Exploring the Impact of Nickel Exposure on Female Fertility.

Introduction Infertility affects an estimated 186 million individuals globally and is associated with numerous mental health issues. Trace elements are essential for reproductive health, yet the role of nickel in female fertility is not well understood. Previous research has shown conflicting evidence regarding nickel's impact on ovarian function and its potential to disrupt reproductive processes. Methods We utilized data from the National Health and Nutrition Examination Survey (NHANES) focusing on a cohort of 7,839 women, with an emphasis on 1,404 women aged 18 to 35. Logistic regression was employed to investigate the relationship between urinary nickel levels and fertility status, controlling for age, BMI, and race/ethnicity. Results The fertility analysis included 880 fertile and 106 infertile women, identifying age as a significant predictor of fertility status. Nickel exposure did not demonstrate a statistically significant association with fertility. The racial distribution within the groups showed a higher proportion of non-Hispanic White women in the fertile category and Mexican American women in the infertile group, although race was not a significant predictor in the regression model. Conclusions We found no significant relationship between nickel exposure and fertility status when adjusted for race, BMI, and age. Age was the only significant factor associated with fertility. These results highlight the complexity of the interplay between environmental exposures and reproductive health, suggesting that further research is necessary to elucidate the role of nickel and other trace elements in fertility.

A US perspective on closing the carbon cycle to defossilize difficult-to-electrify segments of our economy.

Electrification to reduce or eliminate greenhouse gas emissions is essential to mitigate climate change. However, a substantial portion of our manufacturing and transportation infrastructure will be difficult to electrify and/or will continue to use carbon as a key component, including areas in aviation, heavy-duty and marine transportation, and the chemical industry. In this Roadmap, we explore how multidisciplinary approaches will enable us to close the carbon cycle and create a circular economy by defossilizing these difficult-to-electrify areas and those that will continue to need carbon. We discuss two approaches for this: developing carbon alternatives and improving our ability to reuse carbon, enabled by separations. Furthermore, we posit that co-design and use-driven fundamental science are essential to reach aggressive greenhouse gas reduction targets.

Enantiomeric composition of α-pinene affects catches of bark and wood boring beetles, and associated species, in ethanol-baited multiple-funnel traps.

In 2009, we determined the effects of the enantiomeric composition of the kairomone, α-pinene, on trap catches of arboreal beetles (Coleoptera) in stands of eastern pine trees with resin dominated by (+)-α-pinene. We hypothesized that the responses of beetles would correlate with the predominant enantiomer of α-pinene found in host pines. Lures of (+)-, racemic (±), and (-)-α-pinene were added separately to ethanol-baited multiple-funnel traps. Species such as Monarthrum mali (Fitch), Dendroctonus terebrans (Olivier), Ips grandicollis (Eichhoff), and Pachylobius picivorus (Germar) (Coleoptera: Curculionidae) showed a preference for traps co-baited with (-)-α-pinene. α-Pinene enhanced attraction of Hylastes salebrosus Eichhoff, Hylastes porculus Erickson and Hylastes tenuis Eichhoff (Coleoptera: Curculionidae) to ethanol-baited traps with no effects from enantiomeric composition of α-pinene. The attraction of the ambrosia beetles, Xyleborinus saxesenii (Ratzeburg) and Dryoxylon onoharaense (Murayama) (Coleoptera: Curculionidae) to ethanol-baited traps was interrupted by the addition of α-pinene, regardless of enantiomeric composition. Species such as Xylosandrus germanus (Blandford), Cnestus mutilatus (Blandford) and Stenoscelis brevis (Boheman) (Coleoptera: Curculionidae) were unaffected by the presence of α-pinene. Trap catches of some species of longhorn beetles and bark beetle predators (Coleoptera: Cerambycidae, Cleridae, Elateridae, Histeridae, and Trogossitidae) were increased by the addition of α-pinene, although results varied by location. Platysoma spp. (Coleoptera: Histeridae) showed a marked preference for traps co-baited with (+)-α-pinene in Florida and Georgia. In summary, we found that the enantiomeric composition of α-pinene in hosts was not a good predictor of enantiomeric preferences by beetles.

Methods for health workforce projection model: systematic review and recommended good practice reporting guideline.

BACKGROUND: Health workforce projection models are integral components of a robust healthcare system. This research aims to review recent advancements in methodology and approaches for health workforce projection models and proposes a set of good practice reporting guidelines. METHODS: We conducted a systematic review by searching medical and social science databases, including PubMed, EMBASE, Scopus, and EconLit, covering the period from 2010 to 2023. The inclusion criteria encompassed studies projecting the demand for and supply of the health workforce. PROSPERO registration: CRD 42023407858. RESULTS: Our review identified 40 relevant studies, including 39 single countries analysis (in Australia, Canada, Germany, Ghana, Guinea, Ireland, Jamaica, Japan, Kazakhstan, Korea, Lesotho, Malawi, New Zealand, Portugal, Saudi Arabia, Serbia, Singapore, Spain, Thailand, UK, United States), and one multiple country analysis (in 32 OECD countries). Recent studies have increasingly embraced a complex systems approach in health workforce modelling, incorporating demand, supply, and demand-supply gap analyses. The review identified at least eight distinct types of health workforce projection models commonly used in recent literature: population-to-provider ratio models (n = 7), utilization models (n = 10), needs-based models (n = 25), skill-mixed models (n = 5), stock-and-flow models (n = 40), agent-based simulation models (n = 3), system dynamic models (n = 7), and budgetary models (n = 5). Each model has unique assumptions, strengths, and limitations, with practitioners often combining these models. Furthermore, we found seven statistical approaches used in health workforce projection models: arithmetic calculation, optimization, time-series analysis, econometrics regression modelling, microsimulation, cohort-based simulation, and feedback causal loop analysis. Workforce projection often relies on imperfect data with limited granularity at the local level. Existing studies lack standardization in reporting their methods. In response, we propose a good practice reporting guideline for health workforce projection models designed to accommodate various model types, emerging methodologies, and increased utilization of advanced statistical techniques to address uncertainties and data requirements. CONCLUSIONS: This study underscores the significance of dynamic, multi-professional, team-based, refined demand, supply, and budget impact analyses supported by robust health workforce data intelligence. The suggested best-practice reporting guidelines aim to assist researchers who publish health workforce studies in peer-reviewed journals. Nevertheless, it is expected that these reporting standards will prove valuable for analysts when designing their own analysis, encouraging a more comprehensive and transparent approach to health workforce projection modelling.

Anticoagulation Therapy in a Patient who had two Consecutive Strokes After Antibiotic Therapy for Infective Endocarditis: A Case Report.

A 77-year-old male presented with altered mentation and was diagnosed with infective endocarditis. Echocardiography revealed aortic valve vegetations. While receiving inpatient antibiotic therapy, the patient experienced an acute ischemic stroke. Magnetic resonance imaging of the brain showed punctate embolic-appearing infarcts in the right cerebellum and in the left occipital, frontal, and parietal lobes. Anticoagulation was not initiated due to a high risk of hemorrhagic transformation. He was readmitted after being discharged due to another episode of altered mentation. Repeat echocardiography indicated increased size of aortic valve vegetations. The patient was then transferred to our hospital for surgical intervention of enlarging vegetations, however was deemed unsuitable for surgery. During hospitalization, he suffered another embolic stroke in the right frontal lobe. By this time, the patient had completed a full course of antibiotics for infective endocarditis, and additional antibiotics were deemed unnecessary by our infectious disease specialists. Literature review highlighted that residual vegetations carry a higher risk for stroke, but no clear guidelines were found on how to intervene or assess the risk of hemorrhage with anticoagulation in this population. Consequently, a decision was made to initiate anticoagulation, Follow-up imaging revealed no evidence of hemorrhagic transformation. Subsequently, the patient remained stable and was discharged to a rehabilitation center, where he did not experience any further events.

Long-term reoperation rates following spinal fusion for neuromuscular scoliosis in nonambulatory patients with cerebral palsy.

PURPOSE: To describe the incidence of reoperation and factors contributing to surgical revision within a minimum of 10 years after spinal fusion for scoliosis in patients with nonambulatory cerebral palsy (CP). METHODS: We conducted a retrospective review of consecutive nonambulatory patients with CP who underwent primary spinal fusion at a single specialty care center with a minimum of 10 years from their index surgery (surgery dates 2001-2011). Causes of reoperation were classified as implant failure/pseudoarthrosis, surgical site infection (SSI), proximal junctional kyphosis, prominent/symptomatic implants, and implant removal. Reoperation rates with 95% confidence intervals were calculated for each time interval, and an actuarial survival curve was generated. RESULTS: 144 patients met inclusion criteria (mean age = 14.3 ± 2.6 years, 62.5% male); 85.4% had 5 years follow-up data; and 66.0% had 10 years follow-up data. Estimates from the actuarial analysis suggest that 14.9% (95% CI: 10.0-22.0) underwent reoperation by 5 years postsurgery, and 21.7% (95% CI: 15.4-30.1) underwent reoperation by 10 years postsurgery. The most common causes for reoperation were implant failure/pseudoarthrosis, SSI, and prominent/symptomatic implants. CONCLUSIONS: To our knowledge, this study is the largest long-term follow-up of nonambulatory patients with CP and neuromuscular scoliosis who underwent spinal fusion. Approximately 22% of these patients required reoperation 10 years after their index surgery, primarily due to implant failure/pseudoarthrosis, SSI, and prominent/symptomatic implants. Complications and reoperations continued throughout the 10 years period after index surgery, reinforcing the need for long-term follow-up as these patients transition into adulthood. LEVEL OF EVIDENCE: III.

A 17-month longitudinal surface sampling study carried out on public transport vehicles operating in England during the COVID-19 pandemic identified low levels of SARS-CoV-2 RNA contamination.

AIMS: To monitor severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) RNA contamination in vehicles operating in England during the pandemic, to better understand transmission risk of SARS-CoV-2 on public transport. METHODS AND RESULTS: We collected 1314 surface samples between December 2020 and April 2022 on trains and buses managed by five different transport operators. The presence of SARS-CoV-2 RNA was investigated through reverse transcription polymerase chain reaction (RT-PCR). SARS-CoV-2 RNA was found on 197 (15%) of the 1314 surfaces sampled, including seat head rests, handholds, and air extract grilles, but the levels of RNA recovered on those samples (median value of 23.4, interquartile range: 14.3-35.4, N gene copies per extraction) made the presence of infectious virus at the time of sampling extremely unlikely. However, detection rates varied over time with peaks broadly coinciding with times of high community transmission, when it was more likely that people infected with SARS-CoV-2 were travelling on public transport. CONCLUSION: During the pandemic, and as in other public spaces, low levels of SARS-CoV-2 RNA were found on surfaces associated with public transport.

AutoGVP: a dockerized workflow integrating ClinVar and InterVar germline sequence variant classification.

SUMMARY: With the increasing rates of exome and whole genome sequencing, the ability to classify large sets of germline sequencing variants using up-to-date American College of Medical Genetics-Association for Molecular Pathology (ACMG-AMP) criteria is crucial. Here, we present Automated Germline Variant Pathogenicity (AutoGVP), a tool that integrates germline variant pathogenicity annotations from ClinVar and sequence variant classifications from a modified version of InterVar (PVS1 strength adjustments, removal of PP5/BP6). This tool facilitates large-scale, clinically focused classification of germline sequence variants in a research setting. AVAILABILITY AND IMPLEMENTATION: AutoGVP is an open source dockerized workflow implemented in R and freely available on GitHub at https://github.com/diskin-lab-chop/AutoGVP.

Exploring the Relationship Between Hepatitis C Virus Infection and Prostate Cancer Risk: A National Health and Nutrition Examination Survey Analysis.

Introduction Prostate cancer and hepatitis C virus (HCV) infection stand as notable worldwide health issues. Investigating the connection between HCV infection and the risk of prostate cancer remains an ongoing endeavor, complicated by contradictory findings in prior research. It is imperative to comprehend this potential relationship in order to enhance strategies for prevention and treatment. This paper seeks to delve into the association between HCV infection and prostate cancer by analyzing data from the National Health and Nutrition Examination Survey (NHANES), a comprehensive cross-section of the US population. Methods Information extracted from the NHANES dataset encompassed the period spanning from March 2017 to March 2020, with a focus on the "medical conditions" and "hepatitis" segments. Employing logistic regression analysis, we aimed to discern the connection between HCV infection and the prior occurrence of prostate cancer. This analysis was conducted while factoring in variables such as weight, hypertension, hyperlipidemia, race, educational level, and marital status to ensure the accuracy of the findings. The results of this examination yielded adjusted odds ratios (OR), coefficients of association (B), and corresponding confidence intervals (CI). Results  The outcomes derived from the comprehensive multivariate logistic regression analysis, utilizing NHANES data, indicated an absence of a statistically noteworthy correlation between HCV infection and the probability of prostate cancer occurrence. While accounting for diverse variables like weight, hypertension, hyperlipidemia, race, educational level, and marital status, no substantial relationship was observed between HCV infection and the risk of prostate cancer. These results are consistent with earlier investigations that similarly struggled to establish a definitive connection between HCV infection and the incidence of prostate cancer. Conclusion  Drawing from NHANES data, this study indicates the absence of a substantial link between HCV infection and the incidence of prostate cancer. The divergent findings observed in prior research accentuate the intricate nature of the connection between HCV infection and prostate cancer. Future investigations should encompass more extensive sample sizes, prospective frameworks, and a meticulous assessment of potential variables that might confound the results. Furthermore, it is important to examine the potential protective impact of HCV infection due to antiviral interventions and its effect on the associated risk of prostate cancer. Such endeavors would offer valuable insights for individuals grappling with these health challenges.

Ewing Sarcoma-Chest Wall Reconstruction Following Resection of Rare Primary Chest Wall Tumor.

Ewing sarcoma (ES) represents the second most common primary osseous malignancy in children and young adults, most often occurring in the diaphysis of the long bones. While rare, ES can present as an osseous tumor of the ribs and/or chest wall. These tumors are known as Askin's tumors and most commonly present with symptoms resembling pneumonia. We report the case of a 26-year-old man who was found to have a right lung mass extending into his anterolateral chest wall after presenting to the hospital for evaluation of unremitting chest pain. Biopsy was performed and the patient diagnosed with ES. After completion of neoadjuvant chemotherapy, the patient underwent resection of the right chest wall mass. The chest wall was reconstructed in a novel fashion with titanium plates and a reinforced tissue matrix patch. Due to a paucity of cases, no treatment or reconstruction algorithm currently exists for management of these malignancies.

Landiolol for Treating Arrhythmias: A State-of-The-Art Review.

This article provides a state-of-the-art review on landiolol, a medication that was recently submitted for 7 approvals. Focusing on its pharmacology, pharmacokinetics, and pharmacodynamics, the analysis underscores landiolol's unique attributes compared to conventional beta-blockers, particularly esmolol. As a sympatholytic agent, landiolol exhibits a short half-life, high cardioselectivity, and minimal impact on blood pressure, setting it apart in the realm of arrhythmia treatment. The review explores landiolol's potential applications, emphasizing scenarios where other beta-blockers may be limited. A detailed examination of its efficacy in preventing postoperative atrial fibrillation reveals promising results from clinical trials, suggesting its utility in diverse surgical settings. Additionally, the article delves into landiolol's role in rate control for atrial fibrillation/flutter, treatment of ventricular tachycardia/fibrillation, and its use in managing sepsis-related tachyarrhythmias. The evolving landscape of landiolol's applications extends beyond cardiac care, including potential anti-inflammatory, antioxidative, analgesic, and anticancer effects. While the outcomes from various studies are promising, challenges persist, requiring further research to optimize dosing strategies, identify optimal patient populations, and elucidate mechanisms underlying its diverse effects. The potential expansion of landiolol's applications highlights the importance of ongoing clinical investigation, offering a promising avenue for enhancing arrhythmia management and addressing broader medical needs.

Characterization of c-di-AMP signaling in the periodontal pathobiont, Treponema denticola.

Pathobionts associated with periodontitis, such as Treponema denticola, must possess numerous sensory transduction systems to adapt to the highly dynamic subgingival environment. To date, the signaling pathways utilized by T. denticola to rapidly sense and respond to environmental stimuli are mainly unknown. Bis-(3'-5') cyclic diadenosine monophosphate (c-di-AMP) is a nucleotide secondary messenger that regulates osmolyte transport, central metabolism, biofilm development, and pathogenicity in many bacteria but is uncharacterized in T. denticola. Here, we studied c-di-AMP signaling in T. denticola to understand how it contributes to T. denticola physiology. We demonstrated that T. denticola produces c-di-AMP and identified enzymes that function in the synthesis (TDE1909) and hydrolysis (TDE0027) of c-di-AMP. To investigate how c-di-AMP may impact T. denticola cellular processes, a screening assay was performed to identify putative c-di-AMP receptor proteins. This approach identified TDE0087, annotated as a potassium uptake protein, as the first T. denticola c-di-AMP binding protein. As potassium homeostasis is critical for maintaining turgor pressure, we demonstrated that T. denticola c-di-AMP concentrations are impacted by osmolarity, suggesting that c-di-AMP negatively regulates potassium uptake in hypoosmotic solutions. Collectively, this study demonstrates T. denticola utilizes c-di-AMP signaling, identifies c-di-AMP metabolism proteins, identifies putative receptor proteins, and correlates c-di-AMP signaling to osmoregulation.

Unifying the Conversation: Membrane Separation Performance in Energy, Water, and Industrial Applications.

Dense polymer membranes enable a diverse range of separations and clean energy technologies, including gas separation, water treatment, and renewable fuel production or conversion. The transport of small molecular and ionic solutes in the majority of these membranes is described by the same solution-diffusion mechanism, yet a comparison of membrane separation performance across applications is rare. A better understanding of how structure-property relationships and driving forces compare among applications would drive innovation in membrane development by identifying opportunities for cross-disciplinary knowledge transfer. Here, we aim to inspire such cross-pollination by evaluating the selectivity and electrochemical driving forces for 29 separations across nine different applications using a common framework grounded in the physicochemical characteristics of the permeating and rejected solutes. Our analysis shows that highly selective membranes usually exhibit high solute rejection, rather than fast solute permeation, and often exploit contrasts in the size and charge of solutes rather than a nonelectrostatic chemical property, polarizability. We also highlight the power of selective driving forces (e.g., the fact that applied electric potential acts on charged solutes but not on neutral ones) to enable effective separation processes, even when the membrane itself has poor selectivity. We conclude by proposing several research opportunities that are likely to impact multiple areas of membrane science. The high-level perspective of membrane separation across fields presented herein aims to promote cross-pollination and innovation by enabling comparisons of solute transport and driving forces among membrane separation applications.

Rotator Cuff Tears Are Related to the Side Sleeping Position.

Purpose: To determine whether there was a relationship between sleep position and symptomatic partial- and full-thickness rotator cuff tears. Methods: A consecutive series of patients that met the inclusion/exclusion criteria (n = 58) were in seen in clinic between July 2019 and December 2019. All of these individuals had a significant partial-thickness (> 50%) or full-thickness rotator cuff tear determined by either ultrasound, magnetic resonance imaging, or both. All patients in this series either had an insidious onset of shoulder pain or their symptoms were related to the basic wear and tear of daily activities. Traumatic rotator cuff tears (those associated with a significant traumatic event such as shoulder instability, motor vehicle accidents, sports related injuries, etc.) were excluded. Previous shoulder surgery, recurrent rotator cuff tears, and worker's compensation cases also were excluded from this series. As part of the history-taking process, the patients were asked what was their preferred sleeping position-side sleeper, back sleeper, or stomach sleeper. A χ2 test was conducted to determine the relationship between rotator cuff pathology and sleep position. Results: Of the 58 subjects, 52 of the patients were side sleepers, 4 were stomach sleepers, 1 was a back sleeper, and 1 preferred all 3 positions. Statistical analysis, using the χ2 test (P < .0001), demonstrated that rotator cuff tears were most often seen in side sleepers. Conclusions: In our study, there appeared to be a relationship between the preference of being a side sleeper and the presence of a rotator cuff tear. Level of Evidence: Level IV, prognostic case series.

The effects of gastrojejunostomy tube placement on pulmonary and gastrointestinal complications following spinal fusion for neuromuscular scoliosis.

To evaluate whether preoperative conversion from a gastrostomy tube (G-tube) to a gastrojejunostomy tube (GJ-tube) decreases short-term postoperative aspiration pneumonia and gastrointestinal complications in children with neuromuscular scoliosis. We conducted a retrospective chart review from January 2006 to October 2021 of pediatric patients who had neuromuscular scoliosis and were fed with a G-tube before spinal fusion. Eligible patients were divided into two groups based on whether they were converted to a GJ-tube preoperatively. Preoperative characteristics and 30-day postoperative outcomes were compared between groups using Chi-square tests. Of 261 eligible patients, 205 were converted to a GJ-tube, while 56 underwent spinal fusion with a G-tube. Common complications following G-tube to GJ-tube conversion were feeding intolerance (25.2%), GJ-tube malfunction (17.7%), and at least one episode of vomiting (17.4%). Within 30 days of discharge, 12.5% of GJ-tube patients and 11.5% of G-tube patients experienced aspiration pneumonia (P = 0.85). The GJ-tube group received postoperative tube feeds 7 hours earlier than the G-tube group on average (51.6 h vs. 44.5 h, P = 0.02). Within 30 days of discharge, one (0.5%) patient from the GJ-tube group died of gastrointestinal complications unrelated to conversion and two (3.6%) patients in the G-tube group died from aspiration pneumonia (P = 0.12). Results suggest that there were no appreciable differences in outcomes between patients converted to a GJ-tube preoperatively compared to those who continued to use a G-tube. However, preoperative characteristics indicate that a higher number of complex patients were converted to a GJ-tube, indicating potential selection bias in this retrospective sample. Level of evidence: Level III.

Intrapericardial Diaphragmatic Hernia Following the Convergence Procedure for Atrial Fibrillation.

This case report highlights a very rare variant of diaphragmatic hernia, namely, an intrapericardial diaphragmatic hernia, which can arise as a complication of the convergence procedure. A 77-year-old man, presenting with chronic shortness of breath and fatigue, was unexpectedly found to have herniation of the transverse colon into the pericardial cavity through a diaphragmatic-pericardial defect. The diaphragmatic defect was repaired with mesh via robotic surgery. The patient reported resolution of his symptoms at the six-month follow-up.

Secondary Analysis of the Rate of Second Primary Lung Cancer From Cancer and Leukemia Group B 140503 (Alliance) Trial of Lobar Versus Sublobar Resection for T1aN0 Non-Small-Cell Lung Cancer.

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.Patients with early-stage non-small-cell lung cancer (NSCLC) who undergo curative surgical resection are at risk for developing second primary lung cancer (SPLC). Cancer and Leukemia Group B 140503 (Alliance) was a multicenter, international, randomized, phase III trial in patients with stage T1aN0 NSCLC (using the TNM staging system seventh edition) and demonstrated the noninferiority for disease-free survival between sublobar resection (SLR) and lobar resection (LR). After surgery, patients underwent computed tomography surveillance as defined by the protocol. The determination of a SPLC was done by the treating physician and recorded in the study database. We performed an analysis of the rate of SPLC (per patient per year) and the 5-year cumulative incidence in the study population and within the SLR and LR arms. Median follow-up was 7 years. The rate per patient per year in the study population, in the SLR arm, and in the LR arm was 3.4% (95% CI, 2.9 to 4.1), 3.8% (95% CI, 2.9 to 4.9), and 3.1% (95% CI, 2.4 to 4.1), respectively. The estimated 5-year cumulative incidence of SPLC in the study population, SLR arm, and LR arm was 15.9% (95% CI, 12.9 to 18.9), 17.2% (95% CI, 12.7 to 21.5), and 14.7% (95% CI, 10.6 to 18.7), respectively.

New-onset as opposed to established atrial fibrillation as a risk factor for incident stroke.

BACKGROUND: Atrial fibrillation (AF) is an established risk factor for acute ischemic stroke (AIS). It remains unclear if new-onset AF confers a higher risk of AIS than longer-standing AF. METHODS: We retrospectively analyzed all stroke-free patients who underwent transthoracic echocardiography (TTE) in the Henry Ford Health System between March 6 and September 6, 2016. Incident AIS and new-onset AF were ascertained by the presence of new diagnostic codes in the electronic medical record over a follow-up period of up to 5 years. Cox proportional hazards regression was used to identify risk factors for new-onset AF or AIS. RESULTS: Of 7310 patients who underwent baseline TTE the mean age was 65 years, 54% were female, 51% were Caucasian, and 46% had left atrial enlargement (LAE). Of at-risk patients, 10.9% developed new-onset AF and 2.9% experienced incident AIS. The risk of new-onset AF among at-risk patients was 3.1 times higher among patients with any degree of LAE compared to those with normal LA size (95% CI 2.6-3.6, P < 0.0001). New-onset AF, more than established AF, in turn had a powerful association with incident AIS. The cumulative 5-year risk of AIS was 3.5% in those without AF, 5.9% in those with established AF prior to TTE, and 20.1% in those with new-onset AF (P < 0.0001). In multivariable analysis new-onset AF had the strongest association with incident AIS (P < 0.0001), followed by increasing age (P = 0.0025), black race (P = 0.0032), and smoking (P = 0.0063). CONCLUSIONS: New-onset AF has a strong relationship with incident AIS. LAE was present in nearly half of stroke-free patients undergoing TTE, and was associated with a significantly higher likelihood of new-onset AF during follow-up. Vigilant cardiac monitoring for AF in individuals with LAE, coupled with the timely initiation of anticoagulation, may be an important strategy for the primary prevention of AF-related stroke.

Degradation by Design: New Cyclin K Degraders from Old CDK Inhibitors.

Small molecules that induce protein degradation hold the potential to overcome several limitations of the currently available inhibitors. Monovalent or molecular glue degraders, in particular, enable the benefits of protein degradation without the disadvantages of high molecular weight and the resulting challenge in drug development that are associated with bivalent molecules like Proteolysis Targeting Chimeras. One key challenge in designing monovalent degraders is how to build in the degrader activity─how can we convert an inhibitor into a degrader? If degradation activity requires very specific molecular features, it will be difficult to find new degraders and challenging to optimize those degraders toward drugs. Herein, we demonstrate that an unexpectedly wide range of modifications to the degradation-inducing group of the cyclin K degrader CR8 are tolerated, including both aromatic and nonaromatic groups. We used these findings to convert the pan-CDK inhibitors dinaciclib and AT-7519 to Cyclin K degraders, leading to a novel dinaciclib-based compound with improved degradation activity compared to CR8 and confirm the mechanism of degradation. These results suggest that general design principles can be generated for the development and optimization of monovalent degraders.

Inhibitory CCK+ basket synapse defects in mouse models of dystroglycanopathy.

Dystroglycan (Dag1) is a transmembrane glycoprotein that links the extracellular matrix to the actin cytoskeleton. Mutations in Dag1 or the genes required for its glycosylation result in dystroglycanopathy, a type of congenital muscular dystrophy characterized by a wide range of phenotypes including muscle weakness, brain defects, and cognitive impairment. We investigated interneuron (IN) development, synaptic function, and associated seizure susceptibility in multiple mouse models that reflect the wide phenotypic range of dystroglycanopathy neuropathology. Mice that model severe dystroglycanopathy due to forebrain deletion of Dag1 or Pomt2, which is required for Dystroglycan glycosylation, show significant impairment of CCK+/CB1R+ IN development. CCK+/CB1R+ IN axons failed to properly target the somatodendritic compartment of pyramidal neurons in the hippocampus, resulting in synaptic defects and increased seizure susceptibility. Mice lacking the intracellular domain of Dystroglycan have milder defects in CCK+/CB1R+ IN axon targeting, but exhibit dramatic changes in inhibitory synaptic function, indicating a critical postsynaptic role of this domain. In contrast, CCK+/CB1R+ IN synaptic function and seizure susceptibility was normal in mice that model mild dystroglycanopathy due to partially reduced Dystroglycan glycosylation. Collectively, these data show that inhibitory synaptic defects and elevated seizure susceptibility are hallmarks of severe dystroglycanopathy, and show that Dystroglycan plays an important role in organizing functional inhibitory synapse assembly.