of disturbances in ways that are likely to have consequences for the long-term stability of forest carbon. To minimize negative effects and maximize resilience of forest carbon, disturbance risks must be accounted for in carbon offset protocols, carbon management practices, and carbon mapping and modeling techniques. This requires detailed mapping and modeling of the quantities and distribution of forest carbon across the United States and hopefully one day globally; the frequency, severity, and timing of disturbances; the mechanisms by which disturbances affect carbon storage; and how climate change may alter each of these elements. Several tools (e.g. fire spread models, imputed forest inventory models, and forest growth simulators) exist to address one or more of the aforementioned items and can help inform management strategies that reduce forest carbon risk, maintain long-term stability of forest carbon, and further explore challenges, uncertainties, and opportunities for evaluating the continued potential of, and threats to, forests as viable mechanisms for forest carbon storage, including carbon offsets. A growing collective body of research and technological improvements have advanced the science, but we highlight and discuss key limitations, uncertainties, and gaps that remain.

Abstract Primary cultures of proximal tubule cells are widely used to model the behavior of kidney epithelial cells in vitro. However, de-differentiation of primary cells upon culture has been observed and appreciated for decades, yet the mechanisms driving this phenomenon remain poorly understood. This confounds the interpretation of experiments using primary kidney epithelial cells and prevents their use to engineer functional kidney tissue ex vivo. In this report, we measure the dynamics of cell-state transformations in early primary culture of mouse proximal tubules to identify key pathways and processes that correlate with and may drive de-differentiation. Our data show that the loss of proximal-tubule-specific genes is rapid, uniform, and sustained even after confluent, polarized epithelial monolayers develop. This de-differentiation occurs uniformly across many common culture condition variations. Changes in early culture were strongly associated with the loss of HNF4A. Exogenous re-expression of HNF4A can promote expression of a subset of proximal tubule genes in a de-differentiated proximal tubule cell line. Using genetically labeled proximal tubule cells, we show that selective pressures very early in culture influence which cells grow to confluence. Together, these data indicate that the loss of in vivo function in proximal tubule cultures occurs very early and suggest that the sustained loss of HNF4A is a key regulatory event mediating this change.

Objective This study describes recency of suicide attempt (SA) and suicidal ideation (SI) at index emergency department (ED) visit and post‐ED‐discharge reattempt among pediatric patients. Methods Secondary analysis from the ED Screen for Teens at Risk for Suicide study included patients ages 12–17 who reported a past SA during screening and received a phone call 3‐month post‐ED‐discharge assessing reattempt. Logistic regressions tested past SA/SI recency as predictors of reattempt. Descriptive statistics on SA/SI recency and reattempt are provided. Results Sample included 351 patients reporting a past SA during screening (70% cisgender female, 59% White, 53% psychiatric chief complaint, mean [SD] age = 15.3 [1.5]). 17% (60/351) reattempted suicide post‐ED‐discharge. Compared to patients who attempted over a year ago, patients with recent SA within 3 months, especially 1 week before screening, had greater odds of reattempting (3 months: p

Abstract Fibrosis is involved in 45% of deaths in the United States, and no treatment exists to reverse the progression of lung or kidney fibrosis. Myofibroblasts are key to the progression and maintenance of fibrosis. We investigated features of cell adhesion necessary for monocytes to differentiate into myofibroblasts, seeking to identify pathways key to myofibroblast differentiation. Blocking antibodies against integrins α3, αM, and αMβ2 de-differentiate myofibroblasts in vitro, lower the pro-fibrotic secretome of myofibroblasts, and treat lung fibrosis and inhibit kidney fibrosis in vivo. Decorin’s collagen-binding peptide can be used to direct functionalized blocking antibodies (against integrins-α3, -αM, -αMβ2) to both fibrotic lungs and fibrotic kidneys, reducing the dose of antibody necessary to treat fibrosis. This targeted immunotherapy blocking key integrins may be an effective therapeutic for the treatment of fibrosis.

Abstract Western blot is a popular biomolecular analysis method for measuring the relative quantities of independent proteins in complex biological samples. However, variability in quantitative western blot data analysis poses a challenge in designing reproducible experiments. The lack of rigorous quantitative approaches in current western blot statistical methodology may result in irreproducible inferences. Here we describe best practices for the design and analysis of western blot experiments, with examples and demonstrations of how different analytical approaches can lead to widely varying outcomes. To facilitate best practices, we have developed the blotRig tool for designing and analyzing western blot experiments to improve their rigor and reproducibility. The blotRig application includes functions for counterbalancing experimental design by lane position, batch management across gels, and analytics with covariates and random effects.

Abstract While the critical role of NKX2-1 and its transcriptional targets in lung morphogenesis and pulmonary epithelial cell differentiation is increasingly known, mechanisms by which chromatin accessibility alters the epigenetic landscape and how NKX2-1 interacts with other co-activators required for alveolar epithelial cell differentiation and function are not well understood. Combined deletion of the histone methyl transferases Prdm3 and Prdm16 in early lung endoderm causes perinatal lethality due to respiratory failure from loss of AT2 cells and the accumulation of partially differentiated AT1 cells. Combination of single-cell RNA-seq, bulk ATAC-seq, and CUT&RUN data demonstrate that PRDM3 and PRDM16 regulate chromatin accessibility at NKX2-1 transcriptional targets critical for perinatal AT2 cell differentiation and surfactant homeostasis. Lineage specific deletion of PRDM3/16 in AT2 cells leads to lineage infidelity, with PRDM3/16 null cells acquiring partial AT1 fate. Together, these data demonstrate that NKX2-1-dependent regulation of alveolar epithelial cell differentiation is mediated by epigenomic modulation via PRDM3/16.

Abstract The continued advancement of electrochemical technologies requires an increasingly detailed understanding of the microscopic processes that control their performance, inspiring the development of new multi-modal diagnostic techniques. Here, we introduce a neutron imaging approach to enable the quantification of spatial and temporal variations in species concentrations within an operating redox flow cell. Specifically, we leverage the high attenuation of redox-active organic materials (high hydrogen content) and supporting electrolytes (boron-containing) in solution and perform subtractive neutron imaging of active species and supporting electrolyte. To resolve the concentration profiles across the electrodes, we employ an in-plane imaging configuration and correlate the concentration profiles to cell performance with polarization experiments under different operating conditions. Finally, we use time-of-flight neutron imaging to deconvolute concentrations of active species and supporting electrolyte during operation. Using this approach, we evaluate the influence of cell polarity, voltage bias and flow rate on the concentration distribution within the flow cell and correlate these with the macroscopic performance, thus obtaining an unprecedented level of insight into reactive mass transport. Ultimately, this diagnostic technique can be applied to a range of (electro)chemical technologies and may accelerate the development of new materials and reactor designs.

The future of humanity depends on successfully adapting key cropping systems for food security, such as corn (Zea mays L.), to global climatic changes, including changing air temperatures. We monitored the effects of climate change on harvested yields using long-term research plots that were established in 2001 near Fort Collins, Colorado, and long-term average yields in the region (county). We found that the average temperature for the growing period of the irrigated corn (May to September) has increased at a rate of 0.023 °C yr−1, going from 16.5 °C in 1900 to 19.2 °C in 2019 (p < 0.001), but precipitation did not change (p = 0.897). Average minimum (p < 0.001) temperatures were positive predictors of yields. This response to temperature depended on N fertilizer rates, with the greatest response at intermediate fertilizer rates. Maximum (p < 0.05) temperatures and growing degree days (GDD; p < 0.01) were also positive predictors of yields. We propose that the yield increases with higher temperatures observed here are likely only applicable to irrigated corn and that irrigation is a good climate change mitigation and adaptation practice. However, since pan evaporation significantly increased from 1949 to 2019 (p < 0.001), the region’s dryland corn yields are expected to decrease in the future from heat and water stress associated with increasing temperatures and no increases in precipitation. This study shows that increases in GDD and the minimum temperatures that are contributing to a changing climate in the area are important parameters that are contributing to higher yields in irrigated systems in this region.

Abstract Background The COVID-19 pandemic brought greater focus to the rural mortality penalty in the U.S., which describes the greater mortality rate in rural compared to urban areas. Although it is widely thought that issues such as access to care, age structure of the population, and differences in behavior are likely drivers of the rural mortality penalty, few studies have attempted to tie delayed access to care in rural populations to healthcare outcomes quantitatively. Therefore, it is critical to try and understand these factors to enable more effective public health policy. Methods We performed a cross-sectional analysis of a population of patients with COVID-19 who were admitted to hospitals in the United States between 3/1/2020 and 2/26/2023 to better understand factors leading to outcome disparities amongst groups that all had some level of access to hospital care. Nevertheless, it is widely thought that rural populations often experience delayed access to care, due to transportation and other constraints. Therefore, we hypothesized that deteriorated patient condition at admission likely explained some of the observed difference in mortality between rural and urban populations. Results Our results supported our hypothesis, showing that the rural mortality penalty persists in this population and that by multiple measures, rural patients were likely to be admitted in worse condition, had worse overall health, and were older. Conclusions Although the pandemic threw the rural mortality penalty into sharp relief, it is important to remember that it existed prior to the pandemic and will continue to exist until effective interventions are implemented. This study demonstrates the critical need to address the underlying factors that resulted in rural-dwelling patients being admitted to the hospital in worse condition than their urban-dwelling counterparts during the COVID-19 pandemic, which likely affected other healthcare outcomes as well.

Abstract Background One major goal of total knee arthroplasty (TKA) is to achieve balanced medial and lateral gaps in flexion and extension. While bone resections are planned by the surgeon, soft tissue laxity is largely intrinsic and patient-specific in the absence of additional soft tissue releases. We sought to determine the variability in soft tissue laxity in patients undergoing TKA. Methods We retrospectively reviewed 113 patients undergoing TKA. Data on preoperative knee deformity were collected. Data from a dynamic intraoperative stress examination were collected by a robotic tracking system to quantify maximal medial and lateral opening in flexion (85–95 degrees) and extension (-5–20 degrees). T-tests were used to assess the differences between continuous variables. Results A valgus stress opened the medial compartment a mean of 4.3 ± 2.3 mm (0.0–12.4 mm) in extension and 4.6 ± 2.3 mm (0.0–12.9 mm) in flexion. A varus stress opened the lateral compartment a mean of 5.4 ± 2.4 mm (0.3–12.6 mm) in extension and 6.2 ± 2.5 mm (0.0–13.4 mm) in flexion. The medial compartment of varus knees opened significantly more in response to valgus stress than valgus knees in both extension (5.2 mm vs. 2.6 mm; P

Abstract Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival. The study met its primary endpoint with an objective response rate of 81% (95% CI 65–92%). Median progression free and overall survival were 14.0 (95% CI, 11.3–36.4) and 23.2 months (95% CI, 16.6–36.4), respectively. The median duration of response was 14.9 months. The regimen was well tolerated without unexpected or severe toxicities. In post-hoc ctDNA analysis, baseline ctDNA features were prognostic: Higher tumor fraction and alternative MAPK drivers portended worse outcomes. ctDNA at resistance identified oncogenic mutations and these were detectable 2–8 cycles prior to radiographic progression. Capecitabine, oxaliplatin, trastuzumab and bevacizumab shows robust clinical activity in HER2+ gastroesophageal adenocarcinoma. Combination of VEGF inhibitors with chemoimmunotherapy and anti-PD1 regimens is warranted.

Abstract Staphylococcus aureus is responsible for a substantial number of invasive infections globally each year. These infections are problematic because they are frequently recalcitrant to antibiotic treatment. Antibiotic tolerance, the ability of bacteria to persist despite normally lethal doses of antibiotics, contributes to antibiotic treatment failure in S. aureus infections. To understand how antibiotic tolerance is induced, S. aureus biofilms exposed to multiple anti-staphylococcal antibiotics are examined using both quantitative proteomics and transposon sequencing. These screens indicate that arginine metabolism is involved in antibiotic tolerance within a biofilm and support the hypothesis that depletion of arginine within S. aureus communities can induce antibiotic tolerance. Consistent with this hypothesis, inactivation of argH, the final gene in the arginine synthesis pathway, induces antibiotic tolerance. Arginine restriction induces antibiotic tolerance via inhibition of protein synthesis. In murine skin and bone infection models, an argH mutant has enhanced ability to survive antibiotic treatment with vancomycin, highlighting the relationship between arginine metabolism and antibiotic tolerance during S. aureus infection. Uncovering this link between arginine metabolism and antibiotic tolerance has the potential to open new therapeutic avenues targeting previously recalcitrant S. aureus infections.

Abstract Genome-wide association studies implicate multiple loci in risk for systemic lupus erythematosus (SLE), but few contain exonic variants, rendering systematic identification of non-coding variants essential to decoding SLE genetics. We utilized SNP-seq and bioinformatic enrichment to interrogate 2180 single-nucleotide polymorphisms (SNPs) from 87 SLE risk loci for potential binding of transcription factors and related proteins from B cells. 52 SNPs that passed initial screening were tested by electrophoretic mobility shift and luciferase reporter assays. To validate the approach, we studied rs2297550 in detail, finding that the risk allele enhanced binding to the transcription factor Ikaros (encoded by IKZF1), thereby modulating expression of IKBKE. Correspondingly, primary cells from genotyped healthy donors bearing the risk allele expressed higher levels of the interferon / NF-κB regulator IKKε. Together, these findings define a set of likely functional non-coding lupus risk variants and identify a regulatory pathway involving rs2297550, Ikaros, and IKKε implicated by human genetics in risk for SLE.

Abstract Globally, catadromous freshwater eels of the genus Anguilla are of conservation concern, including critically endangered European eel (Anguilla anguilla). Pumping stations that move river water to a higher elevation severely impact eels during their seaward spawning migration. Fish-friendly pumps can mitigate fish injury and mortality but here we uniquely rethink a fish-friendly pump as a fish passage solution. In this pluriannual study, the seasonal timing of pump operation was misaligned with the typical silver eel migration period. Eels were almost exclusively nocturnal but night-time pumping represented as little as 5.6% a year. Night-time eel approaches were primarily influenced by pump duration and temperature, but did not align with lunar phase, unlike in unregulated rivers. After reaching the pumping station, eel passage was influenced by weedscreen aperture and increased when the aperture was increased. Passive sensor collision suggested non-pump infrastructure could cause injury and mortality to eels. It is therefore recommended pump operation should align with the timing of silver eel migration, weedscreen and pump entrance efficiencies should be maximised, and non-pump infrastructure must have low fish injury risk. Ultimately, considering the entire structure a fish passage solution will help ensure fish-friendly pumps have high conservation value for anguillid eels globally.

Abstract Background Physical activity and metformin pharmacotherapy are associated with improved clinical outcomes in breast and colorectal cancer survivors. Myokines are cytokines secreted from skeletal muscle that may mediate these associations. Methods This hypothesis‐generating analysis used biospecimens collected from a multi‐centre 2 × 2 factorial randomized design of 116 patients with stage I–III breast and colorectal cancer who were randomized to 12 weeks of (1) aerobic exercise (moderate intensity titrated to 220 min/week); (2) metformin (850 mg daily for 2 weeks and then titrated to 850 mg twice per day); (3) aerobic exercise and metformin; or (4) control. Fourteen myokines were quantified using a multiplex panel. Myokine concentrations were log‐transformed, and main effects analyses were conducted using linear mixed‐effects regression models. The type I error rate was controlled with the Holm sequential testing procedure. Results Randomization to exercise increased leukaemia inhibitory factor (1.26 pg/mL, 95% confidence interval [CI]: 0.69, 1.84; adjusted P = 0.001) and interleukin‐15 (2.23 pg/mL, 95% CI: 0.87, 3.60; adjusted P = 0.013) compared with randomization to no exercise. Randomization to metformin decreased apelin (−2.69 pg/mL, 95% CI: −4.31, −1.07; adjusted P = 0.014) and interleukin‐15 (−1.74 pg/mL, 95% CI: −2.79, −0.69; adjusted P = 0.013) compared with randomization to no metformin. Metformin decreased myostatin, irisin, oncostatin M, fibroblast growth factor 21 and osteocrin; however, these changes were not statistically significant after correction for multiple comparisons. Conclusions This pilot study demonstrates that randomization to exercise and metformin elicit unique effects on myokine concentrations in cancer patients. This hypothesis‐generating observation warrants further basic, translational and clinical investigation and replication.

Introduction: Racial and ethnic disparities in the presentation and outcomes of lung cancer are widely known. To evaluate potential factors contributing to these observations, we measured systemic immune parameters in Black and White patients with lung cancer. Methods: Patients scheduled to receive cancer immunotherapy were enrolled in a multi-institutional prospective biospecimen collection registry. Clinical and demographic information were obtained from electronic medical records. Pretreatment peripheral blood samples were collected and analyzed for cytokines using a multiplex panel and for immune cell populations using mass cytometry. Differences between Black and White patients were determined and corrected for multiple comparisons. Results: A total of 187 patients with NSCLC (Black, 19; White, 168) were included in the analysis. Compared with White patients, Black patients had greater comorbidity (median Charlson Comorbidity Index 5 versus 3; p = 0.04) and were more likely to have received previous chemotherapy (79% versus 47%; p = 0.03). Black patients had significantly lower levels of CCL23 and CCL27 and significantly higher levels of CCL8, CXCL1, CCL26, CCL25, CCL1, IL-1b, CXCL16, and IFN-γ (all p < 0.05, false discovery rate < 0.1). Black patients also exhibited greater populations of nonclassical CD16+ monocytes, NKT-like cells, CD4+ cells, CD38+ monocytes, and CD57+ gamma delta T cells (all p < 0.05). Conclusions: Black and White patients with lung cancer exhibit several differences in immune parameters, with Black patients exhibiting greater levels of numerous proinflammatory cytokines and cell populations. The etiology and clinical significance of these differences warrant further evaluation.

Background: Leg-length discrepancy (LLD) can lead to patient dissatisfaction and decreased function after total hip arthroplasty (THA). This study examines the impact of intraoperative fluoroscopy on the magnitude and incidence of LLD after THA. Methods: Patients undergoing primary THA were identified and stratified into cohorts based on one out of 4 surgical approaches and intraoperative fluoroscopy use. The most recent 100 patients matching each cohort were included. Preoperative and postoperative LLD was assessed radiographically via an interteardrop reference line to lesser trochanter measurement.Magnitude of LLD and the proportion of patients in each cohort with LLD >5 mm, >10 mm, and 15 mm were analyzed. Results: Four hundred patients were stratified into 4 equal cohorts. Overall, THA done with fluoroscopy yielded fewer leg length discrepancies than THA done without fluoroscopy. The anterior-based muscle sparing (ABMS) approach with fluoroscopy had significantly less postoperative LLD than the posterior approach without fluoroscopy (3.4 vs 5.1 mm, P < .01) and the ABMS approach in the lateral position without fluoroscopy (3.4 vs 4.8 mm, P = .03). For LLD >5 mm, the ABMS approach with fluoroscopy cohort had significantly fewer patients compared to the ABMS approach without fluoroscopy (23 vs 41, P < .01). For LLD >10 mm, the ABMS approach with fluoroscopy cohort had significantly fewer patients compared to the posterior approach without fluoroscopy (2 vs 15, P < .01). For LLD >15 mm, relative to the posterior approach without fluoroscopy, all other cohorts had significantly fewer outliers (P < .02). Conclusions: This study supplies evidence that use of intraoperative fluoroscopy is likely beneficial in reducing the magnitude of LLD following THA and reducing the incidence of outlier LLDs >5 mm, >10 mm, and

Background: The purpose of this study was to compare complication rates and clinical outcomes at 1 year or until death based on the surgical approach for total hip replacement in femoral neck fractures. Methods: This retrospective study was performed on 101 patients with displaced femoral neck fractures at our institution between 2005 and 2022. All surgeries were performed by fellowship-trained arthroplasty surgeons via either a posterior Kocher-Langenbeck approach, an abductor sparing anterolateral approach, or a direct anterior approach. Demographics were collected, as well as intraoperative characteristics, discharge information, and complications. Results: Thirty-seven patients underwent a direct anterior approach, 42 underwent an abductor sparing anterolateral approach, and 22 underwent a posterior approach, with no significant difference in demographics between the groups. Of patients, 43.3% were able to be discharged home, while 55.4% of patients went to subacute rehab or other nursing home facility. There was a 30.6% complication rate, a 7% reoperation rate, and a 0.9% dislocation rate. The posterior group was more likely to be discharged to rehab instead of home (82.0% compared to 48.6%, P = .0054) and had a significant increase in complication rate (P = .04). There was a 36.3% rate of transfusion in the posterior group compared to a 5.0% rate in the anterior group (P < .0001). Conclusions: Anterior-based total hip arthroplasty for femoral neck fractures in our series demonstrated a significantly lower rate of postoperative complications, a lower rate of transfusion, and a significantly higher rate of being discharged home. Level of Evidence: Level III.

BackgroundSocially isolated individuals tend to have less access to cognitively stimulating activities, which could adversely impact their cognitive health. The Internet-Based Conversational Engagement Clinical Trial (I-CONECT) intervention was designed to deliver online conversation sessions to socially isolated older old adults to prevent cognitive decline. The current study examined the intervention efficacy on participants’ weekly time spent out-of-home and their social interaction with family and friends.MethodsThe intervention group engaged in frequent conversations with trained interviewers via the Internet. Both intervention and control group participants received 10-min weekly phone check-in calls over 48 weeks, during which they were asked to self-report their time (in hours) spent out of home and whether they had contacted family or friends during this week (yes/no). Linear mixed-effect models for repeated measures were run for time spent out-of-home, and mixed-effect models with a logistic link for contact with family and friends. The intervention effect was modeled by including an interaction term of time (measured in weeks) and group assignments (intervention vs. control). We ran subgroup analyses for participants with normal cognition (NC) and mild cognitive impairment (MCI). All models controlled for age, sex, race, education, and the historical event of COVID-19.Results5,495 weekly records were included in the analysis. The main effect of time was statistically significant (p

IntroductionMeningiomas are the most common primary central nervous system (CNS) tumor in adults, comprising one-third of all primary adult CNS tumors. Although several recent publications have identified molecular alterations in meningioma including characteristic mutations, copy number alterations, and gene expression signatures, our understanding of the drivers of meningioma recurrence is limited.ObjectiveTo identify gene expression signatures of 1p-22q-NF2- meningioma recurrence, with concurrent biallelic inactivation of NF2 and loss of chr1p that are heterogenous but enriched for recurrent meningiomas.MethodsTranscriptomic alterations present in recurrent versus primary 1p-22q-NF2- meningiomas were identified using RNA sequencing (RNA-seq) data in a clinically annotated cohort.ResultsRecurrent 1p-22q-NF2- meningiomas were enriched for a newly identified GSTM1 null genotype compared to primary meningiomas that showed variable GSTM1 expression and independent external validation was performed.ConclusionsThe GSTM1 null genotype is a novel biomarker of 1p-22q-NF2- meningioma recurrence that resolves heterogeneity in existing meningioma subtypes and may be used to guide future clinical management decisions on extent of treatment to improve patient outcomes.

Objective: Pharmacologic or genetic manipulation of O-GlcNAcylation, an intracellular, single sugar post-translational modification, are difficult to interpret due to the pleotropic nature of O-GlcNAc and the vast signaling pathways it regulates. Method: To address the pleotropic nature of O-GlcNAc, we employed either OGT (O-GlcNAc transferase), OGA (O-GlcNAcase) liver knockouts, or pharmacological inhibition of OGA coupled with multi-Omics analysis and bioinformatics. Results: We identified numerous genes, proteins, phospho-proteins, or metabolites that were either inversely or equivalently changed between conditions. Moreover, we identified pathways in OGT knockout samples associated with increased aneuploidy. To test and validate these pathways, we induced liver growth in OGT knockouts by partial hepatectomy. OGT knockout livers showed a robust aneuploidy phenotype with disruptions in mitosis, nutrient sensing, protein metabolism/amino acid metabolism, stress response, and HIPPO signaling demonstrating how OGT is essential in controlling aneuploidy pathways. Conclusion: These data show how a multi-Omics platform can disentangle the pleotropic nature of O-GlcNAc to discern how OGT fine-tunes multiple cellular pathways involved in aneuploidy.

Abstract. Introduction:. Chronic overlapping pain conditions (COPCs), such as chronic low back pain (cLBP) and fibromyalgia, frequently cooccur and incur substantial healthcare costs. However, to date, much focus has been placed on individual anatomically based chronic pain conditions, whereas little is known about the mechanisms underlying progression to multiple (more than 1) COPCs. This study aims to address the gap by investigating the role of common and modifiable risk factors, specifically sleep and circadian rhythm disturbances, in the development of multiple COPCs. Methods:. The study will enroll 300 participants with cLBP, including 200 with cLBP only and 100 with cLBP plus other COPCs (ie, fibromyalgia, temporomandibular disorders, irritable bowel syndrome, and chronic headaches) and follow them up for 12 months. Sleep and circadian rhythms will be assessed using wireless sleep electroencephalography, 24-hour evaluation of the rhythm of urinary 6-sulfatoxymelatonin, actigraphy, and sleep diaries. Pain amplification using quantitative sensory testing, psychological distress using validated self-report measures, and the number of pain sites using a pain body map will also be assessed. Perspectives:. This research aims to (1) comprehensively characterize sleep/circadian disturbances in individuals with single and multiple COPCs using multimodal in-home assessments; (2) examine the associations between sleep/circadian disturbances, changes in pain amplification, and psychological distress; and (3) investigate the relationship among these factors and the progression in the number of pain sites, a proxy for multiple COPCs. The findings will provide insights into the mechanisms leading to multiple COPCs, potentially informing treatment and prevention strategies for these complex conditions.

Background: The purpose of this study is to compare 30-day perioperative outcomes following treatment of intertrochanteric (IT) fractures with intramedullary nail (IMN), total hip arthroplasty (THA), or hemiarthroplasty (HA). Methods: Using the National Surgical Quality Improvement Program database, we conducted a retrospective cohort study of patients who had sustained an IT fracture treated with primary IMN, THA, or HA between 2017 and 2020. International Classification of Diseases, 10th Revision codes S72.141-S72.146, subtypes A through C, were used to identify eligible patients and were cross-referenced to primary Current Procedural Terminology codes, used to identify the following procedure types: 27245: IMN; 27130: THA; and 27236: HA. Revision cases and patients who underwent arthroplasty for osteoarthritis were excluded. Outcomes of interest included reoperation, readmission, operative time, length of stay, and major and minor complications. Multivariate regression was used to evaluate differences in postoperative outcomes between groups. Results: There were 29,809 IT fractures treated with IMN (94.6%), 1493 treated with HA (4.7%), and 217 treated with THA (0.70%). There was a statistically significant increase in 30-day reoperation rates (adjusted odds ratio [aOR] = 1.99 [95% confidence interval = 1.51, 2.63], P < .001) when combining all arthroplasty patients compared to IMN. There was no statistically significant difference in the overall complication rate between IMN (13.58%) and HA (14.60%, aOR = 1.09, P = .315) or THA (11.98%, aOR = 1.00, P = .998). When compared to IMN (0.12%), there was a statistically significantly decreased need for transfusion in the HA group (aOR = 0.71 [95% confidence interval = 0.61, 0.80], P < .001). Conclusions: Primary HA is associated with an increased 30-day reoperation rate and decreased need for blood transfusion, but there were no other significant differences in postoperative morbidity identified among IMN, THA, and HA in the treatment of IT fractures. Given the challenges and inferior outcomes associated with conversion arthroplasty, the lack of significant difference in morbidity between the 3 groups suggests that primary arthroplasty may be a safe and viable treatment option in selected patients with IT fractures. Comparative studies with longer clinical follow-up will be necessary to establish the appropriate indications and further evaluate the clinical outcomes of primary arthroplasty in the treatment of IT fractures.

Arrhythmogenic cardiomyopathy is a severe genetic heart muscle disease characterized by fibro-fatty replacement of the myocardium. Pathogenic variants causal for this disease are mainly located in desmosomal genes, including desmoplakin (DSP). Renal epithelial cells were isolated from a patient carrying the heterozygous c.817C>T (p.Q273*, nonsense) pathogenic variant in DSP, and subsequently reprogrammed using the Cytotune®-iPS 2.0 Sendai Reprogramming Kit. An isogenic control line was generated using CRISPR/Cas9 genome editing. The resulting induced pluripotent stem cell lines were characterized and displayed the required traits for in vitro disease modeling.

The area burned by wildfires in Canada in 2023 is unprecedented in historical records. To help ensure the safety of communities and support the mobilization of firefighting resources, rapid detection of areas affected by wildfires is required. Satellite data are ideally suited to provide near real-time wildfire information over large areas. At the same time, clouds, smoke, and haze can obscure the collection of observations from sensors typically used for mapping purposes. Established methods using coarse spatial resolution satellites (e.g., MODIS, VIIRS) rely upon the combination of daily revisit to enable the rapid and reliable detection of large active fires, in full or in part, and the application of modeling (including spatial buffering) to infer additional, yet still obscured, areas. While timely, these initial maps of wildfire-impacted areas do not capture small fires (those smaller than 200 ha) and, importantly, are not intended to differentiate unburned areas within fire perimeters. To address these limitations, we used data from Sentinel-2A and -2B, and Landsat-8 and -9, which form a virtual constellation of four satellites to revisit and map burned area in Canada's forested ecosystems for the 2023 fire season. Availing upon the high temporal data density and using the Tracking Intra- and Inter-year Change algorithm (TIIC), an aggregate seasonal mapping of wildfires resulted in a total area affected by wildfires in 2023 of 12.74 Mha. Within this total area, 9.51 Mha of treed land cover was impacted. Shrubs and wetlands comprised most of the remaining non-treed area that was burned. Using a 2022 map of aboveground treed biomass (AGB), approximately 0.649 Pg of AGB was impacted by 2023 wildfires, representing an 11-fold increase in AGB impacts relative to a long-term annual average of treed AGB loss. Differences between the estimate of total burned area reported herein and the total burned area indicated by the Natural Resources Canada (NRCan) Fire M3 hotspot fire perimeters (18.64 Mha) were analyzed. Overall, estimates of burned area differed by 5.9 Mha, including over 1.13 Mha of water identified as burned within the NRCan perimeters. Differences in land cover and AGB impacts between the two products were also investigated and quantified. TIIC enables the near-continuous capture of areas impacted by fire through the fire season, allowing for within-year refinement of total burned area, rapid interrogation of land cover types impacted, and estimation of associated biomass consequences.

Most of the genome is transcribed into RNA but only 2% of the sequence codes for proteins. Non-coding RNA transcripts include a very large number of long noncoding RNAs (lncRNAs). A growing number of identified lncRNAs operate in cellular stress responses, for example in response to hypoxia, genotoxic stress, and oxidative stress. Additionally, lncRNA plays important roles in epigenetic mechanisms operating at chromatin and in maintaining chromatin architecture. Here, we address three lncRNA topics that have had significant recent advances. The first is an emerging role for many lncRNAs in cellular stress responses. The second is the development of high throughput screening assays to develop causal relationships between lncRNAs across the genome with cellular functions. Finally, we turn to recent advances in understanding the role of lncRNAs in regulating chromatin architecture and epigenetics, advances that build on some of the earliest work linking RNA to chromatin architecture.

AbstractPer- and polyfluoroalkyl substances (PFASs) are a large class of compounds used in a variety of processes and consumer products. Their unique chemical properties make them ubiquitous and persistent environmental contaminants while also making them economically viable and socially convenient. To date, several reviews have been published to synthesize information regarding the immunotoxic effects of PFASs on the adaptive immune system. However, these reviews often do not include data on the impact of these compounds on innate immunity. Here, current literature is reviewed to identify and incorporate data regarding the effects of PFASs on innate immunity in humans, experimental models, and wildlife. Known mechanisms by which PFASs modulate innate immune function are also reviewed, including disruption of cell signaling, metabolism, and tissue-level effects. For PFASs where innate immune data are available, results are equivocal, raising additional questions about common mechanisms or pathways of toxicity, but highlighting that the innate immune system within several species can be perturbed by exposure to PFASs. Recommendations are provided for future research to inform hazard identification, risk assessment, and risk management practices for PFASs to protect the immune systems of exposed organisms as well as environmental health.

ABSTRACTBackground Orthokeratinized odontogenic cyst (OOC) is a rare developmental odontogenic cyst that is clinically and histomorphologically different than odontogenic keratocyst (OKC).Case Description OOC is a distinct entity from OKC with a unique biological behavior, pathogenesis, and prognosis. The distinction between these entities is paramount because unlike OKCs, OOCs rarely recur after simple enucleation and are not associated with nevoid basal cell carcinoma syndrome. We present a case of an 8-year-old male with an OOC of the right posterior mandible along with a differential diagnosis and discussion of OOCs and its common mimics.

ABSTRACTEmerging evidence indicates that antibiotic-induced dysbiosis can play an etiological role in the pathogenesis of neuropsychiatric disorders. However, most of this evidence comes from rodent models. The objective of this study was to evaluate if antibiotic-induced gut dysbiosis can elicit changes in gut metabolites and behavior indicative of gut-brain axis disruption in common marmosets (Callithrix jacchus) – a nonhuman primate model often used to study sociability and stress. We were able to successfully induce dysbiosis in marmosets using a custom antibiotic cocktail (vancomycin, enrofloxacin and neomycin) administered orally for 28 days. This gut dysbiosis altered gut metabolite profiles, behavior, and stress reactivity. Increase in gut Fusobacterium spp. post-antibiotic administration was a novel dysbiotic response and has not been observed in any rodent or human studies to date. There were significant changes in concentrations of several gut metabolites which are either neurotransmitters (e.g., GABA and serotonin) or have been found to be moderators of gut-brain axis communication in rodent models (e.g., short-chain fatty acids and bile acids). There was an increase in affiliative behavior and sociability in antibiotic-administered marmosets, which might be a coping mechanism in response to gut dysbiosis-induced stress. Increase in urinary cortisol levels after multiple stressors provides more definitive proof that this model of dysbiosis may cause disrupted communication between gut and brain in common marmosets. This study is a first attempt to establish common marmosets as a novel model to study the impact of severe gut dysbiosis on gut-brain axis cross-talk and behavior.

Abstract Habitat‐based approaches to animal conservation are bolstered by an understanding of resource selection, that is, use of resources (i.e., habitat features) relative to their availability in the environment. Quantifying resource selection is especially valuable when data characterizing animal space use are limited, as is often the case with mobile and/or cryptic species. Documenting associations with habitat features can better inform management in space in time, while also revealing key insight into movement ecology and behavior. Here, we evaluate resource selection by a megaomnivore whose highly mobile nature within marine habitats has resulted in an incomplete understanding of drivers of space use. We used satellite telemetry to track 29 green turtles (Chelonia mydas) from an eastern Pacific foraging aggregation in San Diego Bay, California, USA during 2013–2023. Tracking produced 5023 Fastloc‐GPS points which we used to model selection for local environmental resources relative to their availability. We employed logistic models to evaluate associations with seagrass, bathymetry, and water temperatures, implementing a framework that additionally allowed us to explore the roles of season, diel period, and turtle body size. Our methods demonstrate an approach for down‐weighting observations according to assumed telemetry error and autocorrelation. Results from fine‐scale resource selection models provide evidence that green turtles in San Diego Bay select for eelgrass meadows (Zostera marina), particularly during the warmest months of the year, but the strength of this selection changes from day to night. We additionally found day–night shifts in depth and temperature selection that changed with turtle body size and season. We discuss these findings in the context of diel patterns in resting and foraging behavior in addition to seasonal changes in thermally sensitive metabolic rates. Our study documents resource associations and provides quantitative information for the management of sea turtle foraging populations and their habitats. We offer key insight into habitat use by green turtles in the eastern Pacific at a pivotal time when multiple indicators point to population growth and expansion within the region.

This viewpoint reviews the empirical evidence regarding the association between social media use and well-being, including life satisfaction and affective well-being, and the association between social media use and ill-being, including loneliness, anxiety, and depressive symptomology. To frame this discussion, this viewpoint will present 10 widely believed myths about social media, each drawn from popular discourse on the topic. In rebuttal, this viewpoint will offer a warranted claim supported by the research. The goal is to bring popular beliefs into dialogue with state-of-the-art quantitative social scientific evidence. It is the intention of this viewpoint to provide a more accurate and nuanced claim to challenge each myth. This viewpoint will bring attention to the importance of using rigorous scientific evidence to inform public debates about social media use and well-being, especially among adolescents and young adults.

As part of U.S. national efforts to combat the detrimental effect of global climate change, the National Institute of Standards and Technology (NIST) was recently tasked to support efforts in direct air capture (DAC) of carbon dioxide research and deployment. In order to develop test procedures, materials, and documentary standards, key characterization methods relevant to DAC materials have been investigated and used to identify desirable properties for a potential Standard Reference Material (SRM). Select amine-supported materials that previously showed potential for DAC applications have been characterized using commonly available laboratory methods. Further insights into the adsorption characteristics have been gained from developing and applying more specialized characterization tools ideal for probing low concentrations of carbon dioxide. A broad suite of capabilities that examine relevant properties under appropriate conditions gives the most profound insights into a material’s specific performance. We advocate for even more specialized capabilities to be developed and standardized to quantitatively monitor the interactions of CO2 with molecular species in complex and often disordered systems to advance DAC and support carbon dioxide reduction (CDR) in general.