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# Introduction Adductor-related groin pain involves an injury to the common aponeurosis connecting the rectus abdominus and adductor longus to the pubis. It commonly occurs in sports that require cutting and pivoting and can result in significant loss of playing time. Platelet-Rich Plasma (PRP) is often indicated for treatment of musculoskeletal disorders and may represent an alternative treatment for patients with adductor-related groin pain. The purpose of this case report is to describe the non-surgical management of adductor-related groin pain in a competitive soccer player with a with an ultrasound (US)-guided PRP injection and physical therapy management. # Case Description A 17-year-old male competitive soccer player with right-sided adductor-related groin pain was treated with an US-guided PRP and a multi-phased physical therapy regimen based on tissue healing and individual patient/criteria progression. The patient completed 12 physical therapy sessions over six weeks post PRP injection. # Outcomes At the end of treatment, clinically meaningful improvements were observed in pain intensity, passive range of motion, strength (handheld dynamometry, Biodex), functional tests, psychosocial (OSPRO-YF) and patient-reported outcomes (HAGOS, LEFS). The subject returned to sport at six weeks post injection without limitation and at three months follow up, the subject reported that he had returned to 95% of his previous level of play. # Discussion This case report may offer support for PRP as an alternative treatment in the management of adductor-related groin pain. Incorporation of PRP as an adjunct to physical therapy led to improvements on all outcomes that surpassed the clinical significance change criteria. # Level of evidence 5

Purpose: To examine age- and sex-related differences in postoperative functional outcomes at approximately 6 months after anterior cruciate ligament reconstruction (ACLR). Methods: In this study, patients who underwent primary ACLR performed a series of return-to-sport functional tests at 5 to 8 months after surgery. Functional tests included strength tests (knee extensors, knee flexors, hip abductors, and hip extensors), a balance test (Y-balance composite score), and hop tests (single, triple, crossover, and 6-m timed hop tests). Limb symmetry was calculated to compare the reconstructed limb with the uninvolved limb. A 2-way multivariate analysis of covariance was used, and effect size was calculated for data analysis. Results: A total of 176 subjects were included in this study. There were no significant interaction between age and sex on return-to-sport functional tests after ACLR. Also, no main effects of age and sex on return-to-sport functional tests were found in our data. Conclusions: Age and sex do not significantly affect functional test performance after ACLR 6 months postoperatively. Level of Evidence: Level III, retrospective review of prospective cohort study.

Self-supported branched poly­(ethylenimine) scaffolds with ordered macropores are synthesized with and without Al2O3 powder additive by cross-linking poly­(ethylenimine) (PEI) with poly­(ethylene glycol) diglycidyl ether (PEGDGE) at −196 °C. The scaffolds’ CO2 uptake performance is compared with a conventional sorbent, i.e., PEI impregnated on an Al2O3 support. PEI scaffolds with Al2O3 additive show narrow pore size distribution and thinner pore walls than alumina-free materials, facilitating higher CO2 uptake at conditions relevant to direct air capture. The PEI scaffold containing 6.5 wt % Al2O3 had the highest CO2 uptake of 1.23 mmol/g of sorbent under 50% RH 400 ppm of CO2 conditions. In situ DRIFT spectroscopy and temperature-programmed desorption experiments show a significant CO2 uptake contribution via physisorption as well as carbamic acid formation, with lower CO2 binding energies in PEI scaffolds relative to conventional PEI sorbents, likely a result of a lower population of primary amines due to the amine cross-linking reactions during scaffold synthesis. The PEI scaffold containing 6.5 wt % Al2O3 is estimated to have the lowest desorption energy penalty under humid conditions, 4.6 GJ/tCO2, among the sorbents studied.

Purpose: Sperm DNA fragmentation (SDF) is a functional sperm abnormality that can impact reproductive potential, for which four assays have been described in the recently published sixth edition of the WHO laboratory manual for the examination and processing of human semen. The purpose of this study was to examine the global practices related to the use of SDF assays and investigate the barriers and limitations that clinicians face in incorporating these tests into their practice. Materials and Methods: Clinicians managing male infertility were invited to complete an online survey on practices related to SDF diagnostic and treatment approaches. Their responses related to the technical aspects of SDF testing, current professional society guidelines, and the literature were used to generate expert recommendations via the Delphi method. Finally, challenges related to SDF that the clinicians encounter in their daily practice were captured. Results: The survey was completed by 436 reproductive clinicians. Overall, terminal deoxynucleotidyl transferase deoxyuridine triphosphate Nick-End Labeling (TUNEL) is the most commonly used assay chosen by 28.6%, followed by the sperm chromatin structure assay (24.1%), and the sperm chromatin dispersion (19.1%). The choice of the assay was largely influenced by availability (70% of respondents). A threshold of 30% was the most selected cut-off value for elevated SDF by 33.7% of clinicians. Of respondents, 53.6% recommend SDF testing after 3 to 5 days of abstinence. Although 75.3% believe SDF testing can provide an explanation for many unknown causes of infertility, the main limiting factors selected by respondents are a lack of professional society guideline recommendations (62.7%) and an absence of globally accepted references for SDF interpretation (50.3%). Conclusions: This study represents the largest global survey on the technical aspects of SDF testing as well as the barriers encountered by clinicians. Unified global recommendations regarding clinician implementation and standard laboratory interpretation of SDF testing are crucial.

Abstract With the continued emergence of variants of concern, the global threat of COVID-19 persists, particularly in low- and middle-income countries with limited vaccine access. Protein-based vaccines, such as SCB-2019, can be produced on a large scale at a low cost while antigen design and adjuvant use can modulate efficacy and safety. While effective humoral immunity against SARS-CoV-2 variants has been shown to depend on both neutralization and Fc-mediated immunity, data on the effectiveness of protein-based vaccines with enhanced Fc-mediated immunity is limited. Here, we assess the humoral profile, including antibody isotypes, subclasses, and Fc receptor binding generated by a boosting with a recombinant trimer-tag protein vaccine SCB-2019. Individuals who were primed with 2 doses of the ChAdOx1 vaccine were equally divided into 4 groups and boosted with following formulations: Group 1: 9 μg SCB-2019 and Alhydrogel; Group 2: 9 μg SCB-2019, CpG 1018, and Alhydrogel; Group 3: 30 μg SCB-2019, CpG 1018, and Alhydrogel; Group 4: ChAdOx1. Group 3 showed enhanced antibody FcγR binding against wild-type and variants compared to Groups 1 and 2, showing a dose-dependent enhancement of immunity conferred by the SCB-2019 vaccine. Moreover, from day 15 after vaccination, Group 3 exhibited higher IgG3 and FcγR binding across variants of concerns, including Omicron and its subvariants, compared to the ChAdOx1-boosted individuals. Overall, this highlights the potential of SCB-2019 as a cost-efficient boosting regimen effective across variants of concerns.

Abstract Although young children generally experience mild symptoms following infection with SARS-CoV-2, severe acute and long-term complications can occur. SARS-CoV-2 mRNA vaccines elicit robust immunoglobulin profiles in children ages 5 years and older, and in adults, corresponding with substantial protection against hospitalizations and severe disease. Whether similar immune responses and humoral protection can be observed in vaccinated infants and young children, who have a developing and vulnerable immune system, remains poorly understood. To study the impact of mRNA vaccination on the humoral immunity of infant, we use a system serology approach to comprehensively profile antibody responses in a cohort of children ages 6 months to 5 years who were vaccinated with the mRNA-1273 COVID-19 vaccine (25 μg). Responses are compared with vaccinated adults (100 μg), in addition to naturally infected toddlers and young children. Despite their lower vaccine dose, vaccinated toddlers elicit a functional antibody response as strong as adults, with higher antibody-dependent phagocytosis compared to adults, without report of side effects. Moreover, mRNA vaccination is associated with a higher IgG3-dependent humoral profile against SARS-CoV-2 compared to natural infection, supporting that mRNA vaccination is effective at eliciting a robust antibody response in toddlers and young children.

ABSTRACTStochastic weather generators create time series that reproduce key weather dynamics present in long-term observations. The dataset detailed herein is a large-scale gridded parameterization for CLImate GENerator (CLIGEN) that fills spatial gaps in the coverage of existing regional CLIGEN parameterizations, thereby obtaining near-global availability of combined coverages. This dataset primarily covers countries north of 40° latitude with 0.25° spatial resolution. Various CLIGEN parameters were estimated based on 20-year records from four popular global climate products. Precipitation parameters were statistically downscaled to estimate point-scale values, while point-scale temperature and solar radiation parameters were approximated by direct calculation from high-resolution datasets. Surrogate parameter values were used in some cases, such as with wind parameters. Cross-validation was done to assess the downscaling approach for six precipitation parameters using known point-scale values from ground-based CLIGEN parameterizations. These parameter values were derived from daily accumulation records at 7,281 stations and high temporal resolution records at 609 stations. Two sensitive parameters, monthly average storm accumulation and maximum 30-minute intensity, were shown have RMSE values of 1.48 mm and 4.67 mm hr−1, respectively. Cumulative precipitation and the annual number of days with precipitation occurrence were both within 5% of ground-based parameterizations, effectively improving climate data availability.

The Water Erosion Prediction Project (WEPP) model has been widely used for estimating runoff and soil loss. The evaluation of the latest version (version 2021.133) under a range of environmental conditions can provide confidence to its users. The objectives of this study were to evaluate the WEPP model for runoff and soil loss predictions using 1159 plot years of rainfall-runoff events data from field experimental plots with various climates, soils, topographies, and crops. WEPP runoff and soil loss predictions were compared to the observations before and after input parameter calibration. The results showed good predictions of runoff and soil loss were obtained with both the uncalibrated and calibrated WEPP model for all considered scales with Nash-Sutcliffe model efficiencies (NSE) over 0.4. The calibration of input baseline effective hydraulic conductivity (ke), baseline critical shear stress (τc), baseline rill erodibility (kr), and baseline interrill erodibility (ki) improved WEPP model performance with NSE values of 0.98 and 0.91 for average annual runoff and soil loss predictions, respectively. The WEPP model tended to underestimate the runoff and soil loss for large events with runoff over 100 mm and soil loss over 120 t/ha. Good event runoff and soil loss predictions (NSE ≥0.4) were obtained for the most common cropping/management systems considered, including corn, cotton, tilled fallow, and wheat after calibration. This study illustrates the most recent WEPP model's performance for runoff and soil loss predictions, and provides a comprehensive set of results.

Background and Clinical Significance: A brain abscess, defined as a localized intracranial infection that evolves into a purulent collection encased by a vascularized capsule, has higher prevalence among immunocompromised populations. Patients with sickle cell disease (SCD) are particularly vulnerable to bacterial infections due to their compromised immune systems, increasing their susceptibility to pathogens like Salmonella. While Salmonella is typically associated with gastroenteritis, osteomyelitis, and septicemia, its involvement in brain abscesses is exceedingly rare. There are few documented cases of Salmonella brain abscesses in the general population, and among patients with SCD, only one such case has been reported to date. In this report, we describe the second known case of a brain abscess caused by Salmonella infection in a patient with sickle cell disease, contributing to the limited literature on this rare and life-threatening condition. Case Presentation: A 32-year-old African American woman with sickle cell disease presented to the ER after a generalized seizure, reporting two weeks of worsening headaches, fevers, and left upper extremity weakness. Imaging revealed a right frontoparietal brain abscess, which was surgically drained, and cultures identified Salmonella enterica. After antibiotic treatment and a 23-day hospital stay, she was discharged. Four months later, she returned with another seizure during a sickle cell crisis, but follow-up MRI showed only minor scarring, and she was discharged on anticonvulsant therapy. Conclusions: This case emphasizes that Salmonella infections, though typically linked to osteomyelitis and sepsis, can also cause brain abscesses in immunocompromised patients like those with sickle cell disease. It highlights the need to consider infections alongside vascular causes in acute neurological cases and underscores the value of a multidisciplinary approach in managing such complex conditions.

(1) Background: As digital health technology evolves, the role of accurate medical-gloved hand tracking is becoming more important for the assessment and training of practitioners to reduce procedural errors in clinical settings. (2) Method: This study utilized computer vision for hand pose estimation to model skeletal hand movements during in situ aseptic drug compounding procedures. High-definition video cameras recorded hand movements while practitioners wore medical gloves of different colors. Hand poses were manually annotated, and machine learning models were developed and trained using the DeepLabCut interface via an 80/20 training/testing split. (3) Results: The developed model achieved an average root mean square error (RMSE) of 5.89 pixels across the training data set and 10.06 pixels across the test set. When excluding keypoints with a confidence value below 60%, the test set RMSE improved to 7.48 pixels, reflecting high accuracy in hand pose tracking. (4) Conclusions: The developed hand pose estimation model effectively tracks hand movements across both controlled and in situ drug compounding contexts, offering a first-of-its-kind medical glove hand tracking method. This model holds potential for enhancing clinical training and ensuring procedural safety, particularly in tasks requiring high precision such as drug compounding.

Promoting diversity in the scientific workforce is crucial for harnessing the potential of available talent and ensuring equitable access to Science, Technology, Engineering, Mathematics, and Medicine (STEM-M) careers. We have developed an innovative program called Postbaccalaureate Research Opportunity to Promote Equity in Learning (PROPEL) that provides scientific and career development training for postbaccalaureate scholars from historically excluded backgrounds in STEM-M fields with an interest in pursuing a PhD or MD/PhD degree. Our program is distinct from other postbaccalaureate programs in that scholars are hired by individual labs rather than funded centrally by the program. This funding mechanism removes the idea that central funding is necessary to encourage faculty to train diverse scholars and allows the program to scale dynamically according to the needs of the scientific community. The PROPEL program started in 2020 with six scholars and has since grown to an enrollment of over 100, making it the largest postbaccalaureate program for biomedical research in the country. Here, we describe the program structure and curriculum, our strategy for recruitment, the enrollment trends, the program demographics, metrics of scholar engagement, and outcomes for scholars who completed the program in 2023. Our experience demonstrates the strong demand from both scholars and faculty for programming of this type and describes the feasibility of implementation.

Background: Smoking is a major public health concern and an important risk factor to consider during preoperative planning. Smoking has previously been reported as the single most important risk factor for developing postoperative complications after elective orthopedic surgery. However, there is limited literature regarding the postoperative complications associated with smoking following outpatient total shoulder arthroplasty (TSA). The purpose of this study was to investigate the association between smoking status and early postoperative complications following outpatient TSA using a large national database. Methods: We queried the American College of Surgeons National Surgical Quality Improvement Program database for all patients who underwent TSA between 2015 and 2020. Smoking status in National Surgical Quality Improvement Program is defined as any episode of smoking with 12 months prior to surgery. Bivariate logistic regression was used to identify patient demographics, comorbidities, and complications significantly associated with current or recent smoking status in patients who underwent TSA with a length of stay (LOS) of 0. Multivariate logistic regression, adjusted for all significantly associated patient demographics and comorbidities, was used to identify associations between current or recent smokers and 30-day postoperative complications. Results: 22,817 patients were included in the analysis, 2367 (10.4%) were current or recent smokers and 20,450 (89.6%) were nonsmokers. These patients were further stratified based on LOS: 2428 (10.6%) patients had a LOS of 0 days, 15,267 (66.9%) patients had a LOS of 1 day, and 5122 (22.4%) patients had a LOS of 2 days. Within the outpatient cohort (LOS = 0), 202 (8.3%) patients were current or recent smokers and 2226 (91.7%) were nonsmokers. Multivariate logistic regression identified current or recent smoking status to be independently associated with higher rates of myocardial infarction (odds ratio [OR] 9.80, 95% confidence interval [CI] 1.48-64.96; P = .018), deep vein thrombosis (OR 20.05, 95% CI 1.63-247.38; P = .019), and readmission (OR 2.82, 95% CI 1.19-6.67; P = .018) following outpatient TSA. Readmission was most often due to pulmonary complication (n = 10, 22.7%). Conclusion: Current or recent smoking status is independently associated with higher rates of myocardial infarction, deep vein thrombosis, and readmission following TSA performed in the outpatient setting. Current or recent smokers may benefit from an inpatient setting of minimum 2 nights. As outpatient TSA becomes increasingly popular, refining proper patient selection criteria is imperative to optimizing postoperative outcomes.

Background: The purpose of this study was to investigate the association between in-hospital length of stay (LOS) and postoperative complication rates within 30 days of total shoulder arthroplasty (TSA). Methods: All patients who underwent either anatomic or reverse TSA between 2015 and 2019 were queried from the American College of Surgeons National Surgical Quality Improvement database. The study population was stratified into three cohorts as follows: LOS 0 (same-day discharge), LOS 1 (next-day discharge), and LOS 2–3 (LOS of 2-3 days). Patient demographics and comorbidities were compared between cohorts using bivariate analysis. Multivariate logistic regression analysis was conducted to investigate the relationship between LOS and postoperative complications. Results: In comparison to the LOS 0 day cohort, LOS 2–3 day cohort had a greater likelihood of developing overall complication (OR, 2.598; P

Purpose: Sperm DNA fragmentation (SDF) has been associated with male infertility and poor outcomes of assisted reproductive technology (ART). The purpose of this study was to investigate global practices related to the management of elevated SDF in infertile men, summarize the relevant professional society recommendations, and provide expert recommendations for managing this condition. Materials and Methods: An online global survey on clinical practices related to SDF was disseminated to reproductive clinicians, according to the CHERRIES checklist criteria. Management protocols for various conditions associated with SDF were captured and compared to the relevant recommendations in professional society guidelines and the appropriate available evidence. Expert recommendations and consensus on the management of infertile men with elevated SDF were then formulated and adapted using the Delphi method.Results: A total of 436 experts from 55 different countries submitted responses. As an initial approach, 79.1% of reproductive experts recommend lifestyle modifications for infertile men with elevated SDF, and 76.9% prescribe empiric antioxidants. Regarding antioxidant duration, 39.3% recommend 4–6 months and 38.1% recommend 3 months. For men with unexplained or idiopathic infertility, and couples experiencing recurrent miscarriages associated with elevated SDF, most respondents refer to ART 6 months after failure of conservative and empiric medical management. Infertile men with clinical varicocele, normal conventional semen parameters, and elevated SDF are offered varicocele repair immediately after diagnosis by 31.4%, and after failure of antioxidants and conservative measures by 40.9%. Sperm selection techniques and testicular sperm extraction are also management options for couples undergoing ART. For most questions, heterogenous practices were demonstrated. Conclusions: This paper presents the results of a large global survey on the management of infertile men with elevated SDF and reveals a lack of consensus among clinicians. Furthermore, it demonstrates the scarcity of professional society guidelines in this regard and attempts to highlight the relevant evidence. Expert recommendations are proposed to help guide clinicians.

Abstract Objectives To assess the adequacy of gadolinium in sialography as an alternative contrast agent for patients with iodine allergies. To directly compare images taken with gadolinium versus iodine‐based contrast agents using the Iowa Sialography Classification System. Methods Retrospective chart review was performed on patients undergoing sialography between February 2008 and July 2022. Patients with sialograms obtained with gadolinium were identified and matched to similar sialograms obtained with iodine‐based contrast agent. Patients were matched based on duct location, duct side, and initial radiology findings. Blinded reevaluation of sialograms was performed first independently and then by consensus by two head and neck radiologists to evaluate overall image adequacy and grade using the Iowa Sialography Classification System. Results Four patients with six sialograms (one bilateral parotid and one parotid + submandibular) obtained with gadolinium were identified and reevaluated. Five patients with six sialograms (one bilateral parotid) obtained with iodine‐based were matched to the gadolinium sialograms. The overall adequacy of images for gadolinium sialograms was graded at an average of 4.25 (4 = good and 5 = excellent); whereas, the overall adequacy of iodine‐based sialograms was graded at an average of 5. Inter‐observer variability was observed in three sialograms obtained with gadolinium (50%), while no interobserver variability was observed in sialograms obtained with iodine‐based contrast agent. Conclusion Gadolinium is an adequate alternative to use in sialography for patients with iodine allergies undergoing contemporary digital infusion sialography. Adverse reactions to iodine contrast agents are rare in sialography; however, the precautionary use of gadolinium is acceptable for the diagnostic and therapeutic benefits in sialography. Level of Evidence: IV

Abstract Background Research conducted in urban areas has highlighted the impact of housing instability on people who inject drugs (PWID), revealing that it exacerbates vulnerability to drug-related harms and impedes syringe service program (SSP) use. However, few studies have explored the effects of houselessness on SSP use among rural PWID. This study examines the relationship between houselessness and SSP utilization among PWID in eight rural areas across 10 states. Methods PWID were recruited using respondent-driven sampling for a cross-sectional survey that queried self-reported drug use and SSP utilization in the prior 30 days, houselessness in the prior 6 months and sociodemographic characteristics. Using binomial logistic regression, we examined the relationship between experiencing houselessness and any SSP use. To assess the relationship between houselessness and the frequency of SSP use, we conducted multinomial logistic regression analyses among participants reporting any past 30-day SSP use. Results Among 2394 rural PWID, 56.5% had experienced houselessness in the prior 6 months, and 43.5% reported past 30-day SSP use. PWID who had experienced houselessness were more likely to report using an SSP compared to their housed counterparts (adjusted odds ratio [aOR] = 1.24 [95% confidence intervals [CI] 1.01, 1.52]). Among those who had used an SSP at least once (n = 972), those who experienced houselessness were just as likely to report SSP use two (aOR = 0.90 [95% CI 0.60, 1.36]) and three times (aOR = 1.18 [95% CI 0.77, 1.98]) compared to once. However, they were less likely to visit an SSP four or more times compared to once in the prior 30 days (aOR = 0.59 [95% CI 0.40, 0.85]). Conclusion This study provides evidence that rural PWID who experience houselessness utilize SSPs at similar or higher rates as their housed counterparts. However, housing instability may pose barriers to more frequent SSP use. These findings are significant as people who experience houselessness are at increased risk for drug-related harms and encounter additional challenges when attempting to access SSPs.

Abstract Background White matter hyperintensities (WMH), a marker of cerebral small vessel disease and predictor of cognitive decline, are observed at higher rates in persons with HIV (PWH). The use of cocaine, a potent central nervous system stimulant, is disproportionately common in PWH and may contribute to WMH. Methods The sample included of 110 PWH on antiretroviral therapy. Fluid‐attenuated inversion recovery (FLAIR) and T1‐weighted anatomical MRI scans were collected, along with neuropsychological testing. FLAIR images were processed using the Lesion Segmentation Toolbox. A hierarchical regression model was run to investigate predictors of WMH burden [block 1: demographics; block 2: cerebrovascular disease (CVD) risk; block 3: lesion burden]. Results The sample was 20% female and 79% African American with a mean age of 45.37. All participants had persistent HIV viral suppression, and the median CD4+ T‐cell count was 750. Nearly a third (29%) currently used cocaine regularly, with an average of 23.75 (SD = 20.95) days in the past 90. In the hierarchical linear regression model, cocaine use was a significant predictor of WMH burden (β = .28). WMH burden was significantly correlated with poorer cognitive function (r = −0.27). Finally, higher WMH burden was significantly associated with increased serum concentrations of interferon‐γ‐inducible protein 10 (IP‐10) but lower concentrations of myeloperoxidase (MPO); however, these markers did not differ by COC status. Conclusions WMH burden is associated with poorer cognitive performance in PWH. Cocaine use and CVD risk independently contribute to WMH, and addressing these conditions as part of HIV care may mitigate brain injury underlying neurocognitive impairment.

The Water Erosion Prediction Project (WEPP) model code was modified extensively to support the simulation of nonpoint source (NPS) pollutant sourcing and transport in nonuniform hillslopes based on NPS science from the Soil and Water Assessment Tool (SWAT). This was accomplished utilizing WEPP's overland flow element (OFE) in place of SWAT's hydrologic response unit (HRU) construct which enabled more physically plausible routing within a hillslope. In addition, several improvements to the NPS code base were implemented. These include: free-source format, modern-Fortran conventions, minor enhancements to NPS model science, and code refactoring. This manuscript documents all model development activities, presents a comparison of relevant WEPP and WEPP-WQ code bases, and performs a local sensitivity analysis of the final model code for the most important input parameters and processes. Sensitivity results indicated that the model performed as expected according to its design and provided important insights for potential subsequent validation studies.

Heat shock protein 90 (Hsp90) is a family of chaperone proteins that consists of four isoforms: Hsp90α, Hsp90β, glucose-regulated protein 94 (Grp94), and tumor necrosis factor type 1 receptor-associated protein (TRAP1). They are involved in modulating the folding, maturation, and activation of their client proteins to regulate numerous intracellular signaling pathways. Previous studies demonstrated that pan-Hsp90 inhibitors reduce inflammatory signaling pathways resulting in a reduction of inflammation and pain but show toxicities in cancer-related clinical trials. Further, the role of Hsp90 isoforms in inflammation remains poorly understood. This study aimed to determine anti-inflammatory activities of Hsp90 isoforms selective inhibitors on the lipopolysaccharide (LPS)-induced inflammation in BV-2 cells, a murine microglial cell line. The production of inflammatory mediators such as nitric oxide (NO), interleukin 1 beta (IL-1β), and tumor necrosis factor-alpha (TNF-α) was measured. We also investigated the impact of Hsp90 isoform inhibitors on the activation of nuclear factor kappa B (NF-κB), nuclear factor erythroid 2–related factor 2 (Nrf2), and mitogen-activated protein kinases (MAPKs). We found that selective inhibitors of Hsp90β reduced the LPS-induced production of NO, IL-1β, and TNF-α via diminishing the activation of NF-κB and Extracellular signal-regulated kinases (ERK) MAPK. The Hsp90α, Grp94, TRAP1 inhibitors had limited effect on the production of inflammatory mediators. These findings suggest that Hsp90β is the key player in LPS-induced neuroinflammation. Thereby providing a more selective drug target for development of medications involved in pain management that can potentially contribute to the reduction of adverse side effects associated with Hsp90 pan inhibitors.

IntroductionLow back pain is the most common type of chronic pain. We examined pain-related behaviors across 18 weeks in rats that received injury to one or two lumbar intervertebral discs (IVD) to determine if multi-level disc injuries enhance/prolong pain.MethodsTwenty-three Sprague-Dawley adult female rats were used: 8 received disc puncture (DP) of one lumbar IVD (L5/6, DP-1); 8 received DP of two lumbar IVDs (L4/5 & L5/6, DP-2); 8 underwent sham surgery.ResultsDP-2 rats showed local (low back) sensitivity to pressure at 6- and 12-weeks post-injury, and remote sensitivity to pressure (upper thighs) at 12- and 18-weeks and touch (hind paws) at 6, 12 and 18-weeks. DP-1 rats showed local and remote pressure sensitivity at 12-weeks only (and no tactile sensitivity), relative to Sham DP rats. Both DP groups showed reduced distance traveled during gait testing over multiple weeks, compared to pre-injury; only DP-2 rats showed reduced distance relative to Sham DP rats at 12-weeks. DP-2 rats displayed reduced positive interactions with a novel adult female rat at 3-weeks and hesitation and freezing during gait assays from 6-weeks onwards. At study end (18-weeks), radiological and histological analyses revealed reduced disc height and degeneration of punctured IVDs. Serum BDNF and TNFα levels were higher at 18-weeks in DP-2 rats, relative to Sham DP rats, and levels correlated positively with remote sensitivity in hind paws (tactile) and thighs (pressure).DiscussionThus, multi-level disc injuries resulted in earlier, prolonged and greater discomfort locally and remotely, than single-level disc injury. BDNF and TNFα may have contributing roles.

BackgroundPrevious research showed that 5-hydroxytryptophan (5HTP), a metabolic precursor of serotonin, reduces allergic lung inflammation by inhibiting eosinophil migration across endothelial monolayers.ObjectiveIt is unknown if serotonin receptors are involved in mediating this 5HTP function or if serotonin receptor (HTR) single nucleotide polymorphisms (SNPs) associate with lung function in humans.MethodsSerotonin receptor subtypes were assessed by qPCR, western blot, confocal microscopy, pharmacological inhibitors and siRNA knockdown. HTR SNPs were assessed in two cohorts.ResultsPharmacological inhibition or siRNA knockdown of the serotonin receptors HTR1A or HTR1B in endothelial cells abrogated the inhibitory effects of 5HTP on eosinophil transendothelial migration. In contrast, eosinophil transendothelial migration was not inhibited by siRNA knockdown of HTR1A or HTR1B in eosinophils. Surprisingly, these HTRs were intracellular in endothelial cells and an extracellular supplementation with serotonin did not inhibit eosinophil transendothelial migration. This is consistent with the inability of serotonin to cross membranes, the lack of selective serotonin reuptake receptors on endothelial cells, and the studies showing minimal impact of selective serotonin reuptake inhibitors on asthma. To extend our HTR studies to humans with asthma, we examined the CHIRAH and GALA cohorts for HTR SNPs that affect HTR function or are associated with behavior disorders. A polygenic index of SNPs in HTRs was associated with lower lung function in asthmatics.ConclusionsSerotonin receptors mediate 5HTP inhibition of transendothelial migration and HTR SNPs associate with lower lung function. These results may serve to aid in design of novel interventions for allergic inflammation.

Abstract Predicting the subcutaneous (SC) pharmacokinetics (PK) of antibodies in humans is challenging, with clinical data currently being the only reliable data source for modeling SC absorption and bioavailability. Recombinant human hyaluronidase PH20 (rHuPH20) is an enzyme that facilitates SC delivery of high‐dose, high‐volume therapeutics. Numerous monoclonal antibodies have been co‐administered SC with rHuPH20 in a clinical setting, establishing an extensive PK database. The goal of this work is to demonstrate how aggregated clinical data can be leveraged in a universal modeling framework for characterizing SC antibody PK, resulting in parameterization that can be used in predictive simulations of new antibodies. Data for 10 individual antibodies co‐administered SC with rHuPH20 were obtained from publicly available sources. PK modeling of each antibody was conducted using the same model structure, but uniquely parameterized. The model structure consisted of a two‐compartment model to capture linear kinetics, plus a target‐binding mechanism to accommodate nonlinear kinetics driven by antibody‐target complex formation and elimination. The clinical PK profiles for all antibodies were accurately described using the universal modeling framework. The SC PK parameters of absorption and bioavailability were consistent across the range of antibody and target properties evaluated. SC administration with rHuPH20 yielded a 30% increase in absorption rate on average and similar or better bioavailability. These parameter values can serve as initial conditions for model‐based PK predictions for new antibodies co‐administered SC with rHuPH20 to enable evaluation of optimal SC dose and schedule regimens prior to and during clinical development.

ObjectivePositive antinuclear antibodies (ANAs) cause diagnostic dilemmas for clinicians. Currently, no tools exist to help clinicians interpret the significance of a positive ANA in individuals without diagnosed autoimmune diseases. We developed and validated a risk model to predict risk of developing autoimmune disease in positive ANA individuals.MethodsUsing a de-identified electronic health record (EHR), we randomly chart reviewed 2,000 positive ANA individuals to determine if a systemic autoimmune disease was diagnosed by a rheumatologist. A priori, we considered demographics, billing codes for autoimmune disease-related symptoms, and laboratory values as variables for the risk model. We performed logistic regression and machine learning models using training and validation samples.ResultsWe assembled training (n = 1030) and validation (n = 449) sets. Positive ANA individuals who were younger, female, had a higher titer ANA, higher platelet count, disease-specific autoantibodies, and more billing codes related to symptoms of autoimmune diseases were all more likely to develop autoimmune diseases. The most important variables included having a disease-specific autoantibody, number of billing codes for autoimmune disease-related symptoms, and platelet count. In the logistic regression model, AUC was 0.83 (95% CI 0.79-0.86) in the training set and 0.75 (95% CI 0.68-0.81) in the validation set.ConclusionWe developed and validated a risk model that predicts risk for developing systemic autoimmune diseases and can be deployed easily within the EHR. The model can risk stratify positive ANA individuals to ensure high-risk individuals receive urgent rheumatology referrals while reassuring low-risk individuals and reducing unnecessary referrals.

Adolescent alcohol drinking is linked to high rates of adult alcohol problems and alcohol use disorder (AUD). The Neurobiology of Alcohol Drinking in Adulthood (NADIA) consortium adolescent intermittent ethanol (AIE) models adolescent binge drinking, followed by abstinent maturation to adulthood to determine the persistent AIE changes in neurobiology and behavior. AIE increases adult alcohol drinking and preference, increases anxiety and reward seeking, and disrupts sleep and cognition, all risks for AUD. In addition, AIE induces changes in neuroimmune gene expression in neurons and glia that alter neurocircuitry and behavior. HMGB1 is a unique neuroimmune signal released from neurons and glia by ethanol that activates multiple proinflammatory receptors, including Toll-like receptors (TLRs), that spread proinflammatory gene induction. HMGB1 expression is increased by AIE in rat brain and in post-mortem human AUD brain, where it correlates with lifetime alcohol consumption. HMGB1 activation of TLR increase TLR expression. Human AUD brain and rat brain following AIE show increases in multiple TLRs. Brain regional differences in neurotransmitters and cell types impact ethanol responses and neuroimmune gene induction. Microglia are monocyte-like cells that provide trophic and synaptic functions, that ethanol proinflammatory signals sensitize or “prime” during repeated drinking cycles, impacting neurocircuitry. Neurocircuits are differently impacted dependent upon neuronal-glial signaling. Acetylcholine is an anti-inflammatory neurotransmitter. AIE increases HMGB1-TLR4 signaling in forebrain, reducing cholinergic neurons by silencing multiple cholinergic defining genes through upregulation of RE-1 silencing factor (REST), a transcription inhibitor known to regulate neuronal differentiation. HMGB1 REST induction reduces cholinergic neurons in basal forebrain and cholinergic innervation of hippocampus. Adult brain hippocampal neurogenesis is regulated by a neurogenic niche formed from multiple cells. In vivo AIE and in vitro studies find ethanol increases HMGB1-TLR4 signaling and other proinflammatory signaling as well as reducing trophic factors, NGF, and BDNF, coincident with loss of the cholinergic synapse marker vChAT. These changes in gene expression-transcriptomes result in reduced adult neurogenesis. Excitingly, HMGB1 antagonists, anti-inflammatories, and epigenetic modifiers like histone deacetylase inhibitors restore trophic the neurogenesis. These findings suggest anti-inflammatory and epigenetic drugs should be considered for AUD therapy and may provide long-lasting reversal of psychopathology.

Background: Rotator cuff tears are a common injury encountered by orthopedic surgeons. Reverse shoulder arthroplasty (RSA) has become a treatment option for those with acute tears, as well as those with prior failed rotator cuff repair (RCR). The objective of this study was to determine if there are differences in postoperative outcomes for patients with previous RCR compared to those undergoing primary RSA for rotator cuff tears. Methods: A comprehensive literature search was conducted using PubMed, EMBASE, Scopus, and Cochrane Library databases. All relevant studies were reviewed by two authors according to inclusion and exclusion criteria defined in the study. Demographics and postoperative outcomes including functional scores, range of motion, pain scores, and complications were recorded. Results: Six level III articles encompassing 2176 shoulders were included in the analysis (846 with previous RCR and 1330 without). Average postoperative American Shoulder and Elbow Surgeons scores were 75.41 in the prior RCR group and 81.61 in the group without prior repair (mean difference [MD] = −5.95, P ≤ .0001 I2 = 36). Average postoperative Simple Shoulder Test scores were 8.40 in the RCR group and 9.57 in the group without prior RCR (MD = −0.93, P ≤ .0001, I2 = 66). Average postoperative Constant Score was 62.97 in the RCR group and 66.63 in the group without prior RCR (MD = −5.02, P ≤ .0001, I2 ≤ 0.001). Average postoperative University of California at Los Angeles Shoulder Scale score was 28.27 in the RCR group and 29.13 in the group without prior RCR (MD = −1.75, P ≤ .001, I2 ≤ 0.001). Average postoperative visual analog scale pain score was 1.77 in the RCR group and 0.95 in the group without prior RCR (MD = 0.75, P ≤ .0001, I2 = 35). Conclusion: Patients with prior RCR undergoing RSA have worse postoperative functional scores and pain scores than those without prior RCR. However, these differences are below the minimal clinically important difference for each outcome.

Abstract Membrane-based organic solvent separations are rapidly emerging as a promising class of technologies for enhancing the energy efficiency of existing separation and purification systems. Polymeric membranes have shown promise in the fractionation or splitting of complex mixtures of organic molecules such as crude oil. Determining the separation performance of a polymer membrane when challenged with a complex mixture has thus far occurred in an ad hoc manner, and methods to predict the performance based on mixture composition and polymer chemistry are unavailable. Here, we combine physics-informed machine learning algorithms (ML) and mass transport simulations to create an integrated predictive model for the separation of complex mixtures containing up to 400 components via any arbitrary linear polymer membrane. We experimentally demonstrate the effectiveness of the model by predicting the separation of two crude oils within 6-7% of the measurements. Integration of ML predictors of diffusion and sorption properties of molecules with transport simulators enables for the rapid screening of polymer membranes prior to physical experimentation for the separation of complex liquid mixtures.

Purpose: Sperm DNA fragmentation (SDF) testing was recently added to the sixth edition of the World Health Organization laboratory manual for the examination and processing of human semen. Many conditions and risk factors have been associated with elevated SDF; therefore, it is important to identify the population of infertile men who might benefit from this test. The purpose of this study was to investigate global practices related to indications for SDF testing, compare the relevant professional society guideline recommendations, and provide expert recommendations. Materials and Methods: Clinicians managing male infertility were invited to take part in a global online survey on SDF clinical practices. This was conducted following the CHERRIES checklist criteria. The responses were compared to professional society guideline recommendations related to SDF and the appropriate available evidence. Expert recommendations on indications for SDF testing were then formulated, and the Delphi method was used to reach consensus. Results: The survey was completed by 436 experts from 55 countries. Almost 75% of respondents test for SDF in all or some men with unexplained or idiopathic infertility, 39% order it routinely in the work-up of recurrent pregnancy loss (RPL), and 62.2% investigate SDF in smokers. While 47% of reproductive urologists test SDF to support the decision for varicocele repair surgery when conventional semen parameters are normal, significantly fewer general urologists (23%; p=0.008) do the same. Nearly 70% would assess SDF before assisted reproductive technologies (ART), either always or for certain conditions. Recurrent ART failure is a common indication for SDF testing. Very few society recommendations were found regarding SDF testing. Conclusions: This article presents the largest global survey on the indications for SDF testing in infertile men, and demonstrates diverse practices. Furthermore, it highlights the paucity of professional society guideline recommendations. Expert recommendations are proposed to help guide clinicians.

Abstract Targeted protein degradation via “hijacking” of the ubiquitin-proteasome system using proteolysis targeting chimeras (PROTACs) has evolved into a novel therapeutic modality. The design of PROTACs is challenging; multiple steps involved in PROTAC-induced degradation make it difficult to establish coherent structure-activity relationships. Herein, we characterize PROTAC-mediated ternary complex formation and degradation by employing von Hippel–Lindau protein (VHL) recruiting PROTACs for two different target proteins, SMARCA2 and BRD4. Ternary-complex attributes and degradation activity parameters are evaluated by varying components of the PROTAC’s architecture. Ternary complex binding affinity and cooperativity correlates well with degradation potency and initial rates of degradation. Additionally, we develop a ternary-complex structure modeling workflow to calculate the total buried surface area at the interface, which is in agreement with the measured ternary complex binding affinity. Our findings establish a predictive framework to guide the design of potent degraders.

Abstract Background Dupuytren’s disease (DD) is a fibroproliferative hand disorder associated with various medical conditions, including diabetes mellitus (DM). The reported prevalence of DM among DD patients varies widely, primarily due to small sample sizes in previous studies. Methods This was a retrospective cohort study using data from the TriNetX Research Database. We analyzed the overall prevalence of DD between 2010 and 2020, comparing the DM, type 1 diabetes mellitus (T1DM), and type 2 diabetes mellitus (T2DM) cohorts. Within the DM group, patients were further categorized based on hemoglobin A1c (HbA1c) values and prescribed anti-diabetic agents (insulin or metformin). We compared the prevalence of DD diagnosis in each group using prevalence ratios and differences. Results There is a higher prevalence of DD in patients with T2DM than in patients with T1DM (relative risk [RR]: 1.641; 95% confidence interval [CI]: [1.356, 1.986]). Among patients with diabetes, there is a higher prevalence of DD in those taking insulin compared to those taking metformin (RR: 0.801, 95% CI: [0.774, 0.83]). The prevalence of DD varies depending on HbA1c levels, with a prevalence of 0.463% in patients having levels within the diabetic range, while lower prevalences of 0.392% and 0.416% are found in patients with prediabetes or uncontrolled diabetes, respectively. Conclusions This study provides further insight into the relationship between DM and DD. These findings may be attributed to the increased accumulation of advanced glycosylated end products (AGEs) in patients with diabetes. Future research exploring the connection between AGE accumulation and DD development may enhance our understanding of the relationship between DD and DM.

Abstract RNA binding proteins (RBPs) act as critical facilitators of spatially regulated gene expression. Muscleblind-like (MBNL) proteins, implicated in myotonic dystrophy and cancer, localize RNAs to myoblast membranes and neurites through unknown mechanisms. We find that MBNL forms motile and anchored granules in neurons and myoblasts, and selectively associates with kinesins Kif1bα and Kif1c through its zinc finger (ZnF) domains. Other RBPs with similar ZnFs associate with these kinesins, implicating a motor-RBP specificity code. MBNL and kinesin perturbation leads to widespread mRNA mis-localization, including depletion of Nucleolin transcripts from neurites. Live cell imaging and fractionation reveal that the unstructured carboxy-terminal tail of MBNL1 allows for anchoring at membranes. An approach, termed RBP Module Recruitment and Imaging (RBP-MRI), reconstitutes kinesin- and membrane-recruitment functions using MBNL-MS2 coat protein fusions. Our findings decouple kinesin association, RNA binding, and membrane anchoring functions of MBNL while establishing general strategies for studying multi-functional, modular domains of RBPs.

Natural-hazard crises generate much uncertainty among individuals, organizations, and communities. As feelings of uncertainty grow, individuals experience higher levels of stress and negative impacts to their psychological well-being. People desperately seek information and guidance on what to do and expect, along with how to adapt when faced with crises. While crisis-response organizations are key information disseminators, individuals also seek information from non-crisis-response organizations such as places where they work, volunteer, attend school, or worship. As the frequency of natural-hazard crises increases, so do the expectations of non-crisis-response organizations as valuable information sources.However, there is limited research on the information needs of internal stakeholders and the adequacy of the information provided. In this paper, a new reliable and valid scale, Crisis Information Needs and Adequacy for Internal Stakeholders (CINA-IS) is introduced. Three studies to develop and test this scale are described in detail. This 6-item, one-factor scale can be used to assess the adequacy of the information provided during a crisis from the perspective of internal stakeholders. Organizations and those who study them are encouraged to use this scale to improve internal crisis communication. Adequately meeting internal stakeholders' information needs has the potential to help reduce uncertainty and negative psychological impacts on an organizations’ most important asset – its people.

The United States of America (US) has the highest annual number of human babesiosis cases caused by Babesia microti (Bm). Babesia, like malaria-causing Plasmodium, are protozoan parasites that live within red blood cells (RBCs). Both infectious diseases can be associated with hemolysis and organ damage, which can be fatal. Since babesiosis was made a nationally notifiable condition by the Centers for Disease Control and Prevention (CDC) in January 2011, human cases have increased, and drug-resistant strains have been identified. Both the Bm ligand(s) and RBC receptor(s) needed for invasion are unknown, partly because of the difficulty of developing a continuous in vitro culture system. Invasion pathways are relevant for therapies (e.g., RBC exchange) and vaccines. We hypothesize that there is at least one RBC surface antigen that is essential for Bm invasion and that all Bm hosts express this. Because most RBC surface antigens that impact Plasmodium invasion are in human blood group (hBG) systems, which are generated by 51 genes, they were the focus of this study. More than 600 animals with at least one hBG system gene ortholog were identified using the National Center for Biotechnology Information (NCBI) command-line tools. Google Scholar searches were performed to determine which of these animals are susceptible to Bm infection. The literature review revealed 28 Bm non-human hosts (NHH). For 5/51 (9.8%) hBG system genes (e.g., RhD), no NHH had orthologs. This means that RhD is unlikely to be an essential receptor for invasion. For 24/51 (47.1%) hBG system genes, NHH had 4–27 orthologs. For the ABO gene, 15/28 NHH had an ortholog, meaning that this gene is also unlikely to generate an RBC antigen, which is essential for Bm invasion. Our prior research showed that persons with blood type A, B, AB, O, RhD+, and RhD- can all be infected with Bm, supporting our current study’s predictions. For 22/51 (43.1%) hBG system genes, orthologs were found in all 28 NHH. Nineteen (37.3%) of these genes encode RBC surface proteins, meaning they are good candidates for generating a receptor needed for Bm invasion. In vitro cultures of Bm, experimental Bm infection of transgenic mice (e.g., a CD44 KO strain), and analyses of Bm patients can reveal further clues as to which RBC antigens may be essential for invasion.

IntroductionWorkplace exposure to respirable crystalline silica (cSiO2) has been epidemiologically linked to lupus. Consistent with this, repeated subchronic intranasal cSiO2 instillation in lupus-prone NZBWF1 mice induces inflammation-/autoimmune-related gene expression, ectopic lymphoid tissue (ELT), autoantibody (AAb) production in the lung within 5 to 13 wk followed systemic AAb increases and accelerated onset and progression of glomerulonephritis within 13 to 17 wk. Interestingly, dietary docosahexaenoic acid (DHA) supplementation suppresses these pathologic effects, but the underlying molecular mechanisms remain unclear.MethodsThis study aimed to test the hypothesis that dietary DHA supplementation impacts acute transcriptional and autoantibody responses in the lungs of female NZBWF1 mice 1 and 4 wk after a single high-dose cSiO2 challenge. Groups of mice were initially fed a control (Con) diet or a DHA-containing diet (10 g/kg). Cohorts of Con- and DHA-fed were subjected to a single intranasal instillation of 2.5 mg cSiO2 in a saline vehicle (Veh), while a Con-fed cohort was instilled with Veh only. At 1 and 4 wk post-instillation (PI), we compared cSiO2’s effects on innate-/autoimmune-related gene expression and autoantibody (AAb) in lavage fluid/lungs of Con- and DHA-fed mice and related these findings to inflammatory cell profiles, histopathology, cell death, and cytokine/chemokine production.ResultsDHA partially alleviated cSiO2-induced alterations in total immune cell and lymphocyte counts in lung lavage fluid. cSiO2-triggered dead cell accumulation and levels of inflammation-associated cytokines and IFN-stimulated chemokines were more pronounced in Con-fed mice than DHA-fed mice. Targeted multiplex transcriptome analysis revealed substantial upregulation of genes associated with autoimmune pathways in Con-fed mice in response to cSiO2 that were suppressed in DHA-fed mice. Pathway analysis indicated that DHA inhibited cSiO2 induction of proinflammatory and IFN-regulated gene networks, affecting key upstream regulators (e.g., TNFα, IL-1β, IFNAR, and IFNγ). Finally, cSiO2-triggered AAb responses were suppressed in DHA-fed mice.DiscussionTaken together, DHA mitigated cSiO2-induced upregulation of pathways associated with proinflammatory and IFN-regulated gene responses within 1 wk and reduced AAb responses by 4 wk. These findings suggest that the acute short-term model employed here holds substantial promise for efficient elucidation of the molecular mechanisms through which omega-3 PUFAs exert protective effects against cSiO2-induced autoimmunity.

Summary: Cancer cells maintain telomeres by upregulating telomerase or alternative lengthening of telomeres (ALT) via homology-directed repair at telomeric DNA breaks. 8-Oxoguanine (8oxoG) is a highly prevalent endogenous DNA lesion in telomeric sequences, altering telomere structure and telomerase activity, but its impact on ALT is unclear. Here, we demonstrate that targeted 8oxoG formation at telomeres stimulates ALT activity and homologous recombination specifically in ALT cancer cells. Mechanistically, an acute 8oxoG induction increases replication stress, as evidenced by increased telomere fragility and ATR kinase activation at ALT telomeres. Furthermore, ALT cells are more sensitive to chronic telomeric 8oxoG damage than telomerase-positive cancer cells, consistent with increased 8oxoG-induced replication stress. However, telomeric 8oxoG production in G2 phase, when ALT telomere elongation occurs, impairs telomeric DNA synthesis. Our study demonstrates that a common oxidative base lesion has a dual role in regulating ALT depending on when the damage arises in the cell cycle.

ABSTRACTAntibodies represent the primary correlate of immunity following most clinically approved vaccines. However, their mechanisms of action vary from pathogen to pathogen, ranging from neutralization, to opsonophagocytosis, to cytotoxicity. Antibody functions are regulated both by antigen specificity (Fab domain) and by the interaction of their Fc domain with distinct types of Fc receptors (FcRs) present in immune cells. Increasing evidence highlights the critical nature of Fc:FcR interactions in controlling pathogen spread and limiting the disease state. Moreover, variation in Fc-receptor engagement during the course of infection has been demonstrated across a range of pathogens, and this can be further influenced by prior exposure(s)/immunizations, age, pregnancy, and underlying health conditions. Fc:FcR functional variation occurs at the level of antibody isotype and subclass selection as well as post-translational modification of antibodies that shape Fc:FcR-interactions. These factors collectively support a model whereby the immune system actively harnesses and directs Fc:FcR interactions to fight disease. By defining the precise humoral mechanisms that control infections, as well as understanding how these functions can be actively tuned, it may be possible to open new paths for improving existing or novel vaccines.

Abstract Environmental DNA (eDNA) analysis has matured to the point that it is ready for deployment in many applications, particularly in aquatic environments. But public agencies have yet to adopt eDNA methods into their environmental decision making routines at scale, even when eDNA offers clear advantages to those now in use. This article provides a perspective on this gap by considering adoption of a new technology as a path‐dependent, social process in which some paths lead to outcomes that provide far greater benefits than others. We use the diffusion of innovations to investigate eDNA adoption by government agencies, in an effort to (1) identify likely paths toward institutionalized uptake, and (2) suggest ways of avoiding societally inefficient adoption outcomes. Because—as in any scientific endeavor—the best eDNA practices will continue to change, public agencies must remain open to improvements while building a useful and validated array of methods for routine eDNA application. Here we suggest one mechanism for doing so, which we call collaborative governance.

Abstract Environmental DNA (eDNA) has gained popularity as a tool for ecosystem biomonitoring and biodiversity assessment. Although much progress has been made regarding laboratory and fieldwork protocols, the issue of sampling efficiency requires further investigation, particularly in three‐dimensional marine systems. This study focuses on fish community composition in marine ecosystems and aims to analyze the efficiency of sampling design given the sampling effort for distinguishing between different communities. We sampled three fjords in Northern Norway, taking samples along fjord transects and at three different depths, and amplified a fragment of the mitochondrial 12S rRNA gene of bony fishes using the MiFish primers. We evaluated the effect of (i) the number of sampling stations, (ii) samples' spatial distribution, and (iii) the data treatment approach (presence/absence versus semiquantitative) for maximizing the efficiency of eDNA metabarcoding sampling when inferring differences of fish community compositions between fjords. We found that the manner of data treatment strongly affected the minimum number of sampling stations required to detect differences among communities; because the semiquantitative approach retained some information about abundance of the underlying reads, it was the most efficient. Furthermore, we found little‐to‐no difference of fish communities in samples from intermediate depths when comparing vertical fish communities. Lastly, we found that the differences between fish communities at the surface were the highest across the horizontal distance and overall, samples ~30 km apart showed the highest variation in the horizontal distribution. Boosting sampling efficiency (reducing sampling effort without compromising ecological inferences) can significantly contribute to enhanced biodiversity management and efficient biomonitoring plans.

Abstract Marine heatwaves can drive large‐scale shifts in marine ecosystems, but studying their impacts on whole species assemblages is difficult. Analysis combining microscopic observations with environmental DNA (eDNA) metabarcoding of the ethanol preservative of an ichthyoplankton biorepository spanning a 23 years time series captures major and sometimes unexpected changes to fish assemblages in the California Current Large Marine Ecosystem during and after the 2014–2016 Pacific Marine Heatwave. Joint modeling efforts reveal patterns of tropicalization with increases in southern, mesopelagic species and associated declines in commercially important temperate fish species (e.g., North Pacific Hake [Merluccius productus] and Pacific Sardine [Sardinops sagax]). Data show shifts in fisheries assemblages (e.g., Northern Anchovy, Engraulis mordax) even after the return to average water temperatures, corroborating ecosystem impacts found through multiple traditional surveys of this study area. Our innovative approach of metabarcoding preservative eDNA coupled with quantitative modeling leverages the taxonomic breadth and resolution of DNA sequences combined with microscopy‐derived ichthyoplankton identification to yield higher‐resolution, species‐specific quantitative abundance estimates. This work opens the door to economically reconstruct the historical dynamics of assemblages from modern and archived samples worldwide.

Abstract Environmental DNA (eDNA) data make it possible to measure and monitor biodiversity at unprecedented resolution and scale. As use‐cases multiply and scientific consensus grows regarding the value of eDNA analysis, public agencies have an opportunity to decide how and where eDNA data fit into their mandates. Within the United States, many federal and state agencies are individually using eDNA data in various applications and developing relevant scientific expertise. A national strategy for eDNA implementation would capitalize on recent scientific developments, providing a common set of next‐generation tools for natural resource management and public health protection. Such a strategy would avoid patchwork and possibly inconsistent guidelines in different agencies, smoothing the way for efficient uptake of eDNA data in management. Because eDNA analysis is already in widespread use in both ocean and freshwater settings, we focus here on applications in these environments. However, we foresee the broad adoption of eDNA analysis to meet many resource management issues across the nation because the same tools have immediate terrestrial and aerial applications.

IntroductionLeaky gut has been linked to autoimmune disorders including lupus. We previously reported upregulation of anti-flagellin antibodies in the blood of lupus patients and lupus-prone mice, which led to our hypothesis that a leaky gut drives lupus through bacterial flagellin-mediated activation of toll-like receptor 5 (TLR5).MethodsWe created MRL/lpr mice with global Tlr5 deletion through CRISPR/Cas9 and investigated lupus-like disease in these mice.ResultContrary to our hypothesis that the deletion of Tlr5 would attenuate lupus, our results showed exacerbation of lupus with Tlr5 deficiency in female MRL/lpr mice. Remarkably higher levels of proteinuria were observed in Tlr5-/- MRL/lpr mice suggesting aggravated glomerulonephritis. Histopathological analysis confirmed this result, and Tlr5 deletion significantly increased the deposition of IgG and complement C3 in the glomeruli. In addition, Tlr5 deficiency significantly increased renal infiltration of Th17 and activated cDC1 cells. Splenomegaly and lymphadenopathy were also aggravated in Tlr5-/- MRL/lpr mice suggesting impact on lymphoproliferation. In the spleen, significant decreased frequencies of regulatory lymphocytes and increased germinal centers were observed with Tlr5 deletion. Notably, Tlr5 deficiency did not change host metabolism or the existing leaky gut; however, it significantly reshaped the fecal microbiota.ConclusionGlobal deletion of Tlr5 exacerbates lupus-like disease in MRL/lpr mice. Future studies will elucidate the underlying mechanisms by which Tlr5 deficiency modulates host-microbiota interactions to exacerbate lupus.

Managed dyke realignment is a method of creating more coastal wetland environments, by breaching constructed dykes (levees) to allow seawater driven by tides to flood the land surface and enable re-establishment of salt marshes over time. However, coastal land regions that are protected by dykes experience major hydrodynamic changes after breaching. To investigate these dynamics, a dyke in Atlantic Canada was purposefully breached and the adjacent land surface allowed to flood with the tides. Field measurements pre- and post-breach provide a rare opportunity to model the hydrodynamics of early dyke realignment in a hypertidal estuary in the Bay of Fundy. These include measurements of water levels and current velocities at spring tide collected across of field site. A numerical model with an unstructured flexible mesh (Delft3D-FM) was applied to examine the impacts of tidal flooding from a river channel, through the dyke breach and across the previously agricultural landscape that was historically a salt marsh. The model was used to simulate the hydrodynamics inside and around the breach before and after seawater flooding during spring tides, to evaluate the initial impacts of this nature-based method of managed dyke realignment. The results indicate that the breach was not wide enough to influence water levels within the Missaguash River. The depth-averaged current speeds can exceed 1 m s−1 within the breach and are typically

Study objective: Identify optimal P2Y12 inhibitor durations balancing ischemic-benefit and bleeding-risk outcomes after acute myocardial infarction (AMI) in older men and women. Design: Observational retrospective cohort with 2 years of follow-up, using clone-censor-weight marginal structural models to emulate randomization. Setting: 20 % sample of US Medicare administrative claims data. Participants: P2Y12 inhibitor new users ≥66 years old following 2008–2013 AMI hospitalization. Exposures: 12- to 24-month P2Y12 inhibitor durations in 1-month intervals. Main outcome measures: Effectiveness outcome (composite of all-cause mortality, recurrent AMI, ischemic stroke), safety outcome (hospitalized bleed), and negative control outcome (heart failure hospitalization). Results: Of 28,488 P2Y12 inhibitor new users, 51 % were female, 50 % were > 75 years old, 88 % were White/non-Hispanic, and 93 % initiated clopidogrel. Negative control outcome results for 16- through 24-month durations appeared most likely to meet assumptions of no unmeasured confounding. Compared to men taking 24-month therapy, men taking 16-month therapy had higher 2-year risks of the composite effectiveness outcome (relative risk [RR] = 1.08; 95 % confidence interval [95%CI]:1.00–1.15) with similar bleeding risks (RR = 0.98; 95%CI:0.85–1.13). Compared to women taking 24-month therapy, women taking 16-month therapy had similar 2-year risks of the composite effectiveness outcome (RR = 0.98; 95%CI:0.92–1.04) and lower bleeding risks (RR = 0.88; 95%CI:0.80–0.96). Conclusions: Older men taking 24-month P2Y12 inhibitor therapy had the lowest composite effectiveness outcome risk with no increased bleeding risk compared to shorter durations. Women taking 16-month versus 24-month P2Y12 inhibitor therapy had similar composite effectiveness outcome risks but a substantially lower hospitalized bleeding risk, suggesting durations beyond 15–17 months lacked benefit while increasing bleeding risk.

Abstract Achieving effective weed control is crucial for Wisconsin conventional corn growers farming in atrazine prohibition areas. Upon request from our extension clientele, a field study was conducted at Arlington and Brooklyn, WI, in 2021 and 2022 (four site‐years). The study aimed to evaluate the weed control efficacy of comprehensive two‐pass (PRE followed by POST) herbicide program treatments containing products with a wide range of active ingredients and sites of action from various manufacturers without atrazine and glyphosate, in conventional tillage non‐transgenic corn production. Nine and eight out of the 11 two‐pass herbicide programs investigated provided >90% giant foxtail (Setaria faberi Herrm), common ragweed (Ambrosia artemisiifolia L.), velvetleaf (Abutilon theophrasti Medik) and waterhemp [Amaranthus tuberculatus (Moq.) J.D. Sauer] control in 2021, respectively. However, only three treatments provided >90% waterhemp control and the greatest giant foxtail control in 2022 was 79%. Greater end‐of‐season broadleaf and grass weed control was observed in 2021 compared to 2022 due to lower weed pressure and timely early‐season rainfall in 2021. The two‐pass programs, acetochlor/mesotrione fb dicamba/tembotrione (94%–100%) and acetochlor/flumetsulan/clopyralid fb nicosulfuron + dicamba/diflufenzopyr (85%–100%), provided the most consistent broadleaf control across all site‐years. These results demonstrate that a well‐designed and timely deployed two‐pass herbicide program can provide effective control of common broadleaf and grass weeds in conventional corn production assuming moderate weed pressure and timely rainfall for soil residual herbicide activation, otherwise effective weed control, particularly of grass weeds, in the absence of atrazine and glyphosate can be challenging. These results are also translatable to support weed management decisions for glyphosate‐resistant corn hybrids in non‐atrazine prohibition areas.