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Circadian rhythms and the light-dark cycle interact to regulate amyloid plaque accumulation and tau phosphorylation in 5xFAD mice [preprint]
No full textThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Background: Circadian disruption has long been appreciated as a downstream consequence of Alzheimer's Disease in humans. However, an upstream role for behavioral circadian disruption in regulating AD pathology remains an open question.
Methods: To determine the role of the central circadian clock in the suprachiasmatic nucleus (SCN) in regulating amyloid pathology, we crossed the 5xFAD amyloid mouse model with mice harboring deletion of the critical clock gene Bmal1 in GABAergic neurons using VGAT-iCre, which is expressed in >95% of SCN cells. To examine the role the light-dark cycle in this process, we aged these mice in either regular 12:12 light-dark (LD) or constant darkness (DD) conditions. Transcriptional, behavioral, and physiological rhythms were examined in VGAT-iCre; 5xFAD; Bmal1 fl/fl (VGAT-BMAL1KO;5xFAD) mice under varying light conditions. Amyloid plaque deposition, peri-plaque tau phosphorylation, and other pathology was examined by immunohistochemistry, and transcriptomic changes were examined by high-throughput qPCR.
Results: VGAT-BMAL1KO;5xFAD mice showed loss of SCN BMAL1 expression and severe disruption of behavioral rhythms in both LD and DD, with loss of day-night rhythms in consolidated sleep and blunting of rhythmic clock gene expression in the brain. Surprisingly, VGAT-BMAL1KO;5xFAD mice kept under LD showed reduced total plaque accumulation and peri-plaque tau phosphorylation, compared to Cre-negative controls. These changes were gated by the light-dark cycle, as they were absent in VGAT-BMAL1KO;5xFAD mice kept in DD conditions. Total plaque accumulation was also reduced in control 5xFAD mice kept in DD as compared to LD, suggesting a general effect of light-dark cycle on amyloid aggregation. Expression of murine presenilin 1 (Psen1) -- which catalyzes the processing of sAPPβ into Aβ -- as well as APP cleavage to C-terminal fragments, were suppressed in VGAT-BMAL1KO;5xFAD under LD conditions.
Conclusions: These studies elucidated an interaction between the circadian clock in GABAergic neurons and the light-dark cycle in regulating amyloid pathology and suggest that decoupling the central clock form the light-dark cycle may reduce APP cleavage and plaque formation. These results call into question the proposed simple positive feedback loop between circadian rhythm disruption and Alzheimer's Disease pathology.No embarg
Association between vaccine uptake and SARS-CoV-2 infection among staff at a jail and prison in the USA
No full textPurpose: This study aims to examine the association between correctional staff occupational characteristics with vaccine uptake and severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection.
Design/methodology/approach: SARS-CoV-2 infection and vaccination rates among 2,016 correctional staff in the Northeast (March 27, 2020 to September 13, 2022) were examined using a cross-sectional design. Using multiple logistic regression, the authors examined vaccination status and demographic and occupational characteristics associated with infection. Logistic regression was used to assess significant predictors of infection and whether the addition of initial vaccination better predicted infection.
Findings: About 63.9% of staff were vaccinated according to initial vaccination recommendations and 17.4% received at least one additional booster. During the study period, 47.7% tested positive for SARS-CoV-2. After adjusting for demographic and occupational characteristics, younger age, male sex, and no receipt of vaccination were significant predictors of infection. After accounting for variance in infection related to significant demographic and occupational factors, the addition of vaccination status better predicted infection among staff.
Research limitations/implications: Vaccination status differs by staff occupational and demographic characteristics, though vaccination saliently predicts infection when controlling for variance from those characteristics. Findings can inform future vaccine uptake efforts.
Originality/value: While controlling for important demographic and occupational factors, vaccine uptake predicted lower odds of SARS-CoV-2 infection among correctional staff.No embarg
Cardiac Rehabilitation Among Veterans: A Narrative Review
No full textPurpose: Cardiac rehabilitation (CR) is a valuable secondary preventive intervention for Veterans given their increased risk of cardiovascular disease. Adults cared for in the Veterans Affairs (VA) healthcare system are a unique population that receives healthcare from the largest integrated care network in the United States. Yet, this group faces distinct challenges in utilizing CR. In this review, we evaluated the existing data regarding CR utilization and outcomes among U.S. Veterans.
Review methods: A literature search was conducted using PubMed and Scopus for cardiac rehabilitation and U.S. Veterans.
Summary: Veterans have 3 potential options for attending CR: in-person at their local VA medical centers, home-based CR through their local VA medical centers, and in-person at community CR centers. However, participation remains low. A significant barrier to participation is transportation to in-person CR. Home-based CR shows promise in addressing this barrier and has demonstrated resilience in the face of pandemic restrictions. Cardiac rehabilitation outcomes among Veterans who participate include improved exercise capacity, fewer depressive symptoms, and decreased mortality. Despite its benefits for secondary prevention among Veterans, there remains a paucity of data about the current uptake of CR, the impact of mental health on uptake, possible sex-based or racial disparities, and long-term outcomes.No embarg
Artificial intelligence for the diagnosis of pediatric appendicitis: A systematic review
No full textBackground: While acute appendicitis is the most frequent surgical emergency in children, its diagnosis remains complex. Artificial intelligence (AI) and machine learning (ML) tools have been employed to improve the accuracy of various diagnoses, including appendicitis. The purpose of this study was to systematically review the current body of evidence regarding the efficacy of AL and ML approaches for the diagnosis of acute pediatric appendicitis.
Methods: This systematic review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify articles from Pubmed, Scopus, and iEEE Xplore. Study information, methodological details, and outcome metrics were extracted and summarized across studies. Quality of reporting was appraised using The Transparent Reporting of a multivariable prediction model of Individual Prognosis Or Diagnosis (TRIPOD) statement.
Results: Fourteen studies were included in the final analysis of which ten were published after 2019. Two studies originated in the United States while half were carried out in Europe. Artificial Neural Network and Random Forest AI methods were the most commonly used modeling approaches. Commonly used predictors were pain and laboratory blood findings. The average area under the curve that was reported among the fourteen studies was greater than 80 %.
Conclusions: AI and ML technologies have the potential to improve the accuracy of acute appendicitis diagnosis in pediatric patients. Further investigation is needed to identify barriers to adoption of these technologies and to assess their efficacy in real world usage once integrated into clinical workflows.No embarg
Standardized Clinical Terms and Definitions for Interstitial Lung Disease: A Consensus Statement from the Fleischner Society
No full textBackground: Despite advances in diagnosis and management, the interstitial lung disease (ILD) lexicon is plagued by ambiguous and inconsistent terminology that complicates communication and impedes knowledge generation. The objective of this Fleischner Society Consensus Statement was to produce standardized terminology for ILD multidisciplinary diagnoses and major phenotypes.
Methods: Interviews with 10 experts were used to identify ILD clinical diagnoses and major phenotypes. The preferred term for each entity and potential alternatives were identified, alongside rationale for the preferred term. Entities with >1 potential term were the subject of an online modified Delphi survey posed to the 29 committee members, aiming to achieve consensus. Committee members rated their agreement with the initially preferred term (strongly agree, agree, neutral/unsure, disagree, strongly disagree; scored from 5 to 1, respectively), with the option to provide additional comments. Median score 4 and interquartile range 1 was considered consensus agreement. Terms not reaching agreement were discussed by video conference, followed by an additional survey that incorporated feedback.
Results: From the 60 initial terms, there were 2 root terms that required upfront consensus prior to survey initiation (ILD and interstitial pneumonia) and another 8 terms that had no alternative suggested by the committee or in the literature. Agreement was met by 47/50 terms (94%) in round 1 of the survey. The 3 terms (6%) not reaching agreement met agreement in round 2.
Conclusions: This document provides standardized recommended terms for ILD multidisciplinary diagnoses and major phenotypes that will facilitate communication among clinicians, researchers, patients, and other stakeholders.No embarg
Urgent Versus Delayed Surgical Treatment of Open Distal Radius Fractures: A Multicenter Retrospective Study
Get PDFPurpose: Controversy exists on the urgency of operative treatment for low energy open distal radius fractures. Two medical centers shifted practice and no longer take all open distal radius fractures emergently to the operating for debridement. The purpose of this study is to provide preliminary data to evaluate if this is associated with unacceptably high infection rates.
Methods: A retrospective chart review was performed for 55 open distal radius fractures in 54 patients at two level one trauma centers. Patients underwent irrigation and closed reduction in the emergency department followed by definitive closed treatment or operative treatment with surgical irrigation, debridement, and fixation, either within 24 hours or after discharge. The main outcome measure was infection, with secondary outcomes of complications or secondary procedures.
Results: In this cohort, 4 of 55 patients experienced infections (7.2%.) There were no infections in low energy injuries. Twenty-four patients went to the operating room 2 or more days from presentation or were treated nonoperatively with only 1 postoperative infection (4.2%). All infections were in high energy mechanism injuries with at least one additional risk factor: smoking, polytrauma, or Gustilo Anderson type 2 injury.
Conclusions: These data suggest that in patients with low energy injury mechanisms and type 1 injuries, delay in formal operative debridement is not associated with an elevated infection risk in this small case series. Future prospective studies with larger sample sizes are needed to definitively evaluate whether some open distal radius fracture patterns may not require emergent operative debridement.
Type of study/level of evidence: Prognostic IV.No embarg
Selective chr21 homolog silencing reveals polymorphisms influence the epigenetic silencing and functional dosage of RWDD2B [preprint]
Get PDFThis article is a preprint. Preprints are preliminary reports of work that have not been certified by peer review.Polymorphisms that affect chr21 gene expression have significance for both variable severity in Down syndrome and common multifactorial conditions. Results here demonstrate "selective homolog silencing" in cells from even one individual can provide a valuable complement to large studies. In trisomic iPSC subclones that silence different chr21 homologs (via -based silencing), we discovered unusually large, homolog-specific, differences in in iPSCs, cortical organoids and endothelial cells. RNA FISH showed transcription almost entirely from the H1 homolog, correlated with CpG promoter methylation differences. Polymorphisms different on H1 versus H2/H3 had strongest eQTLs in GTEx, especially in brain. Collective results indicate RWDD2B functional dosage is more frequently disconnected from copy number even compared to neighboring genes. RWDD2B function is unknown, but nearby methyl-eQTLs are implicated in osteoarthritis, and potential roles in inflammation or immune response merit consideration. This study has significance for RWDD2B regulation and demonstrates a cell-based methodology to study polymorphisms.No embarg
Association of Socioeconomic Position with Incident Hypertension Hospitalization and Blood Pressure Control among Participants in the Coronary Artery Risk Development in Young Adults (CARDIA) Study
Get PDFBackground: The rate of hypertension hospitalizations is increasing among US adults. Individuals with low socioeconomic position are more likely to have high blood pressure (BP), which may increase their risk of hypertension hospitalization and adverse post-discharge outcomes.
Methods: We analyzed data from the Coronary Artery Risk Development in Young Adults (CARDIA) cohort study, which enrolled 5,115 adults aged 18 to 30 years from 4 urban US communities in 1985-1986. Hospitalizations were identified by self-report during study exams and annual interviews, with hypertension hospitalizations determined through medical record review, through August 2020. Socioeconomic position included education, family income, having private health insurance, and neighborhood deprivation assessed at the last study visit prior to the hypertension hospitalization. Uncontrolled BP (≥140/90 mmHg) was determined at the first CARDIA study visit after hypertension hospitalization.
Results: Overall, 67 CARDIA participants were hospitalized for hypertension. The hazard ratio of hypertension hospitalization among participants who had less than high school versus high school or more education was 3.12 [95%CI: 1.78, 5.48], whose family income was <25,000 was 2.43 [95%CI: 1.44, 4.11], who had no private versus private insurance was 2.58 [95%CI: 1.56, 4.28] and those in tertile 3 versus tertile 1 of neighborhood deprivation index (most versus least deprived) was 3.06 [95%CI: 1.23, 7.58]. Among 46 participants who attended a CARDIA study visit following hospital discharge, 23 (50%) had uncontrolled BP.
Conclusion: Adults with low socioeconomic position were more likely to be hospitalized for hypertension. Uncontrolled BP was common following hypertension hospitalization.No embarg
Biological rhythms: Living your life, one half-day at a time
Get PDFCircadian rhythms play a preeminent role in our life, organizing our physiology and behavior on a daily basis to resonate with our fluctuating environment. However, recent studies reveal that hundreds of mouse and human genes are expressed with a 12-h pattern. We take a close look at mammalian 12-h rhythms, their potential mechanisms and functions, and evidence linking them to circatidal rhythms, which enable marine animals to adapt to tides.No embarg
Successful management of recurrent thrombosis of prosthetic mitral valve induced by eosinophilia secondary to parasitic infection
Get PDFAcute prosthetic heart valve thrombosis (PHVT) is a severe complication affecting patients who have undergone heart valve replacement surgery. We present a case of acute recurrent PHVT associated with parasite-induced eosinophilia. A man in his early 50s with rheumatic heart disease underwent mechanical mitral valve replacement 5 years ago and received well-managed anticoagulation with regular follow-up visits. The patient developed a sudden onset of dyspnoea and was diagnosed with mechanical valve thrombosis, which was managed with thrombolysis. However, the valve became stuck again just a week after the initial episode while the patient was still in the hospital and was receiving anticoagulation within the target range. Concurrently, he experienced skin rashes and itching, prompting an investigation that revealed hypereosinophilia secondary to parasite infestation. The patient's valve functions well after thrombolysis and parasite infection treatment. The eosinophil counts were monitored to remain within the normal range.No embarg