Sex-specific differences in physiological parameters related to SARS-CoV-2 infections among a national cohort (COVI-GAPP study) (preprint)

Considering sex as a biological variable in modern digital health solutions, we investigated sex-specific differences in the trajectory of four physiological parameters across a COVID-19 infection. A wearable medical device measured breathing rate, heart rate, heart rate variability, and wrist skin temperature in 1163 participants (mean age = 44.1 years, standard deviation [SD]=5.6; 667 [57%] females). Participants reported daily symptoms and confounders in a complementary app. A machine learning algorithm retrospectively ingested daily biophysical parameters to detect COVID-19 infections. COVID-19 serology samples were collected from all participants at baseline and follow-up. We analysed potential sex-specific differences in physiology and antibody titres using multilevel modelling and t-tests. Over 1.5 million hours of physiological data were recorded. During the symptomatic period of infection, men demonstrated larger increases in skin temperature, breathing rate and heart rate as well as larger decreases in heart rate variability than women. The COVID-19 infection detection algorithm performed similarly well for men and women. Our study belongs to the first research to provide evidence for differential physiological responses to COVID-19 between females and males, highlighting the potential of wearable technology to inform future precision medicine approaches. This work has received support from the Princely House of the Principality of Liechtenstein, the government of the Principality of Liechtenstein, the Hanela Foundation in Switzerland, and the Innovative Medicines Initiative (IMI) 2 Joint Undertaking under grant agreement No 101005177. This Joint Undertaking receives support from the European Union's Horizon 2020 research and innovation programme and EFPIA.

COVID-19 Case and Mortality Surveillance using Daily SARS-CoV-2 in Wastewater Samples adjusting for Meteorological Conditions and Sample pH (preprint)

BackgroundWastewater monitoring is increasingly used for community surveillance of infectious diseases, especially after the COVID-19 pandemic as the genomic footprints of pathogens shed by infected individuals can be traced in the environment. However, detection and concentration of pathogens in the environmental samples and their efficacy in predicting infectious diseases can be influenced by meteorological conditions and quality of samples. ObjectivesThis research examines whether meteorological conditions and sample pH affect SARS-CoV-2 concentrations in wastewater samples, and whether the association of SARS-CoV-2 with COVID-19 cases and mortality improves when adjusted for meteorological conditions and sample pH value in Miami-Dade County, FL. MethodsDaily wastewater samples were collected from Miami-Dade Wastewater Treatment Plant in Key Biscayne, Florida from August 2021 to August 2022. The samples were analyzed for pH and spiked with OC43. RNA was extracted from the concentrated wastewater sample and SARS-CoV-2 was quantified using qPCR. COVID-19 and mortality data were acquired from the Centers for Disease Control and Prevention (CDC) and meteorological data from the National Climatic Data Center. COVID-19 case and mortality rates were modelled with respect to time-lagged wastewater SARS-CoV-2 adjusting for meteorological conditions, and sample pH value and OC43 recovery. ResultsTemperature, dew point, pH values and OC43 recovery showed significant associations with wastewater SARS-CoV-2. Time-lagged wastewater SARS-CoV-2 showed significant associations with COVID-19 case and mortality incidence rates. This association improved when wastewater SARS-CoV-2 levels were adjusted for (or instrumented on) meteorological conditions, OC43 recovery, and sample pH. A 0.47% change in COVID-19 case incidence rate was associated with 1% change in wastewater SARS-CoV-2 ({beta} [~] 0.47; 95% CI = 0.29 - 0.64; p < 0.001). A 0.12 % change in COVID-19 mortality rate was associated with 1 % change in SARS-CoV-2 in wastewater 44 days prior. A 0.07% decline in COVID-19 mortality rate was associated with a unit increase in ambient temperature 28 days prior. DiscussionTime lagged wastewater SARS-CoV-2 (and its adjustment for sample pH and RNA recovery) and meteorological conditions can be used for the surveillance of COVID-19 case and mortality. These findings can be extrapolated to improve the surveillance of other infectious diseases by proactive measurements of infectious agent(s) in the wastewater samples, adjusting for meteorological conditions and sample pH value.

Lessening the Impact of Opioid Misuse at a Federally Qualified Health Center in New York: Outcomes of an Integrated Workforce Training Program.

The COVID-19 pandemic has placed an unprecedented burden on patients, health care providers, and communities and has been particularly challenging for medically underserved populations impacted by the social determinants of health, as well as people with co-occurring mental health and substance use risks. This case study examines outcomes and lessons learned from a multisite low-threshold medication-assisted treatment (MAT) program at a federally qualified health center in partnership with a large suburban public university in New York to integrate and train Health Resources & Services Administration Behavioral Health Workforce Education and Training-funded graduate student trainees in social work and nursing in screening, brief intervention, and referral to treatment and patient care coordination, including social determinants of health and medical and behavioral comorbidities. The MAT program for the treatment of opioid use disorder has a low threshold for entry that is accessible and affordable, reduces barriers to care, and uses a harm reduction approach. Outcome data showed an average 70% retention rate in the MAT program and reductions in substance use. And, while more than 73% of patients reported being somewhat or definitely impacted by the pandemic, most patients endorsed the effectiveness of telemedicine and telebehavioral health, such that 86% indicated the pandemic did not affect the quality of their health care. The main implementation lessons learned were the importance of increasing the capacity of primary care and health care centers to deliver integrated care, using cross-disciplinary practicum experiences to enhance trainee competencies, and addressing the social determinants of health among populations with social vulnerabilities and chronic medical conditions.

Herd immunity, vaccination and moral obligation.

The public health benefits of herd immunity are often used as the justification for coercive vaccine policies. Yet, 'herd immunity' as a term has multiple referents, which can result in ambiguity, including regarding its role in ethical arguments. The term 'herd immunity' can refer to (1) the herd immunity threshold, at which models predict the decline of an epidemic; (2) the percentage of a population with immunity, whether it exceeds a given threshold or not; and/or (3) the indirect benefit afforded by collective immunity to those who are less immune. Moreover, the accumulation of immune individuals in a population can lead to two different outcomes: elimination (for measles, smallpox, etc) or endemic equilibrium (for COVID-19, influenza, etc). We argue that the strength of a moral obligation for individuals to contribute to herd immunity through vaccination, and by extension the acceptability of coercion, will depend on how 'herd immunity' is interpreted as well as facts about a given disease or vaccine. Among other things, not all uses of 'herd immunity' are equally valid for all pathogens. The optimal conditions for herd immunity threshold effects, as illustrated by measles, notably do not apply to the many pathogens for which reinfections are ubiquitous (due to waning immunity and/or antigenic variation). For such pathogens, including SARS-CoV-2, mass vaccination can only be expected to delay rather than prevent new infections, in which case the obligation to contribute to herd immunity is much weaker, and coercive policies less justifiable.

Outcomes 1 year after non-operative management of uncomplicated appendicitis in children: Children with AppendicitiS during the CoronAvirus panDEmic (CASCADE) study.

BACKGROUND: A major shift in treatment of appendicitis occurred early in the SARS-CoV-2 pandemic with non-operative management used commonly outside research protocols and in units with limited previous experience. This study aims to compare real-world outcomes of surgery versus non-operative management of uncomplicated appendicitis in children with 1-year follow-up. METHOD: A prospective multicentre observational study of children treated for uncomplicated appendicitis at 74 hospitals in the UK and Ireland from 1 April to 31 July 2020 was performed. Propensity-score matched analysis was conducted using age, sex, C-reactive protein at diagnosis and duration of symptoms as covariates. Primary outcomes were success of non-operative management defined as achieving 1-year follow-up without undergoing appendicectomy due to recurrent appendicitis or ongoing symptoms, and occurrence of any predefined complication (intra-abdominal collection, wound infection, bowel obstruction or reintervention). RESULTS: Of 1464 children with presumed uncomplicated appendicitis, 1027 (70.2 per cent) underwent surgery and 437 (29.9 per cent) underwent non-operative management. Ninety-four children (21.5 per cent) treated by initial non-operative management required appendicectomy during the index hospital admission while recurrent appendicitis after discharge occurred in 25 (10.4 per cent) children within 1 year. The overall success rate of non-operative management at 1 year was 63.1 per cent (95 per cent c.i. 58.0 to 68.3 per cent). For propensity-score matched analyses, 688 children undergoing surgery and 307 undergoing non-operative management were included. Any predefined complication occurred in 50 (7.3 per cent) children undergoing surgery and in four (1.3 per cent) children undergoing non-operative management (OR 5.9 (95 per cent c.i. 2.1 to 16.6)) in the propensity-score matched cohort. There was no mortality or stoma formation. CONCLUSION: Non-operative management is a safe and valid alternative to appendicectomy in children with uncomplicated appendicitis.

Mitigation of influenza-mediated inflammation by immunomodulatory matrix-bound nanovesicles.

Cytokine storm describes a life-threatening, systemic inflammatory syndrome characterized by elevated levels of proinflammatory cytokines and immune cell hyperactivation associated with multi-organ dysfunction. Matrix-bound nanovesicles (MBV) are a subclass of extracellular vesicle shown to down-regulate proinflammatory immune responses. The objective of this study was to assess the efficacy of MBV in mediating influenza-induced acute respiratory distress syndrome and cytokine storm in a murine model. Intravenous administration of MBV decreased influenza-mediated total lung inflammatory cell density, proinflammatory macrophage frequencies, and proinflammatory cytokines at 7 and 21 days following viral inoculation. MBV decreased long-lasting alveolitis and the proportion of lung undergoing inflammatory tissue repair at day 21. MBV increased the proportion of activated anti-viral CD4+ and CD8+ T cells at day 7 and memory-like CD62L+ CD44+, CD4+, and CD8+ T cells at day 21. These results show immunomodulatory properties of MBV that may benefit the treatment of viral-mediated pulmonary inflammation with applicability to other viral diseases such as SARS-CoV-2.

Monkeypox viral nucleic acids detected using both DNA and RNA extraction workflows.

Molecular methods have been used to detect human pathogens in wastewater with sampling typically performed at wastewater treatment plants (WWTP) and upstream locations within the sewer system. A wastewater-based surveillance (WBS) program was established at the University of Miami (UM) in 2020, which included measurements of SARS-CoV-2 levels in wastewater from its hospital and within the regional WWTP. In addition to the development of a SARS-CoV-2 quantitative PCR (qPCR) assay, qPCR assays to detect other human pathogens of interest were also developed at UM. Here we report on the use of a modified set of reagents published by the CDC to detect nucleic acids of Monkeypox virus (MPXV) which emerged during May of 2022 to become a concern worldwide. Samples collected from the University hospital and from the regional WWTP were processed through DNA and RNA workflows and analyzed by qPCR to detect a segment of the MPXV CrmB gene. Results show positive detections of MPXV nucleic acids in the hospital and wastewater treatment plant wastewater which coincided with clinical cases in the community and mirrored the overall trend of nationwide MPXV cases reported to the CDC. We recommend the expansion of current WBS programs' methods to detect a broader range of pathogens of concern in wastewater and present evidence that viral RNA in human cells infected by a DNA virus can be detected in wastewater.

Modified Banff Criteria in Assessing SARS-CoV-2-Associated Renal Pathology: An Autopsy Study.

Introduction SARS-CoV-2 is an epitheliotropic viral agent with epithelial tropism. Although the clinical significance and severity of affection is the most pronounced in the respiratory system, other organs and systems are also infected and, hence affected, such as the central nervous system, gastrointestinal tract, cardiovascular, and urinary systems. Herein, we set out to evaluate the presence and degree of morphological changes within the renal parenchyma and its relation to disease outcome. Materials and methods A retrospective non-clinical approach was utilized for the means of the study. All patients with real-time reverse transcriptase-polymerase chain reaction proven infection, subject to an autopsy performed in a period of two calendar years, were included in the study. Kidney tissue histopathology samples were analyzed using a modified Banff criteria system for acute onset and chronic changes. The results were compared for statistical significance with overall patient survival from symptom onset to death. Furthermore, SARS-CoV-2 viral presence was evaluated in renal structures by means of immunohistochemistry. Results A total of 40 patients were included in the study. Immunohistochemistry showed viral presence within a myriad of renal structured - endothelial cells, tubular cells, and podocytes. Modified Banff criteria showed significant acute changes within the parenchyma, including endotheliitis, glomerulitis, mesangial matrix expansion, tubulitis, capillaritis, arteritis, thrombosis (including thrombotic microangiopathy in four patients), and hemorrhages. Individual cases also presented with signs of rhabdomyolysis - myoglobulin casts. Signs of chronic injury were also present in most patients. However, when calculated as scores, neither acute nor chronic changes showed a correlation with time from symptom onset to death. Conclusion The results of the present study show both viral presence and a myriad of induced changes in the contents of SARS-CoV-2 infection within the renal parenchyma. The lack of correlation with the degree of changes, when compared to survival, is an encouraging fact that the changes are unlikely to play a role in direct tanatogenesis while having the potential to manifest as chronic kidney disease in the future.

Proximity-Induced Nucleic Acid Degrader (PINAD) Approach to Targeted RNA Degradation Using Small Molecules.

Nature has evolved intricate machinery to target and degrade RNA, and some of these molecular mechanisms can be adapted for therapeutic use. Small interfering RNAs and RNase H-inducing oligonucleotides have yielded therapeutic agents against diseases that cannot be tackled using protein-centered approaches. Because these therapeutic agents are nucleic acid-based, they have several inherent drawbacks which include poor cellular uptake and stability. Here we report a new approach to target and degrade RNA using small molecules, proximity-induced nucleic acid degrader (PINAD). We have utilized this strategy to design two families of RNA degraders which target two different RNA structures within the genome of SARS-CoV-2: G-quadruplexes and the betacoronaviral pseudoknot. We demonstrate that these novel molecules degrade their targets using in vitro, in cellulo, and in vivo SARS-CoV-2 infection models. Our strategy allows any RNA binding small molecule to be converted into a degrader, empowering RNA binders that are not potent enough to exert a phenotypic effect on their own. PINAD raises the possibility of targeting and destroying any disease-related RNA species, which can greatly expand the space of druggable targets and diseases.

Air filtration mitigates aerosol levels both during and after endoscopy procedures.

Objectives: Upper gastrointestinal endoscopies are aerosol-generating procedures, increasing the risk of spreading airborne pathogens. We aim to quantify the mitigation of airborne particles via improved ventilation, specifically laminar flow theatres and portable high-efficiency particulate air (HEPA) filters, during and after upper gastrointestinal endoscopies. Methods: This observational study included patients undergoing routine upper gastrointestinal endoscopy in a standard endoscopy room with 15-17 air changes per hour, a standard endoscopy room with a portable HEPA filtration unit, and a laminar flow theatre with 300 air changes per hour. A particle counter (diameter range 0.3 µm-25 µm) took measurements 10 cm from the mouth. Three analyses were performed: whole procedure particle counts, event-based counts, and air clearance estimation using post-procedure counts. Results: Compared to a standard endoscopy room, for whole procedures we observe a 28.5x reduction in particle counts in laminar flow (p < 0.001) but no significant effect of HEPA filtration (p = 0.50). For event analysis, we observe for lateral flow theatres reduction in particles >5 µm for oral extubation (12.2x, p < 0.01), reduction in particles <5 µm for coughing/gagging (6.9x, p < 0.05), and reduction for all sizes in anesthetic throat spray (8.4x, p < 0.01) but no significant effect of HEPA filtration. However, we find that in the fallow period between procedures HEPA filtration reduces particle clearance times by 40%. Conclusions: Laminar flow theatres are highly effective at dispersing aerosols immediately after production and should be considered for high-risk cases where patients are actively infectious or the supply of personal protective equipment is limited. Portable HEPA filers can safely reduce the fallow time between procedures by 40%.

Employer-sponsored behavioral health program impacts on care utilization and cost.

OBJECTIVES: To examine the impact of an employer-sponsored behavioral health (BH) program on all-cause health care utilization and cost. STUDY DESIGN: Retrospective analysis of health insurance claims data obtained from a large employer in western New York covering a 25-month period between 2016 and 2018. Those employees treated by the employer-sponsored BH program were compared against a contemporaneous comparison group of employees of the same employer who had eligible BH diagnoses for the program but were treated elsewhere. METHODS: A difference-in-differences method was used to estimate the program's impact on all-cause care utilization (physician office visits and acute care utilization) and total cost of care, including prescription drug costs. RESULTS: Program participation was associated with a reduction of approximately 28% in total cost of care including prescription drug costs (P = .043) over an 18-month period following the initial program encounter, as well as 27% reductions in primary care provider (PCP) visits (P = .001) and non-BH specialist visits (P = .005). No significant impacts were observed for acute care utilization and BH specialist visit rates. CONCLUSIONS: The results suggest that the employer-sponsored BH program implementation may have shifted treatments of certain BH conditions away from PCPs and non-BH specialists who may not have the proper training or resources to manage such conditions. Therefore, these results are consistent with the expectation that improved access to BH care is likely to improve efficiency in the health care system via provision of more appropriate care for those who need it.

Teleconsultations in paediatric dermatology: a UK-wide clinician survey

The COVID-19 pandemic catapulted dermatology services into a digital era, with the rapid introduction of teleconsultations. Potential benefits include widening access to healthcare and environmental sustainability. Barriers to successful teleconsultations include reduced diagnostic accuracy and technical issues. National Health Service operational planning guidance recommends that >= 25% of consultations are delivered remotely (https://www.england.nhs.uk/wp-content/uploads/ 2021/03/B0468-implementation-guidance-21-22-prioritiesand- operational-planning-guidance.pdf). Yet there is a lack of data regarding the acceptability and effectiveness of paediatric dermatology teleconsultations. We conducted a survey to explore clinicians' experience of teleconsultations in paediatric dermatology, focusing on paediatric eczema, to inform a future clinical trial. The survey was created using an online platform (Microsoft Forms) and piloted by paediatric dermatologists. It was circulated via email to members of the British Society for Paediatric Dermatology, the British Association of Dermatologists and the UK Dermatology Clinical Trials Network (DCTN). It remained open for 7 weeks from July to September 2021. Descriptive analysis was undertaken using Microsoft Excel. There were 120 responses, the majority from consultant dermatologists (59%). Prior to COVID-19, the most commonly provided teleconsultation service was advice and guidance (A+G) to general practitioners (GPs;55% responses). The majority of responders (63%) conducted no teleconsultations. Teleconsultations accounted for < 25% of all consultations in 98% responses. Since the pandemic there has been a marked shift in practice. Forty-nine per cent of responders now conduct > 25% of consultations as teleconsultations. Only 8% provide no teleconsultations. Teleconsultations are now being offered for new consultations [n = 62 (80%)], followup consultations [n = 101 (84%)] and A+G for GPs [n = 96 (80%)]. The most common format is telephone consultations with photographs (72%). For follow-up of paediatric eczema, the most effective format was felt to be telephone consultations with photographs [n = 52 (43%)], followed by video consultations with photographs [n = 32 (27%)]. Over half of responders (54%) felt that teleconsultations were less effective than face-to-face appointments for follow-up of paediatric eczema. Seventeen (21%) responders felt they could accurately assess eczema severity using a video vs. 27 (34%) using photographs. Reported barriers to teleconsultations included poorquality images, technical problems, reduced diagnostic accuracy and impaired communication. Importantly, the issue of safeguarding children was a concern. The majority of clinicians felt that teleconsultations were beneficial for reducing footfall in hospitals and minimizing time missed from school. Our results demonstrate variation in clinician opinion on the effectiveness of teleconsultations and the optimal format for paediatric eczema follow-up appointments. As part of a UK DCTN-themed research call award, we plan to conduct a patient survey, qualitative patient interviews and a health economics analysis of teleconsultations for paediatric eczema. This feasibility work will help to inform a future clinical trial.

Deep Learning Assessment for Mining Important Medical Image Features of Various Modalities.

Deep learning (DL) is a well-established pipeline for feature extraction in medical and nonmedical imaging tasks, such as object detection, segmentation, and classification. However, DL faces the issue of explainability, which prohibits reliable utilisation in everyday clinical practice. This study evaluates DL methods for their efficiency in revealing and suggesting potential image biomarkers. Eleven biomedical image datasets of various modalities are utilised, including SPECT, CT, photographs, microscopy, and X-ray. Seven state-of-the-art CNNs are employed and tuned to perform image classification in tasks. The main conclusion of the research is that DL reveals potential biomarkers in several cases, especially when the models are trained from scratch in domains where low-level features such as shapes and edges are not enough to make decisions. Furthermore, in some cases, device acquisition variations slightly affect the performance of DL models.

A series of diabetic ketoacidosis associated with the use of sodium-glucose co-transporter-2 inhibitors in secondary care

Background and aims: Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) are associated with diabetic ketoacidosis (DKA), though limited real-world case series are published. The aim of this study is to examine the number and characteristics of patients admitted with SGLT2i-associated DKA to our hospital over a 4-month period. Method(s): Patients were identified retrospectively following referral to the diabetes team with SGLT2i-associated DKA between September-December 2021. Medical notes were reviewed and data related to the patients' characteristics, diabetes control, usual medications and previous medical comorbidities were collected. Result(s): Twenty-two patients with SGLT2i-associated DKA were iden tified;21 (95.5%) were hyperglycaemic and 1 (4.5%) was euglycaemic. Patients had a mean age (+/-standard deviation) 60.8+/-12.3 years and HbA1c 89.2+/-29.2 mmol/mol (10.3%). Of these patients 45.5% were diagnosed with DKA alone, though some had concurrent bacterial (27.3%) or COVID-19 (18.2%) infection. There was significant treatment heterogeneity;nine (40.9%) patients were treated with insulin and 13 (59.1%) patients with other agents. Thirteen (59.1%) patients had no significant medical co-morbidity, though nine (40.9%) patients had underlying cardiovascular, respiratory and/or malignant co-morbidity. Of the 22 patients admitted with DKA, 19 (86.4%) were discharged alive, and three patients (13.6%) died during the admission. Conclusion(s): We observed no specific characteristics which predisposed to SGLT2i-associated DKA or more severe ketoacidosis in this cohort, consistent with previous studies. Most cases were in hyperglycaemic DKA, and people with SGLT2i-associated euglycaemic DKA may have been missed. Given the number of cases observed in our hospital and the associated mortality, greater awareness of the condition is essential.

A Systematic Review of Chest Imaging Findings in Long COVID Patients.

Long COVID is the persistence of one or more COVID-19 symptoms after the initial viral infection, and there is evidence supporting its association with lung damage. In this systematic review, we provide an overview of lung imaging and its findings in long COVID patients. A PubMed search was performed on 29 September 2021, for English language studies in which lung imaging was performed in adults suffering from long COVID. Two independent researchers extracted the data. Our search identified 3130 articles, of which 31, representing the imaging findings of 342 long COVID patients, were retained. The most common imaging modality used was computed tomography (CT) (N = 249). A total of 29 different imaging findings were reported, which were broadly categorized into interstitial (fibrotic), pleural, airway, and other parenchymal abnormalities. A direct comparison between cases, in terms of residual lesions, was available for 148 patients, of whom 66 (44.6%) had normal CT findings. Although respiratory symptoms belong to the most common symptoms in long COVID patients, this is not necessarily linked to radiologically detectable lung damage. Therefore, more research is needed on the role of the various types of lung (and other organ) damage which may or may not occur in long COVID.