Measuring the fitted filtration efficiency of cloth masks, medical masks and respirators

medRxiv

ObjectiveTo study the comparative effectiveness of angiotensin receptor blockers (ARB) and angiotensin-converting enzyme inhibitors (ACEi) in ethnic minority groups in the UK.DesignObservational cohort study using a reference trial emulation approach benchmarked against the ONTARGET trial.SettingUK Clinical Practice Research Datalink Aurum data from 01/01/2001-31/07/2019.ParticipantsBlack, South Asian, or White patients treated with ARB or ACEi who met the ONTARGET trial criteria.Main outcome measuresThe primary composite outcome was: cardiovascular-related death, myocardial infarction, stroke, or hospitalisation for heart failure with individual components studied as secondary outcomes. Angioedema was a safety endpoint. We assessed outcomes using a propensity-score—weighted Cox proportional hazards model for ARB vs ACEi with heterogeneity by ethnicity assessed on the relative and absolute scale.Results17,593 Black, 30,805 South Asian, and 524,623 White patients were included. We benchmarked results against ONTARGET comparing ARB with ACEi for the primary outcome (hazard ratio [HR] 0.96, 95% CI: 0.95 to 0.98) and found no evidence of treatment effect heterogeneity (Pint=0.422). Results were consistent for most secondary outcomes. However, for cardiovascular-related death, there was strong evidence of heterogeneity (Pint=0.002), with ARB associated with more events in Black individuals and with fewer events in White individuals compared to ACEi, and no differences in South Asian individuals. For angioedema, HR 0.56 (95% CI: 0.46 to 0.67) for ARB vs ACEi (Pint=0.306). Absolute risks were …

JAMA Network Open

ImportanceAlthough major bleeding is among the most common and prognostically important perioperative complications, the relative timing of bleeding events is not well established. This information is critical for preventing bleeding complications and for informing the timing of pharmacologic thromboprophylaxis.ObjectiveTo determine the timing of postoperative bleeding among patients undergoing surgery for up to 30 days after surgery.Design, Setting, and ParticipantsThis is a secondary analysis of a prospective cohort study. Patients aged 45 years or older who underwent inpatient noncardiac surgery were recruited in 14 countries between 2007 and 2013, with follow-up until December 2014. Data analysis was performed from June to July 2023.ExposureNoncardiac surgery requiring overnight hospital admission.Main Outcomes and MeasuresThe primary outcome (postoperative major bleeding) was a …

Membranes

Electrically conductive membranes (ECMs) have emerged as a multifunctional separation technology that integrates membrane filtration with electrochemical reactions. Physical stability remains a critical challenge for ECMs synthesized by coating polymer membranes with conductive materials. In this article, polydopamine (PDA) and polyethyleneimine (PEI) were used to facilitate the synthesis of significantly more stable ECMs using poly(vinylidene fluoride) (PVDF) ultrafiltration membranes and carbon nanotubes (CNTs). Four different synthesis methods were compared in terms of the final surface stability and separation properties: (1) CNTs deposited on PEI-crosslinked PDA-coated PVDF membranes, (2) PEI-crosslinked CNTs deposited on PDA-coated PVDF, (3) PDA, PEI and CNTs sequentially deposited layer-by-layer on PVDF, and (4) PEI-crosslinked PDA deposited on CNT-coated PVDF. The results revealed that method 1 generated ECMs with the greatest physical stability, highest electrical conductivity (18,518 S/m), and sufficient permeability (395.2 L/(m2·h·bar). In comparison, method 2 resulted in membranes with the highest permeability (2128.5 L/(m2·h·bar), but with low surface conductivity (502 S/m) and poor physical stability (i.e., 53–75% lower peel-off forces compared to other methods). Overall, methods 1, 3, and 4 can be used to make highly conductive membranes with a 97–99% removal of methyl orange by electrochemical degradation at −3 V.

ACS Applied Polymer Materials

Electrochemical membranes (ECMs) are an emerging multifunctional separation technology that enables simultaneous contaminant filtration and reaction due to their electrically conductive porous surface coatings. Physical coating stability remains a technical challenge for ECMs, which are largely based on carbonaceous nanomaterials or metallic thin films. In this research, binding chemistry based on polydopamine (PDA) and polyethylenimine (PEI) was developed to prepare physically stable ECMs. Poly(vinylidene fluoride) (PVDF) ultrafiltration membranes were coated with PEI cross-linked PDA followed by the deposition of carboxyl-functionalized single/double-walled carbon nanotubes (SW/DWCNTs-COOH). Fabricated membranes were characterized for their structural, physicochemical, electrochemical, and separation properties. In a batch electrochemical system, the membranes achieved >99.2 …

People living with chronic kidney disease (CKD) often experience multimorbidity and require polypharmacy. Kidney dysfunction can also alter the pharmacokinetics and pharmacodynamics of medications, which can modify their risks and benefits; the extent of these changes is not well understood for all situations or medications. The principle of drug stewardship is aimed at maximizing medication safety and effectiveness in a population of patients through a variety of processes including medication reconciliation, medication selection, dose adjustment, monitoring for effectiveness and safety, and discontinuation (deprescribing) when no longer necessary. This Review is aimed at serving as a resource for achieving optimal drug stewardship for patients with CKD. We describe special considerations for medication use during pregnancy and lactation, during acute illness and in patients with cancer, as well as …

Respiratory Care

BACKGROUNDAerosol barrier enclosure systems have been designed to prevent airborne contamination, but their safety has been questioned. A vacuum tent was designed with active continuous suctioning to minimize risks of aerosol dispersion. We tested its efficacy, risk of rebreathing, and usability on a bench, in healthy volunteers, and in an ergonomic clinical assessment study.METHODSFirst, a manikin with airway connected to a breathing simulator was placed inside the vacuum tent to generate active breathing, cough, and CO2 production; high-flow nasal cannula (HFNC) was applied in the manikin’s nares. Negative pressure was applied in the vacuum tent’s apex port using wall suction. Fluorescent microparticles were aerosolized in the vacuum tent for qualitative assessment. To quantify particles inside and around vacuum tent (aerosol retention), an airtight aerosol chamber with aerosolized latex …

The Canadian Journal of Chemical Engineering

Electrochemical membranes (ECMs) and porous electrodes have gained much attention in a broad range of applications including water and wastewater treatment, energy production and storage, and carbon dioxide capture. Lab scale batch experiments (electrochemical stirred cells) are the baseline for developing ECMs and porous electrodes. We observed electrochemical dissolution of metal fasteners (alligator clips), used to hold porous conductive and non‐conductive membranes in batch electrochemical cells, despite being kept outside the electrolyte. The electrolyte migrated through the porous membranes by the action of capillary forces, forming a closed electrochemical circuit with the metal fasteners. This unexpected leaching can lead to misleading results for electrochemical experiments on porous electrodes and ECMs. In this study, we compared (1) porous membranes versus non‐porous electrodes …

Purpose of programA key barrier to becoming a living kidney donor is an inefficient evaluation process, requiring more than 30 tests (eg, laboratory and diagnostic tests), questionnaires, and specialist consultations. Donor candidates make several trips to hospitals and clinics, and often spend months waiting for appointments and test results. The median evaluation time for a donor candidate in Ontario, Canada, is nearly 1 year. Longer wait times are associated with poorer outcomes for the kidney transplant recipient and higher health care costs. A shorter, more efficient donor evaluation process may help more patients with kidney failure receive a transplant, including a pre-emptive kidney transplant (ie, avoiding the need for dialysis). In this report, we describe the development of a quality improvement intervention to improve the efficiency, effectiveness, and patient-centeredness of the donor candidate evaluation …

Journal of Hazardous Materials

Wastewater generated from e-waste leaching is rich in precious metals including gold, silver and platinum. Conventional precipitation and solvent extraction are chemically intensive separations with concerning environmental externalities. Sorbents, in particular carbon nanotubes, have low chemical consumption, and have shown promise for gold adsorption due to their high specific surface area and chemical functionalization potential. However, regenerating sorbents used to adsorb Au is hazardous requiring strong acids. Herein, we delineate the effect of various functional groups on the sidewalls of multiwall carbon nanotubes (MWCNTs) on gold adsorption, and we introduced an acid-free electrochemical technique for Au elution from MWCNTs. Pristine MWCNTs (P-MWCNTs), carboxylic functionalised MWCNTs (COOH-MWCNTs) and amide functionalised MWCNTs (NH 2-MWCNTs) were compared for their …

Journal of Nephrology

BackgroundThe pharmacological management of hyperkalemia traditionally considered calcium or sodium polystyrene sulfonate and, since recently, the novel binders patiromer and sodium zirconium cyclosilicate. We evaluated their patterns of use, duration of treatment and relative effectiveness/safety in Swedish routine care.MethodsObservational study of adults initiating therapy with sodium polystyrene sulfonate or a novel binder (sodium zirconium cyclosilicate or patiromer) in Stockholm 2019–2021. We quantified treatment duration by repeated dispensations, compared mean achieved potassium concentration within 60 days, and potential adverse events between treatments.ResultsA total of 1879 adults started treatment with sodium polystyrene sulfonate, and 147 with novel binders (n= 41 patiromer and n= 106 sodium zirconium cyclosilicate). Potassium at baseline for all treatments was 5.7 mmol/L. Sodium …

Clinical Kidney Journal

Since the 1950s, sodium polystyrene sulphonate (SPS) has been the dominant cation exchange agent prescribed for hyperkalaemia. Clinicians have had plenty of time to learn of SPS's advantages and limitations. The demands of drug regulatory agencies regarding the incorporation of medications into the market were not so stringent then as they are today, and the efficacy and safety of SPS have been questioned. In recent years, two novel cation exchangers, patiromer and sodium zirconium cyclosilicate, have received (or are in the process of receiving) regulatory approval in multiple jurisdictions globally, after scrutiny of carefully conducted trials regarding their short-term and mid-term efficacy. In this debate, we defend the view that all three agents are likely to have similar efficacy. Harms are much better understood for SPS than for newer agents, but currently there are no data to suggest that novel agents …

Separation and Purification Technology

Catalytic membrane microreactors (CMMRs) are an exciting new technology that combine catalysis with membranes by seeding the high internal surface area of membranes with catalysts. This enables the continuous purification and production of organic compounds with high catalytic activity, while maintaining nanocatalyst size and stability. This study reports a simple two-step batch reaction approach for synthesizing stable Pd-immobilized catalytic membranes to transform 4-nitrophenol (4-NP) to 4-aminophenol (4-AP) in a flow-through CMMR system. The product (4-AP) is an essential intermediate for the polymer and solvent chemical industry. Pd-immobilized membranes exhibited strong catalytic activity for 4-NP reduction in the presence of NaBH 4, with 4-fold higher reduction (79.7%) and 2-fold higher reduction rate (1.08 mol m− 2 h− 1) as compared to control membranes without catalysts. The catalytic …

Langmuir

Wettability plays a significant role in controlling multiphase flow in porous media for many industrial applications, including geologic carbon dioxide sequestration, enhanced oil recovery, and fuel cells. Microfluidics is a powerful tool to study the complexities of interfacial phenomena involved in multiphase flow in well-controlled geometries. Recently, the thiolene-based polymer called NOA81 emerged as an ideal material in the fabrication of microfluidic devices, since it combines the versatility of conventional soft photolithography with a wide range of achievable wettability conditions. Specifically, the wettability of NOA81 can be continuously tuned through exposure to UV–ozone. Despite its growing popularity, the exact physical and chemical mechanisms behind the wettability alteration have not been fully characterized. Here, we apply different characterization techniques, including contact angle measurements, X …

Chemical Engineering Journal

Emerging contaminants in potable waters and wastewaters are a global concern exacerbated by industrial growth. Graphene-based nanomaterials (e.g., rGO) incorporated at a membrane’s surface have been shown to enhance separation performance by increasing adsorption and altering membrane pore size. However, rGO surface-deposited membranes demonstrate low water fluxes and poor stability due to high rGO interlayer packing density and nanosheet swelling. Herein, a cationic polyelectrolyte cross-linked rGO nanocomposite membrane was developed to address these issues. These membranes were formed by a layer of iron doped rGO (rGO–Fe) cross-linked with hyperbranched polyethylenimine (HPEI) vacuum-deposited onto a polydopamine (PDA) coated polyethersulfone (PES) ultrafiltration membrane. The HPEI cross-linking of iron-doped rGO was accomplished by 1) activating the carbonyl …

JAMA Network Open

ImportanceAmong patients with bipolar disorder, discordant findings have been published on the nephrotoxic effects of lithium therapy.ObjectiveTo quantify absolute and relative risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) in people who initiated lithium compared with valproate therapy and to investigate the association between cumulative use and elevated lithium levels and kidney outcomes.Design, Setting, and ParticipantsThis cohort study had a new-user active-comparator design and used inverse probability of treatment weights to minimize confounding. Included patients initiated therapy with lithium or valproate from January 1, 2007, to December 31, 2018, and had a median follow-up of 4.5 years (IQR, 1.9-8.0 years). Data analysis began in September 2021, using routine health care data from the period 2006 to 2019 from the Stockholm Creatinine Measurements project, a …

Nephrology Dialysis Transplantation

Background and Aims The pharmacological management of hyperkalemia has traditionally considered sodium polystyrene sulfonate (SPS) and, since late 2018, the novel potassium (K+) binders Patiromer and Sodium Zirconium Cyclosilicate (SZC). This study evaluated their patterns of use, duration of treatment and relative effectiveness in reducing plasma K+ levels in Stockholm´s contemporary routine care. Method Observational study of all adults who newly-filled a prescription for SPS, Patiromer or SZC during 2019–2021 in Stockholm, Sweden. Sweden offers universal healthcare and covers the cost of prescribed medications. We described patient characteristics of new initiators, including their comorbidities, medication use, eGFR and pre-treatment plasma K+ levels. We then quantified treatment duration by evaluating all subsequent dispensations. Lastly, we compared …

Canadian Journal of Kidney Health and Disease

BackgroundMost patients with end-stage kidney disease (ESKD) appreciate the importance of exercise and would like to increase their physical activity; however, they report a few key barriers, including (1) lack of physician advice to do so, (2) lack of safe and convenient programs (ie, appropriate for home or neighborhood), and (3) cost. Importantly, patients indicated in a previous survey that they would prefer an exercise program that improves muscle strength and symptoms, and are less interested in cardiovascular disease prevention.ObjectiveTo test the feasibility of a simple, prescribed exercise program using Nordic walking poles in patients with ESKD treated with dialysis.DesignRandomized multicenter pilot trial of an exercise intervention that includes Nordic walking poles, personalized physician exercise prescriptions, pedometers, and access to exercise videos, compared with standard of care, in patients …

American Journal of Kidney Diseases

Rationale & ObjectiveDirect oral anticoagulants (DOACs) have progressively replaced vitamin K antagonists (VKAs) for stroke prevention in patients with nonvalvular atrial fibrillation (AF). DOACs cause fewer bleeding complications, but their other advantages, particularly related to kidney outcomes, remain inconclusive. We studied the risks of chronic kidney disease (CKD) progression and acute kidney injury (AKI) after DOAC and VKA administration for nonvalvular AF.Study DesignRetrospective cohort study.Setting & ParticipantsCohort study of Swedish patients enrolled in the Stockholm Creatinine Measurements (SCREAM) project with a diagnosis of nonvalvular AF during 2011-2018.ExposureInitiation of DOAC or VKA treatment.OutcomePrimary outcomes were CKD progression (composite of >30% estimated glomerular filtration rate [eGFR] decline and kidney failure) and AKI (by diagnosis or KDIGO-defined …

medRxiv

Chronic pain is a multifactorial condition presenting significant diagnostic and prognostic challenges. Biomarkers for the classification and the prediction of chronic pain are therefore critically needed. In this multi-dataset study of over 523,000 participants, we applied machine learning to multi-dimensional biological data from the UK Biobank to identify biomarkers for 35 medical conditions associated with pain (e.g., clinical diagnosis of rheumatoid arthritis, fibromyalgia, stroke, gout, etc.) or self-reported chronic pain (e.g., back pain, knee pain, etc). Biomarkers derived from blood immunoassays, brain and bone imaging, and genetics were effective in predicting medical conditions associated with chronic pain (area under the curve (AUC) 0.62-0.87) but not self-reported pain (AUC 0.50-0.62). Among the biomarkers identified was a composite blood-based signature that predicted the onset of various medical conditions approximately nine years in advance (AUC 0.59-0.72). Notably, all biomarkers worked in synergy with psychosocial factors, accurately predicting both medical conditions (AUC 0.69-0.91) and self-report pain (AUC 0.71-0.92). Over a period of 15 years, individuals scoring high on both biomarkers and psychosocial risk factors had twice the cumulative incidence of diagnoses for pain-associated medical conditions (Hazard Ratio (HR): 2.26) compared to individuals scoring high on biomarkers but low on psychosocial risk factors (HR: 1.06). In summary, we identified various biomarkers for chronic pain conditions and showed that their predictive efficacy heavily depended on psychological and social influences. These findings underscore …

medRxiv

ImportanceChildren prenatally exposed to maternal diabetes have a higher risk of developing obesity and metabolic disorders. Alterations in the brain development is hypothesized as a potential mechanism underlying this relationship but has not been fully tested in humans.ObjectivesTo examine the mediating role of child brain structure in the relationships between prenatal exposure to maternal diabetes and child adiposity.Design, setting and participantsThis was a cross-sectional study of children (ages 9-to-10-years-old) from the baseline assessment of the Adolescent Brain and Cognitive Development (ABCD) Study® (N=11,875).ExposuresPrenatal exposure to maternal diabetes was determined via self-reported questionnaire.Main outcomes and measuresChild adiposity markers included age- and sex-specific body mass index (BMI z-scores), waist circumference, and waist-to-height ratio (WHtR). T1-weighted magnetic resonance imaging (MRI) was used to assess brain structure. Linear mixed effects models examined associations of prenatal exposure to maternal diabetes with child adiposity markers and brain structure controlling for sociodemographic covariates. Mediation models were performed to investigate the mediating role of brain structure on the association between maternal diabetes exposure and child adiposity markers.ResultsThe sample consisted of 8,521 children (agem: 9.92±0.63 years; sex: 51.4% males; 7% exposed to maternal diabetes). Children prenatally exposed vs. unexposed to maternal diabetes had greater BMI z-scores (β (95% CI) = 0.175 (0.093, 0.256; FDR corrected P<0.001), waist circumference (β (95% CI …

medRxiv

Background Physical activity has been associated with preventing the development of type 2 diabetes and atherosclerotic cardiovascular disease. However, our understanding of the precise molecular mechanisms underlying these effects remains incomplete and good biomarkers to objectively assess physical activity are lacking. Methods We analyzed 3072 serum proteins in 26 men, normal weight or overweight, undergoing 12 weeks of a combined strength and endurance exercise intervention. We estimated insulin sensitivity with hyperinsulinemic euglycemic clamp, maximum oxygen uptake, muscle strength, and used MRI/MRS to evaluate body composition and organ fat depots. Muscle and subcutaneous adipose tissue biopsies were used for mRNA sequencing. Additional association analyses were performed in samples from up to 47,747 individuals in the UK Biobank, as well as using 2-sample Mendelian randomization and mice models. Results Following 12 weeks of exercise intervention, we observed significant changes in 283 serum proteins. Notably, 66 of these proteins were elevated in overweight men and positively associated with liver fat before the exercise regimen, but were normalized after exercise. Furthermore, for 19.7% and 12.1% of the exercise-responsive proteins, corresponding changes in mRNA expression levels in muscle and fat, respectively, were shown. The protein CD300LG displayed consistent alterations in blood, muscle, and fat. Serum CD300LG exhibited positive associations with insulin sensitivity, and to angiogenesis-related gene expression in both muscle and fat. Furthermore, serum CD300LG was …

medRxiv

Digital health technologies offer valuable advantages to dementia researchers and clinicians as screening tools, diagnostic aids, and monitoring instruments. To support the use and advancement of these resources, a comprehensive overview of the current technological landscape is essential. A multi-stakeholder working group, convened by the Digital Medicine Society (DiMe), conducted a landscape review to identify digital health technologies for Alzheimers disease and related dementia populations. We searched studies indexed in PubMed, Embase, and APA PsycInfo to identify manuscripts published between May 2003 to May 2023 reporting analytical validation, clinical validation, or usability/feasibility results for relevant digital health technologies. Additional technologies were identified through community outreach. We collated 172 peer-reviewed manuscripts, poster presentations, or regulatory documents for 106 different technologies for Alzheimers disease and related dementia assessment covering diverse populations such as Lewy Body, vascular dementias, frontotemporal dementias, and all severities of Alzheimers disease. Wearable sensors represent 32% of included technologies, non-wearables 61%, and technologies with components of both account for the remaining 7%. Neurocognition is the most prevalent concept of interest, followed by physical activity and sleep. Clinical validation is reported in 69% of evidence, analytical validation in 34%, and usability/feasibility in 20% (not mutually exclusive). These findings provide a landscape overview for clinicians and researchers to appraise the clinical utility and relative maturity of …

medRxiv

Obsessive-compulsive disorder (OCD) affects ~1% of the population and exhibits a high SNP-heritability, yet previous genome-wide association studies (GWAS) have provided limited information on the genetic etiology and underlying biological mechanisms of the disorder. We conducted a GWAS meta-analysis combining 53,660 OCD cases and 2,044,417 controls from 28 European-ancestry cohorts revealing 30 independent genome-wide significant SNPs and a SNP-based heritability of 6.7%. Separate GWAS for clinical, biobank, comorbid, and self-report sub-groups found no evidence of sample ascertainment impacting our results. Functional and positional QTL gene-based approaches identified 249 significant candidate risk genes for OCD, of which 25 were identified as putatively causal, highlighting WDR6, DALRD3, CTNND1 and genes in the MHC region. Tissue and single-cell enrichment analyses highlighted hippocampal and cortical excitatory neurons, along with D1- and D2-type dopamine receptor-containing medium spiny neurons, as playing a role in OCD risk. OCD displayed significant genetic correlations with 65 out of 112 examined phenotypes. Notably, it showed positive genetic correlations with all included psychiatric phenotypes, in particular anxiety, depression, anorexia nervosa, and Tourette syndrome, and negative correlations with a subset of the included autoimmune disorders, educational attainment, and body mass index.. This study marks a significant step toward unraveling its genetic landscape and advances understanding of OCD genetics, providing a foundation for future interventions to address this debilitating …

medRxiv

Background: The impact of pre-infection vaccination on the risk of long COVID remains unclear in the pediatric population. Further, it is unknown if such pre-infection vaccination can mitigate the risk of long COVID beyond its established protective benefits against SARS-CoV-2 infection. Objective: To assess the effectiveness of BNT162b2 on long COVID risks with various strains of the SARS-CoV-2 virus in children and adolescents, using comparative effectiveness methods. To disentangle the overall effectiveness of the vaccine on long COVID outcomes into its independent impact and indirect impact via prevention of SARS-CoV-2 infections, using causal mediation analysis. Design: Real-world vaccine effectiveness study and mediation analysis in three independent cohorts: adolescents (12 to 20 years) during the Delta phase, children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. Setting: Twenty health systems in the RECOVER PCORnet electronic health record (EHR) Program. Participants: 112,590 adolescents (88,811 vaccinated) in the Delta period, 188,894 children (101,277 vaccinated), and 84,735 adolescents (37,724 vaccinated) in the Omicron period. Exposures: First dose of the BNT162b2 vaccine vs. no receipt of COVID-19 vaccine. Measurements: Outcomes of interest include conclusive or probable diagnosis of long COVID following a documented SARS-CoV-2 infection, and body-system-specific condition clusters of post-acute sequelae of SARS-CoV-2 infection (PASC), such as cardiac, gastrointestinal, musculoskeletal, respiratory, and syndromic categories. The effectiveness was reported as (1 …

medRxiv

Background Cytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyper-inflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare DOCK8 variants in CSS patients. Objective We explore the role of CSS patient derived DOCK8 mutations on cytolytic activity in NK cells. We further study effects of Dock8-/- in murine models of CSS. Methods DOCK8 cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNlower case Greek gamma) production were explored by flow cytometry (FCM). A third CSS patient DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8-/- mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNlower case Greek gamma levels) upon challenge with lymphochoriomeningitic virus (LCMV) and excess IL-18. Results Both patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. Dock8-/- mice tolerated excess IL-18 but developed features of CSS upon LCMV infection …

medRxiv

Background and Objectives Cohort studies investigating respiratory disease pathogenesis aim to pair mechanistic investigations with longitudinal virus detection but are limited by the burden of methods tracking illness over time. In this study, we explored the utility of a smartphone app to robustly identify symptomatic respiratory illnesses, while reducing burden and facilitating real-time data collection and adherence monitoring. Methods The AERIAL TempTracker smartphone app was assessed in the AERIAL and COCOON birth cohort studies. Participants recorded daily temperatures and associated symptoms/medications in TempTracker for 6 months, with daily use adherence measured over this period. Regular participant feedback was collected at quarterly study visits. Symptomatic respiratory illnesses meeting study criteria prompted an automated app alert and collection of a nose/throat swab for testing of eight respiratory viruses. Results In total, 32,764 daily TempTracker entries from 348 AERIAL participants and 30,542 entries from 361 COCOON participants were recorded. This corresponded to an adherence median of 67.0% (range 1.9$[ndash]100%) and 55.4% (range 1.1–100%) of each participants study period, respectively. Feedback was positive, with 75.5% of responding families reporting no barriers to use. A total of 648 symptomatic respiratory illness events from 249/709 participants were identified with significant variability between individuals in the frequency (0–16 events per participant), duration (1–13 days), and virus detected (rhinovirus in 42.7%). Conclusions A smartphone app provides a reliable method to capture the …

medRxiv

Importance Masks reduce transmission of SARS-CoV2 and other respiratory pathogens. Comparative studies of the fitted filtration efficiency of different types of masks of are few.   Objective To describe the fitted filtration efficiency against small aerosols (0.02 – 1 µm) of medical and non-medical masks and respirators when worn, and how this is affected by user modifications (hacks) and by overmasking with a cloth mask.   Design We tested a 2-layer woven-cotton cloth mask of a consensus design, ASTM-certified level 1 and level 3 masks, a non-certified mask, KF94s, KN95s, an N95 and a CaN99.   Setting Closed rooms with ambient particles supplemented by salt particles.   Participants 12 total participants; 21 – 55 years, 68% female, 77% white, NIOSH 1 to 10.   Main Outcome and Measure Using standard methods and a PortaCount 8038, we counted 0.02–1µm particles inside and outside masks and respirators, expressing results as the percentage filtered by each mask. We also studied level 1 and level 3 masks with earguards, scrub caps, the knot-and-tuck method, and the effects of braces or overmasking with a cloth mask.   Results Filtration efficiency for the cloth mask was 47-55%, for level 1 masks 52-60%, for level 3 masks 60-77%. A non-certified KN95 look-alike, two KF94s, and three KN95s filtered 57-77%, and the N95 and CaN99 97-98% without fit testing. External braces and overmasking with a well-fitting cloth mask increased filtration, but earguards, scrub caps, and the knot-and-tuck method did not.   Limitations Limited number of masks of each type sampled; no adjustment for multiple comparisons.   Conclusions and Relevance …

medRxiv

Objectives Prevention of fetal growth restriction/small for gestational age is adequate if screening is accurate. Ultrasound and biomarkers can achieve this goal; however, both are often inaccessible. This study aimed to develop, validate, and deploy a prognostic prediction model for screening fetal growth restriction/small for gestational age using only medical history. Methods From a nationwide health insurance database (n=1,697,452), we retrospectively selected visits of 12-to-55-year-old females to 22,024 healthcare providers of primary, secondary, and tertiary care. This study used machine learning (including deep learning) to develop prediction models using 54 medical-history predictors. After evaluating model calibration, clinical utility, and explainability, we selected the best by discrimination ability. We also externally validated and compared the models with those from previous studies, which were rigorously selected by a systematic review of Pubmed, Scopus, and Web of Science. Results We selected 169,746 subjects with 507,319 visits for predictive modeling. The best prediction model was a deep-insight visible neural network. It had an area under the receiver operating characteristics curve of 0.742 (95% confidence interval 0.734 to 0.750) and a sensitivity of 49.09% (95% confidence interval 47.60% to 50.58% using a threshold with 95% specificity). The model was competitive against the previous models in a systematic review of 30 eligible studies of 381 records, including those using either ultrasound or biomarker measurements. We deployed a web application to apply the model. Conclusions Our model used only medical history …

medRxiv

Young-onset Alzheimer's Disease(AD) is a rare form of AD characterized by early symptom onset (< 65 years) and heterogeneous clinical phenotypes. Previous studies have consistently shown that patients with late-onset AD exhibit alterations in the default mode network-a large-scale brain network associated with self-related processing and autobiographical memory. However, the functional organization of the default-mode network is far less clear in young-onset AD. Here, we assessed default-mode network effective connectivity in two common young-onset AD variants (i.e., typical amnestic variant and posterior cortical atrophy) and healthy participants to identify disease- and variant-specific differences in the default-mode network. This case-control study was conducted with thirty-nine young-onset AD patients, including typical amnestic (n = 26, 15 females, mean age = 61) and posterior cortical atrophy (n = 13; 8 females, mean age = 61.8), and 24 age-matched healthy participants (13 females, mean age=60.1). All participants underwent resting-state functional MRI and extensive neuropsychological testing. Spectral dynamic causal modelling was performed to quantify resting-state effective connectivity between default-mode network regions. Parametric empirical Bayes analysis was then performed to characterise group differences in effective connectivity. Our results showed that patients with typical AD variant showed increased connectivity from medial prefrontal cortex to posterior default-mode network nodes as well as reduced inhibitory connectivity from hippocampus to other default-mode network nodes, relative to healthy controls …

medRxiv

Background Treatment with monoclonal antibodies against amyloid-beta; slowed cognitive decline in recent randomized clinical trials in patients with mild cognitive impairment (MCI) and early dementia due to Alzheimers disease (AD). However, stringent trial eligibility criteria may affect generalizability of these findings to clinical practice. Methods We extracted eligibility criteria for trials of aducanumab, lecanemab and donanemab from published reports, and applied these to participants with MCI or early clinical AD dementia from the population-based Rotterdam Study. Participants underwent questionnaires, genotyping, brain MRI, cognitive testing, and cardiovascular assessment. We had continuous linkage with medical records and pharmacy dispensary data. We determined amyloid status using an established and validated prediction model based on age and APOE genotype. We assessed progression to dementia within 5 years among participants with MCI, stratified for eligibility. Results Of 968 participants (mean age: 75 years, 56% women), 779 had MCI and 189 early clinical AD dementia. Across the three drug trials, around 40% of participants would be ineligible because of predicted amyloid negativity. At least one clinical exclusion criterion was present in 76.3% (95% CI; 73.3-79.3) of participants for aducanumab, 75.8% (73.0-78.7) for lecanemab, and 59.8% (56.4-63.3) for donanemab. Criteria that most often led to exclusion were a history of cardiovascular disease (35.2%), use of anticoagulant (31.2%), use of psychotropic or immunological medications (20.4%), history of anxiety or depression (15.9%), or lack of social support (15 …

medRxiv

INTRODUCTION Gene carriers of frontotemporal dementia can remain cognitively well despite neurodegeneration. A better understanding of brain structural, perfusion and functional patterns in pre-symptomatic stage could inform accurate staging and potential mechanisms. METHODS We included 207 pre-symptomatic carriers and 188 relatives without mutations. The grey matter volume, cerebral perfusion, and resting-state functional network maps were co-analyzed using linked independent component analysis (LICA). Multiple regression analysis was used to investigate the relationship of LICA components to genetic status and cognition. RESULTS Pre-symptomatic carriers showed an age-related decrease in the left frontoparietal network integrity while non-carriers did not. Executive functions of pre-symptomatic carriers dissociated from the level of atrophy and cerebrovascular dysfunction, but became dependent on the left frontoparietal network integrity in older age. DISCUSSION The frontoparietal network integrity of pre-symptomatic carriers showed a distinctive relationship to age and cognition compared to non-carriers, despite atrophy and hypoperfusion. Functional network integrity may contribute to brain resilience in pre-symptomatic frontotemporal dementia, mitigating the effects of atrophy and hypoperfusion.

medRxiv

INTRODUCTION Cerebrovascular reactivity (CVR) is an indicator of cerebrovascular health and its signature in hereditary frontotemporal dementia (FTD) remains unknown. We investigated CVR in genetic FTD and its relationship to cognition. METHODS CVR differences were assessed between 284 pre-symptomatic and 124 symptomatic mutation carriers, and 265 non-carriers, using resting-state fluctuation amplitudes (RSFA) on component-based and voxel-level RSFA maps. Associations and interactions between RSFA, age, genetic status, and cognition were examined using generalised linear models. RESULTS Compared to non-carriers, mutation carriers exhibited greater RSFA reductions, predominantly in frontal cortex. These reductions increased with age. The RSFA in these regions correlated with cognitive function in symptomatic and, to a lesser extent, pre-symptomatic individuals, independent of disease stage. DISCUSSION CVR impairment in genetic FTD predominantly affects frontal cortical areas, and its preservation may yield cognitive benefits for at-risk individuals. Cerebrovascular health may be a potential target for biomarker identification and disease-modifying efforts.

medRxiv

Human papillomavirus-associated oropharyngeal squamous cell carcinomas (HPV+OPSCC) release circulating tumor HPV DNA (ctHPVDNA) into the blood which we, and others, have shown is an accurate real-time biomarker of disease status. In a prior prospective observational trial of 34 patients with AJCC 8 stage I-II HPV+OPSCC treated with surgery, we reported that ctHPVDNA was rapidly cleared within hours of surgery in patients who underwent complete cancer extirpation, yet remained elevated in those with macroscopic residual disease. The primary outcomes of this study were to assess 2-year OS and RFS between patients with and without molecular residual disease (MRD) following completion of treatment in this prospective cohort. MRD was defined as persistent elevation of ctHPVDNA at two consecutive time points, without clinical evidence of disease. The secondary outcomes were 2-year OS and RFS between patients with and without detectable MRD after surgery. We observed that patients with MRD after treatment completion were more likely to recur compared to patients without MRD, while there was no difference in recurrence rates between patients with MRD and without MRD on postoperative day 1. OS did not significantly differ between patients with MRD after surgery or treatment completion compared to patients without MRD; however, time to death was significantly different between the groups in both settings, suggesting that with a larger sample size OS would differ significantly between the groups or that the impact of MRD detection on survival is time dependent.

medrxiv

The adaptive immune response is physiologically regulated by the circadian rhythm. Data in lung and melanoma malignancies suggests immunotherapy infusions earlier in the day may be associated with improved response; however, the optimal time of administration for patients with head and neck squamous cell carcinoma (HNSCC) is not known. We aimed to evaluate the association of immunotherapy infusion time with overall survival (OS) and progression free survival (PFS) in patients with HNSCC in an Institutional Review Board-approved, retrospective cohort study. 113 patients met study inclusion criteria and 98 patients were included in a propensity score-matched cohort. In the full unmatched cohort (N = 113), each additional 20 % of infusions received after 1500 h conferred an OS hazard ratio (HR) of 1.35 (95 % C.I.1.2–1.6; p-value = 0.0003) and a PFS HR of 1.34 (95 % C.I.1.2–1.6; p-value < 0.0001). A …

medRxiv

Studies have reported that prior-season influenza vaccination is associated with higher risk of clinical influenza infection among vaccinees. This effect might arise from incomplete consideration of within-season waning and recent infection. Using data from the US Flu Vaccine Effectiveness (VE) Network (2011–2012 to 2018–2019 seasons), we found that repeat vaccinees were vaccinated earlier in a season by one week. After accounting for waning VE, repeat vaccinees were still more likely to test positive for A (H3N2)(OR= 1.11, 95% CI: 1.02–1.21) but not for influenza B or A (H1N1). We found that clinical infection influences individuals’ decision to vaccinate in the following season while protecting against clinical infection of the same (sub) type. However, adjusting for recent clinical infections did not strongly influence the estimated effect of prior-season vaccination. In contrast, we found that adjusting for subclinical …

medRxiv

Collaborative efforts in artificial intelligence (AI) are increasingly common between high-income countries (HICs) and low- to middle-income countries (LMICs). Given the resource limitations often encountered by LMICs, collaboration becomes crucial for pooling resources, expertise, and knowledge. Despite the apparent advantages, ensuring the fairness and equity of these collaborative models is essential, especially considering the distinct differences between LMIC and HIC hospitals. In this study, we show that collaborative AI approaches can lead to divergent performance outcomes across HIC and LMIC settings, particularly in the presence of data imbalances. Through a real-world COVID-19 screening case study, we demonstrate that implementing algorithmic-level bias mitigation methods significantly improves outcome fairness between HIC and LMIC sites while maintaining high diagnostic sensitivity. We compare our results against previous benchmarks, utilizing datasets from four independent United Kingdom Hospitals and one Vietnamese hospital, representing HIC and LMIC settings, respectively.

medRxiv

Retinal fundus imaging is a powerful tool for disease screening and diagnosis in opthalmology. With the advent of machine learning and artificial intelligence, in particular modern computer vision classification algorithms, there is broad scope for technology to improve accuracy, increase accessibility and reduce cost in these processes. In this paper we present the first deep learning model trained on the first Brazilian multi-label opthalmological datatset. We train a multi-label classifier using over 16,000 clinically-labelled fundus images. Across a range of 13 retinal diseases, we obtain frequency-weighted AUC and F1 scores of 0.92 and 0.70 respectively. Our work establishes a baseline model on this new dataset and furthermore demonstrates the applicability and power of artificial intelligence approaches to retinal fundus disease diagnosis in under-represented populations.

medRxiv

The adoption of large language models (LLMs) to assist clinicians has attracted remarkable attention. Existing works mainly adopt the close-ended question-answering task with answer options for evaluation. However, in real clinical settings, many clinical decisions, such as treatment recommendations, involve answering open-ended questions without pre-set options. Meanwhile, existing studies mainly use accuracy to assess model performance. In this paper, we comprehensively benchmark diverse LLMs in healthcare, to clearly understand their strengths and weaknesses. Our benchmark contains seven tasks and thirteen datasets across medical language generation, understanding, and reasoning. We conduct a detailed evaluation of existing sixteen LLMs in healthcare under both zero-shot and few-shot (i.e., 1,3,5-shot) learning settings. We report the results on five metrics (i.e. matching, faithfulness, comprehensiveness, generalizability, and robustness) that are critical in achieving trust from clinical users. We further invite medical experts to conduct human evaluation.