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Background: Sexual health (SH) is influenced by several biological, mental, and social factors which may be negatively impacted by PD. Despite its prevalence and relevance for quality of life, the factors that affect the SH in men with Parkinson's disease (MwPD) are still poorly understood, and research in this area is scarce. Aim: To investigate the impact of motor, non-motor, and social aspects on the SH in MwPD. Method: We conducted a cross-sectional study of 80 men (mean age 53.55+/-10.8) in stages 1-3 of disease progression according to Hoehn and Yahr classification (H&Y), who reported to have sexual activity. The following data were collected for each person (used tests/scales indicated within parentheses and defined in glossary): (1) demographic information and global cognitive capacity (T-MoCA); (2) non-motor aspects of daily life experiences (MDS-UPDRS, part I); (3) motor aspects of daily life experiences (MDS-UPDRS, part II); (4) fatigue (FSS); (5) self-esteem (RSES); (6) sleep disorder (PDSS); (7) couple relationship quality (DAS); (8) depressive signals (BDI); (8) short-term sexual health by International Index of Erectile Function (IIFE); and (9) long-term sexual health by Sexual Quotient-Male (SQ-M). Results: Our results suggest that the quality of marital relationships predicts short-term SH, motor disability level predicts erectile dysfunction, and depression predicts long-term SH in MwPD. Age, disease onset, disease duration, Levodopa dosage, and non-motor symptoms, excluding depression, were not correlated with SH. Conclusion: Our findings confirm that multidimensional factors can affect the SH of MwPD and emphasize that only a multi-professional team can offer proper care to improve SH in MwPD.

Introduction: Nearly all patients with primary ciliary dyskinesia (PCD) report ear-nose-throat (ENT) symptoms. However, scarce evidence exists about how ENT symptoms relate to pulmonary disease in PCD. We explored possible associations between upper and lower respiratory disease among patients with PCD in a multicentre study. Methods: We included patients from the ENT Prospective International Cohort (EPIC-PCD). We studied associations of several reported ENT symptoms and chronic rhinosinusitis (CRS)-defined using patient-reported information and examination findings-with reported sputum production and shortness of breath-using ordinal logistic regression. In a subgroup with available lung function results, we used linear regression to study associations of CRS and FEV1, accounting for relevant factors. Results: We included 457 patients [median age: 15; interquartile range (IQR) 10-24; 54% males]. Shortness of breath associated with reported nasal symptoms and ear pain of any frequency, often or daily hearing problems, headache when bending down [odds ratio (OR) 2.1; 95% confidence interval (CI) 1.29-3.54], and CRS (OR 2.3; 95% CI 1.57-3.38) regardless of polyp presence. Sputum production associated with daily reported nasal (OR 2.2; 95% CI 1.20-4.09) and hearing (OR 2.0; 95% CI 1.10-3.64) problems and CRS (OR 2.1; 95% CI 1.48-3.07). We did not find any association between CRS and FEV1. Conclusion: Reported upper airway symptoms and signs of CRS associated with reported pulmonary symptoms; however, not with lung function. Our results emphasise assessing and managing upper and lower respiratory disease as a common, interdependent entity among patients with PCD.

Importance: Disparities in pulse oximetry accuracy, disproportionately affecting patients of color, have been associated with serious clinical outcomes. Although many have called for pulse oximetry hardware replacement, the cost associated with this replacement is not known. Objective: To estimate the cost of replacing all pulse oximetry hardware throughout a hospital system. Design: Single-center survey, 2023 Setting: Single center. Participants: One academic medical center with three hospitals. Main Outcomes and Measures: Cost of fleet replacement as identified by current day prices for hardware. Results: New and used prices for 5,079/5,678 (89.5%) across three hospitals for pulse oximetry devices were found. The average equipment cost to replace pulse oximetry hardware is $15,704.12 per bed. Replacement and integration costs are estimated at $28.5-31.8 million for the entire medical system. Extrapolating these costs to 5,564 hospitals in the United States results in an estimated cost of $14.1 billion. Conclusions and Relevance: "Simply replacing" pulse oximetry hardware to address disparities may be neither simple, cheap, or timely. Solutions for addressing pulse oximetry accuracy disparities leveraging current technology may be necessary.

Background and Purpose Prompt transfer of medically stable pediatric patients with neurologic diagnoses to the inpatient rehabilitation unit is desirable to address their functional recovery. However, there is limited data on how to prioritize the need for intensive rehabilitation in the presence of ongoing need for mechanical ventilator support, outside the intensive care unit setting. This is especially true for patients who may be candidates for ventilator weaning. This dilemma involves choosing between a facility that primarily focuses on ventilator weaning, such as a long-term acute care hospital, or an inpatient rehabilitation facility that offers greater rehabilitation services but lacks evidence-based guidelines for approaching ventilator weaning in this setting. To address this challenge, this study explores the potential of leveraging inpatient rehabilitation expertise in bedside assessments of respiratory muscle function, specifically using point-of-care diaphragm ultrasound as a promising tool to guide ventilator weaning in the inpatient rehabilitation setting. Methods This is a retrospective case series conducted at a university-affiliated, freestanding acute rehabilitation hospital. We performed a retrospective chart review of pediatric patients (n=17) within this setting who, because of neurological injury or disease, relied on invasive mechanical ventilator support via tracheostomy. Patient characteristics including primary rehabilitation diagnosis were recorded, along with number of hours per day the patient relied on mechanical ventilator support at admission and then at discharge from inpatient rehabilitation hospital. Routinely performed assessments of respiratory muscle function at our facility included three modalities: (i) diaphragm muscle ultrasound B-mode measurements; (ii) inspiratory excursion measurements which measure the expansion of the chest and abdominal wall at specific sites during both tidal volume and vital capacity breaths; and (iii) pulmonary function measures - vital capacity and negative inspiratory force. The primary focus was the length of time that the patient achieved ventilator free breathing at the time of discharge from the acute rehabilitation setting. Results We included 17 patients (age 5-18 years old), all who required full support of mechanical ventilator upon admission to inpatient rehabilitation hospital. Upon discharge, 13 of these patients were either fully or partially weaned (nocturnal ventilator use only) from invasive mechanical ventilator support. Ultrasound determined diaphragm muscle thickening ratio was the assessment most predictive of ventilator weaning outcome. Specifically, all patients with at least one hemidiaphragm that had a thickening ratio >1.2 achieved some degree of ventilator weaning during inpatient rehabilitation stay. Conclusion: For the pediatric inpatient rehabilitation population that utilizes invasive mechanical ventilation because of neurological injury or disease, ultrasound determined diaphragm muscle thickening appears to serve as a useful tool for guiding ventilator management.

Despite sharing the same histologic classification, individual tumors in multi metastatic patients may present with different characteristics and varying sensitivities to anticancer therapies. In this study, we investigate the utility of radiomic biomarkers for prediction of lesion-specific treatment resistance in multi metastatic leiomyosarcoma patients. Using a dataset of n=202 lung metastases (LM) from n=80 patients with 1648 pre-treatment computed tomography (CT) radiomics features and LM progression determined from follow-up CT, we developed a radiomic model to predict the progression of each lesion. Repeat experiments assessed the relative predictive performance across LM volume groups. Lesion-specific radiomic models indicate up to a 5-fold increase in predictive capacity compared with a no-skill classifier, with an area under the precision-recall curve of 0.79 for the most precise model (FDR = 0.01). Precision varied by administered drug and LM volume. The effect of LM volume was controlled by removing radiomic features at a volume-correlation coefficient threshold of 0.20. Predicting lesion-specific responses using radiomic features represents a novel strategy by which to assess treatment response that acknowledges biological diversity within metastatic subclones, which could facilitate management strategies involving selective ablation of resistant clones in the setting of systemic therapy.

Immunotherapies, especially the checkpoint inhibitors such as anti-PD-1 antibodies, have transformed cancer treatment by enhancing immune system's capability to target and kill cancer cells. However, predicting immunotherapy response remains challenging. 18F-AraG is a molecular imaging tracer targeting activated T cells, which may facilitate therapy response assessment by non-invasive quantification of immune cell activity within tumor microenvironment and elsewhere in the body. The aim of this study was to obtain preliminary data on total-body pharmacokinetics of 18F-AraG, as a potential quantitative biomarker for immune response evaluation. Methods: The study consisted of 90-min total-body dynamic scans of four healthy subjects and one non-small cell lung cancer (NSCLC) patient, scanned before and after anti-PD-1 immunotherapy. Compartmental modeling with Akaike information criterion model selection were employed to analyze tracer kinetics in various organs. Additionally, seven sub-regions of the primary lung tumor and four mediastinal lymph nodes were analyzed. Practical identifiability analysis was performed to assess reliability of kinetic parameter estimation. Correlations of SUVmean, SUVR (tissue-to-blood ratio), and Logan plot slope (K_Logan) with total volume-of-distribution (V_T) were calculated to identify potential surrogates for kinetic modeling. Results: Strong correlations were observed between K_Logan and SUVR values with V_T, suggesting that they can be used as promising surrogates for V_T, especially in organs with low blood-volume fraction. Moreover, the practical identifiability analysis suggests that the dynamic 18F-AraG PET scans could potentially be shortened to 60 minutes, while maintaining quantification accuracy for all organs-of-interest. The study suggests that although 18F-AraG SUV images can provide insights on immune cell distribution, kinetic modeling or graphical analysis methods may be required for accurate quantification of immune response post-therapy. While SUVmean showed variable changes in different sub-regions of the tumor post-therapy, the SUVR, K_Logan, and V_T showed consistent increasing trends in all analyzed sub-regions of the tumor with high practical identifiability. Conclusion: Our findings highlight the promise of 18F-AraG dynamic imaging as a non-invasive biomarker for quantifying the immune response to immunotherapy in cancer patients. The promising total-body kinetic modeling results also suggest potentially wider applications of the tracer in investigating the role of T cells in the immunopathogenesis of diseases.

Mass drug administration (MDA) of antifilarial drugs is the main strategy towards the elimination of lymphatic filariasis (LF). Recent clinical trials indicated that the triple drug therapy with ivermectin, diethylcarbamazine and albendazole (IDA) is much more effective against LF than the widely used two-drug combinations (albendazole plus either ivermectin or diethylcarbamazine). For IDA-based MDA, the stop-MDA decision is taken based on microfilariae (mf) prevalence in adults. In this study, we assess how the probability of eventually reaching elimination of transmission depends on the critical threshold used in transmission assessment surveys (TAS-es) to define whether transmission was successfully suppressed and triple-drug MDA can be stopped. This analysis focuses on treatment-naive Indian settings. We do this for a range of epidemiological and programmatic contexts, using the established LYMFASIM model for transmission and control of LF. Based on our simulations, a single TAS one year after the last MDA round provides limited predictive value of having achieved suppressed transmission, while a higher MDA coverage increases elimination probability, thus leading to a higher predictive value. Every additional TAS, conditional on previous TAS-es being passed with the same threshold, further improves predictive value for low values of stop-MDA thresholds. An mf prevalence threshold of 0.5% corresponding to TAS-3 results in [≥]95% predictive value even when the MDA coverage is relatively low.

Background While safety of influenza vaccines is well-established, some studies have suggested potential associations between influenza vaccines and certain adverse events (AEs). This study examined the safety of the 2022 to 2023 influenza vaccines among U.S. adults 65 years and older. Methods A self-controlled case series compared incidence rates of anaphylaxis, encephalitis/encephalomyelitis, Guillain Barre-Syndrome (GBS), and transverse myelitis following 2022 to 2023 seasonal influenza vaccinations (i.e., any, high-dose or adjuvanted) in risk and control intervals among Medicare beneficiaries 65 years and older. We used conditional Poisson regression to estimate incidence rate ratios (IRRs) and 95% confidence intervals (CIs) adjusted for event-dependent observation time, seasonality, and outcome misclassification. For AEs with any statistically significant associations, we stratified results by concomitant vaccination status. Results Among 12.7 million vaccine recipients, we observed 76 anaphylaxis, 276 encephalitis/encephalomyelitis, 134 GBS and 75 transverse myelitis cases. Only rates of anaphylaxis were elevated in risk compared to control intervals. With all adjustments, an elevated, but non-statistically significant, anaphylaxis rate was observed following any (IRR: 2.40, 95% CI: 0.96 to 6.03), high-dose (IRR: 2.31, 95% CI: 0.67 to 7.91), and adjuvanted (IRR: 3.28, 95% CI: 0.71 to 15.08) influenza vaccination; anaphylaxis IRRs were 2.54 (95% CI: 0.49 to 13.05) and 1.64 (95% CI: 0.38 to 7.05) for those with and without concomitant vaccination, respectively. Conclusions Rates of encephalitis/encephalomyelitis, GBS, or transverse myelitis were not elevated following 2022 to 2023 seasonal influenza vaccinations among U.S. adults 65 years and older. There was an increased rate of anaphylaxis following influenza vaccination that may have been influenced by concomitant vaccination.

Background The Diagnostic and Statistical Manual of Mental Disorders (DSM-V) issued new diagnostic criteria for autism spectrum conditions (ASC) which excluded cases of Asperger's syndrome (AS) and pervasive developmental disorder not otherwise specified (PDD-NOS). This negatively affected the support received by those affected. In this study, we explored if AS can be considered a subtype of autism. Methods We explored whether AS is considered a subtype of autism through gene network analysis. We analysed the GEO microarray data of 170 autism patients and then used a weighted gene coexpression network (WGCNA) pipeline. We explored whether these modules share the same expression patterns across autism subtypes. The study had 170 patients grouped into three groups: AS, autism, and PDD-NOS. Results Twenty-one genetic modules were constructed for autism spectrum conditions. However, only one genetic network was significantly down regulated in AS compared to other subtypes. The module genes were significantly involved in the regulation of proteolysis, catabolic processes, and NF-kappaB signalling. Pathway analysis showed the association of these genes with RIPK1-mediated necrosis and regulation of necroptotic cell death. Brain enrichment analysis showed a spatiotemporal distribution. There was significant gene enrichment in the prefrontal cortex during infancy and childhood, and then it changed in adulthood to be more abundant in the cingulum bundle and corpus callosum. Conclusions Our results suggest AS can be a distinct subtype of ASD, showing a similar gene expression pattern. Spatiotemporal distribution of the module genes in different brain regions explains the high functionality in individuals with AS.

BACKGROUND AND OBJECTIVES: Delirium and depression are increasingly common in aging. There is considerable clinical overlap, including shared symptoms and comorbid conditions, including Alzheimer disease (AD), functional decline, and mortality. Despite this, the long-term relationship between depression and delirium remains unclear. This study assessed the associations of depression symptom burden and its trajectory with delirium risk in a 12-year prospective study of older individuals during hospitalization. RESEARCH DESIGN AND METHODS: 319,141 UK biobank participants between 2006-2010 (mean 58y [range 37-74, SD=8], 54% female) reported frequency (0-3) of four depressive symptoms (mood, disinterest, tenseness, or lethargy) in the preceding 2 weeks, and aggregated into a depressive symptom burden score (0-12). New-onset delirium was obtained from hospitalization records during 12y median follow-up. 40,451 (mean age 57 {+/-} 8; range 40-74y) had repeat assessment on average 8y after their first. Cox proportional hazard models examined whether depression symptom burden and trajectory predicted incident delirium during hospitalization. RESULTS: 5,753 (15 per 1000) newly developed delirium during follow-up. Increased risk for delirium was seen for mild (aggregated scores 1-2, hazards ratio, HR=1.16, [95% confidence interval 1.08-1.25], p<0.001), modest (scores 3-5, 1.30 [1.19 -1.43], p<0.001) and severe (scores [≥] 5, 1.38 [1.24 -1.55], p<0.001) depressive symptoms, versus none in the fully adjusted model. These findings were independent of the number of hospitalizations and consistent across hospitalization settings (e.g., surgical, medical, or critical care) and specialty (e.g., neuropsychiatric, cardiorespiratory or other). Worsening depression symptoms ([≥]1 point increase), compared to no change/improved score, were associated with an additional 39% increased risk (1.39 [1.03-1.88], p=0.03) independent of baseline depression burden. The association was strongest in those over 65y at baseline (p for interaction <0.001). DISCUSSION AND IMPLICATIONS: Depression symptom burden and worsening trajectory predicted delirium risk during hospitalization. Increased awareness of subclinical depression symptoms may be warranted for delirium prevention.

Objective To investigate the impact of the COVID-19 pandemic on Group A streptococcal (GAS) cases and related antibiotic prescriptions. Design A retrospective cohort study with supporting dashboards with the approval of NHS England. Setting Primary care practices in England using TPP SystmOne software from January 2018 through March 2023. Participants Patients included were those registered at a TPP practice for each month of the study period. Patients with missing sex or age were excluded, resulting in a population of 23,816,470 in January 2018, increasing to 25,541,940 by March 2023. Main outcome measures We calculated monthly counts and crude rates of GAS cases (sore throat/tonsillitis, scarlet fever, invasive group A strep) and prescriptions linked with a GAS case, before (pre-April 2020), during and after (post-April 2021) COVID-19 restrictions. We calculated the maximum and minimum count and rate for each season (years running September-August), and the rate ratio (RR) of the 2022/23 season to the last comparably high season (2017/18). Results Recording of GAS cases and antibiotic prescription linked with a GAS case peaked in December 2022, higher than the 2017/2018 peak. The peak rate of monthly sore throat/tonsillitis (possible group A strep throat) recording was 5.33 per 1,000 (RR 2022/23 versus 2017/18 1.39 (CI: 1.38 to 1.40)). Scarlet fever recording peaked at 0.51 per 1,000 (RR 2.68 (CI: 2.59 to 2.77)), and invasive group A streptococcal infection (iGAS) at 0.01 per 1,000 (RR 4.37 (CI: 2.94 to 6.48)). First line antibiotics with a record of a GAS infection peaked at 2.80 per 1,000 (RR 1.37 (CI:1.35 to 1.38)), alternative antibiotics at 2.03 per 1,000 (RR 2.30 (CI:2.26 to 2.34)), and reserved antibiotics at 0.09 per 1,000 (RR 2.42 (CI:2.24 to 2.61). For individual antibiotics, azithromycin with GAS indication showed the greatest relative increase (RR 7.37 (CI:6.22 to 8.74)).This followed a sharp drop in recording of cases and associated prescriptions during the period of COVID-19 restrictions where the maximum count and rates were lower than any pre COVID-19 minimum. More detailed demographic breakdowns can be found in our regularly updated dashboard report. Conclusions Rates of scarlet fever, sore throat/tonsillitis and iGAS recording and associated antibiotic prescribing peaked in December 2022. Primary care data can supplement existing infectious disease surveillance through linkages with relevant prescribing data and detailed clinical and demographic subgroups.

Objectives. Alcohol use disorder (AUD) and depression are the most commonly reported psychiatric comorbid conditions. We examined trends in the past-year prevalence of driving under the influence of alcohol (DUIA) among people with major depressive episodes (MDE), AUD, or both in the United States. Methods. We analyzed 543,573 individuals aged 18 years or older from the 2005-2019 National Surveys on Drug Use and Health (NSDUH). Multivariate logistic regression models were applied to examine the adjusted past-year prevalence of DUIA. To assess trends in DUIA over time, annual average percent change (AAPC) was calculated. Results. From 2005 to 2019, DUIA prevalence among US adults with MDE declined significantly from 18.1% to 9.4% (AAPC = -4.9). Decreasing trends in DUIA were also observed among those with AUD (from 55.4% to 37.8%, AAPC = -3.0) and among those with co-occurring MDE and AUD (from 58.3% to 38.8%, AAPC = -3.1). Compared to those with no AUD or MDE (from 8.42% to 3.99%, AAPC = -5.6), individuals with AUD and those with co-occurring MDE and AUD had significantly lower AAPCs. There was no significant AAPC difference between those with MDE and those with no AUD or MDE. Regarding sociodemographic characteristics, younger adults aged 18-34 exhibited the lowest AAPC among all diagnostic groups. Conclusions. From 2005 to 2019, DUIA prevalence declined significantly with varying rates of decrease across different diagnostic groups. Focused public health efforts are needed to engage high-risk groups that have shown a tendency toward less expedient reductions in DUIA.

Background Cohort studies have demonstrated associations between calcific aortic valve disease (CAVD) and Lp(a). As Lp(a) is almost entirely genetically determined, with the increasing clinical availability of genetic information, we aimed to determine if Lp(a), when predicted from genetic data, is associated with CAVD and major adverse cardiovascular events (MACE). Methods Patients undergoing coronary angiography were invited to participate in the study. Of 752 analysable participants, 446 had Lp(a) measured, and 703 had a calculable LPA genetic risk score (GRS). CAVD was categorized as absent/present and by severity. The primary outcomes were presence of CAVD at baseline, and MACE over seven years follow-up. Results The GRS explained 45% of the variation in Lp(a). After adjustment for cardiac risk factors and coronary artery disease, the odds of CAVD increased with Lp(a) (OR 1.039 per 10 unit increase, 95% C.I. 1.022 ? 1.057, p<0.001) and GRS (OR 1.054 per 10-unit increase, 95% C.I. 1.024 ? 1.086; p <0.001). Lp(a) and the GRS as continuous variables were not associated with subsequent MACE. Dichotomised GRS (>54) was associated with MACE, but this relationship became non-significant when coronary artery disease classification was added into the model (OR 1.333, 95% C.I. 0.927 ? 1.912; p = 0.12). Conclusion An LPA GRS can explain 45% of the variation in Lp(a) levels, and both Lp(a) and the GRS are associated with CAVD. An elevated GRS is associated with future cardiac events in a secondary risk setting, but, if coronary artery disease status is known, it does not provide additional prognostic information.

Surgical patients over 70 experience postoperative delirium (POD) complications in up to 50% of procedures. Sleep/circadian disruption has emerged as a potential risk factor for POD in epidemiological studies. However, the relationship remains unclear in a clinical setting. This protocol presents a single-site, prospective, noninvasive observational study designed to examine the relationship between sleep/circadian regulation and POD and how this association is influenced by AD pathology and genetic risk for AD. This novel approach for understanding modifiable risk factors of POD and cognitive decline after surgery could assist with establishing treatments and preventative measures for POD in the future.

Background: Evidence on the impact of COVID-19 vaccination on symptoms, Health-Related Quality of Life (HRQoL), Work Productivity and Activity Impairment (WPAI) is scarce. We analyzed associations between bivalent BA.4/5 BNT162b2 and these patient-reported outcomes (PROs). Methods: Symptomatic US adults who tested positive for SARS-CoV-2 were recruited between 03/02-05/18/2023. PROs were assessed using a CDC-based symptom questionnaire, EQ-5D-5L, WPAI-GH, and PROMIS Fatigue, from pre-COVID to Week 4 following infection. Multivariable analysis using mixed models for repeated measures was conducted, adjusting for several covariates. Results: The study included 641 participants: 314 vaccinated with bivalent BA.4/5 BNT162b2 and 327 unvaccinated/not up-to-date. Mean (SD) age was 46.5 years (15.9), 71.2% were female, 44.2% reported prior infection, 25.7% had [≥]1 comorbidity. The BA.4/5 BNT162b2 cohort reported fewer acute symptoms through Week 4, especially systemic and respiratory symptoms. All PROs were adversely affected, especially at Week 1; however, at that time point, the bivalent BA.4/5 BNT162b2 cohort reported better work performance, driven by less absenteeism, and fewer work hours lost. No significant differences were observed for HRQoL. Conclusions: COVID-19 negatively impacted patient outcomes. Compared with unvaccinated/not up-to-date participants, those vaccinated with bivalent BA.4/5 BNT162b2 reported fewer and less persistent symptoms and improved work performance. Clinicaltrials.gov NCT05160636 Keywords: SARS-CoV-2; BA.4/5 BNT162b2; Bivalent; COVID-19; COVID-19 symptoms; HRQoL; Humanistic; Quality of life; WPAI; PROMIS Fatigue.

Knockout of the ORF8 protein has repeatedly spread through the global viral population during SARS-CoV-2 evolution. Here we use both regional and global pathogen sequencing to explore the selection pressures underlying its loss. In Washington State, we identified transmission clusters with ORF8 knockout throughout SARS-CoV-2 evolution, not just on novel, high fitness viral backbones. Indeed, ORF8 is truncated more frequently and knockouts circulate for longer than for any other gene. Using a global phylogeny, we find evidence of positive selection to explain this phenomenon: nonsense mutations resulting in shortened protein products occur more frequently and are associated with faster clade growth rates than synonymous mutations in ORF8. Loss of ORF8 is also associated with reduced clinical severity, highlighting the diverse clinical impacts of SARS-CoV-2 evolution.

In healthcare systems, optimizing resource allocation without compromising patient care is paramount. This study employs a simulation-based approach to evaluate the efficiency of bed allocation within a hospital setting. Utilizing a patient arrival model with an exponential distribution, we simulated patient trajectories to examine system bottlenecks, particularly focusing on waiting times. Initial simulations painted a scenario of an "unstable" system, where waiting times and queue lengths surged due to the limited number of available beds. Through iterative simulations, we explored the operational research question: "What is the minimum number of beds required to stabilize the system?" Our results, visualized in a series of detailed metrics plots, suggest that the addition of a specific number of beds can significantly reduce patient waiting time and stabilize the system. This research offers insights for hospital management on resource optimization, potentially leading to improved patient care and reduced operational costs.

Activation of the NLRP3-inflammasome has been proposed to play a role in Parkinson's disease pathogenesis based on in vitro and in vivo studies. Currently, clinical trials targeting the NLRP3 pathway in Parkinson's disease are at early stages. However, the evidence supporting NLRP3's involvement in Parkinson's disease from human genetics data remains limited. In this study, we conducted comprehensive analyses of common and rare variants in genes related to the NLRP3-inflammasome in large Parkinson's disease cohorts. Furthermore, we performed pathway-specific analyses using polygenic risk scores and studied potential causal associations using Mendelian randomization with the NLRP3 components and the cytokines released by its activation, IL-1b; and IL-18. Our findings showed no associations of common or rare variants, nor of the pathway polygenic risk score for the NLRP3 inflammasome, with risk of Parkinson's disease. Mendelian randomization analyses suggest that altering the expression of the NLRP3 inflammasome, IL-1b; or IL-18, is not likely to affect Parkinson's disease risk, age-at-onset, or progression. Therefore, our results do not support an important role for the NLRP3 inflammasome in Parkinson's disease pathogenesis or as a strong target for drug development.

The role of gene-environment (GxE) interaction in disease and complex trait architectures is widely hypothesized, but currently unknown. Here, we apply three statistical approaches to quantify and distinguish three different types of GxE interaction for a given disease/trait and E variable. First, we detect locus-specific GxE interaction by testing for genetic correlation (rg) < 1 across E bins. Second, we detect genome-wide effects of the E variable on genetic variance by leveraging polygenic risk scores (PRS) to test for significant PRSxE in a regression of phenotypes on PRS, E, and PRSxE, together with differences in SNP-heritability across E bins. Third, we detect genome-wide proportional amplification of genetic and environmental effects as a function of the E variable by testing for significant PRSxE with no differences in SNP-heritability across E bins. Simulations show that these approaches achieve high sensitivity and specificity in distinguishing these three GxE scenarios. We applied our framework to 33 UK Biobank diseases/traits (average N=325K) and 10 E variables spanning lifestyle, diet, and other environmental exposures. First, we identified 19 trait-E pairs with rg significantly < 1 (FDR<5%) (average rg=0.95); for example, white blood cell count had rg=0.95 (s.e. 0.01) between smokers and non-smokers. Second, we identified 28 trait-E pairs with significant PRSxE and significant SNP-heritability differences across E bins; for example, type 2 diabetes had a significant PRSxE for alcohol consumption (P=1e-13) with 4.2x larger SNP-heritability in the largest versus smallest quintiles of alcohol consumption (P<1e-16). Third, we identified 15 trait-E pairs with significant PRSxE with no SNP-heritability differences across E bins; for example, triglyceride levels had a significant PRSxE effect for composite diet score (P=4e-5) with no SNP-heritability differences. Analyses using biological sex as the E variable produced additional significant findings in each of the three scenarios. Overall, we infer a substantial contribution of GxE and GxSex effects to disease and complex trait variance.

Background: Unstable cerebral hemodynamics places preterm infants at high risk of brain injury. We adapted an innovative, fiber-free, wearable diffuse speckle contrast flow-oximetry (DSCFO) device for continuous monitoring of both cerebral blood flow (CBF) and oxygenation in neonatal piglets and preterm infants. Methods: DSCFO uses two small laser diodes as focused-point and a tiny CMOS camera as a high-density two-dimensional detector to detect spontaneous spatial fluctuation of diffuse laser speckles for CBF measurement, and light intensity attenuations for cerebral oxygenation measurement. The DSCFO was first validated against the established diffuse correlation spectroscopy (DCS) in neonatal piglets and then utilized for continuous CBF and oxygenation monitoring in preterm infants during intermittent hypoxemia (IH) events. Results: Consistent results between the DSCFO and DCS measurements of CBF variations in neonatal piglets were observed. IH events induced fluctuations in CBF, cerebral oxygenation, and peripheral cardiorespiratory vitals in preterm infants. However, no consistent correlation patterns were observed among peripheral and cerebral monitoring parameters. Conclusions: This pilot study demonstrated the feasibility of DSCFO technology to serve as a low-cost wearable sensor for continuous monitoring of multiple cerebral hemodynamic parameters. The results suggested the importance of multi-parameter measurements for understanding deep insights of peripheral and cerebral regulations.