Cold Atmospheric Helium Plasma In The Post-Covid Era: A Promising Tool For The Disinfection Of Silicone Endotracheal Prostheses (preprint)

The COVID-19 pandemic resulted in a high prevalence of laryngotracheal stenosis. The endoluminal tracheal prostheses used to treat this condition are made of medical-grade silicone (MGS). Despite their excellent properties, the main limitation of these prostheses is the formation of a polymicrobial biofilm on their surfaces that interacts with the underlying mucosa, causing local inflammation and interfering with the local healing process, ultimately leading to further complications in the clinical scenario. Cold atmospheric plasma (CAP) shows antibiofilm properties on several microbial species. The present study evaluated the inhibitory effect of CAP on multispecies biofilms grown on MGS surfaces. In addition to the MGS characterization before and after CAP exposure, the cytotoxicity of CAP on immortalized human bronchial epithelium cell line (BEAS-2B) was evaluated. The aging time test reported that CAP could temporarily change the MGS surface wetting characteristics from hydrophilic (80.5 degrees) to highly hydrophilic (< 5 degrees). ATR-FTIR shows no significant alterations in the surficial chemical composition of MGS before and after CAP exposure for 5 min. A significant log reduction of viable cells in mono-species biofilms (log CFU/mL) of C. albicans, S. aureus, and P. aeruginosa (0.636, 0.738, and 1.445, respectively) were detected after CAP exposure. Multi-species biofilms exposed to CAP showed significant viability reduction for C. albicans and S. aureus (1.385 and 0.831, respectively). The protocol was not cytotoxic to BEAS-2B. It could be concluded that CAP can be a simple and effective method to delay the multi-species biofilm formation inside the endotracheal prosthesis.

Epidemiological Changes in Orofacial Trauma between the Pre-Covid and COVID Periods: A Spanish Multicentre Comparative Study of Tertiary Referral Hospitals (preprint)

The Covid-19 pandemic has produced a change in the way of living, socializing and a modification in Health Systems around the world. A multicentre retrospective study was carried out to study orofacial trauma in one of the regions most affected during the first wave of the pandemic, with the participation of the five main tertiary hospitals in Madrid. The aim of this study is to evaluate the epidemiology of orofacial surgical trauma during the 1 year of COVID pandemic and compared to de prior year. Age, sex, mechanism, localization, and treatment were studied. P-value <0.05 was considered statically significative. Reduction of 39.36% (<0.001) in maxillofacial fractures was observed, without significance change in sex, localization or treatment. Significant increase in age (35,92 vs. 40,26) (p = 0.006) was observed. Significant decline in mechanism was noted (p = 0.025), decreasing personal violence (41% vs 35%) and sports (14% vs 8%); increasing in falls (27% vs 35%), precipitation (2 vs 5%), and traffic accidents (12% vs 13%). The mandible was the most frequent fractured bone. The COVID pandemic has produced epidemiological variations in orofacial trauma, making it necessary to monitor social and legal changes that may require reorganization to adjust to population needs.

Incidence and characteristics of post-COVID-19 parkinsonism and dyskinesia related to COVID-19 vaccines.

BACKGROUND: Coronavirus disease 2019 (COVID-19) is an infectious disease mainly affecting the respiratory system; however, a significant prevalence of neurological symptoms has been noted. OBJECTIVES: To investigate the incidence and characteristics of post-COVID-19 parkinsonism and to study dyskinesia related to COVID-19 vaccines. MATERIAL AND METHODS: The MEDLINE, PubMed, Scopus, and Web of Science databases were searched for all manuscripts relevant to post-COVID-19 parkinsonism and dyskinesia related to COVID-19 vaccines. Subsequently, we extracted and analysed data from the manuscripts in a structured manner. RESULTS: We found 24 patients with post-COVID-19 parkinsonism, with a mean onset age of 58 years after a mean of 30 days from the COVID-19 onset. Akinetic-rigid (n = 11) and mixed (n = 6) subtypes were the most common. Asymmetry was present in 13/15 patients. Brain MRI was unremarkable in 11/19, whereas dopaminergic system imaging was abnormal in 8/8 patients. Responsiveness to dopaminergic treatment was observed in 12/15 patients. Four patients improved after immunomodulatory therapy. Comorbidities were present in 9/24, encephalopathy symptoms in 11/24, and loss of smell in 9/13 patients. Most patients (n = 14) suffered serious COVID-19- related complications and three were treated with haloperidol. Parkinsonism improved (n = 5) or resolved (n = 4) during the follow-up. Five patients, with a mean age of 52, developed dyskinesia at a mean of 25 hours after receiving the COVID-19 mRNA vaccines. One patient had a history of neuropsychiatric symptoms and developed functional dyskinesia of the tongue. Four patients had a previous history of Parkinson's Disease (PD) with a mean duration of 10 years and developed dyskinesia and dystonia, which resolved (n = 2) or improved (n = 2) during the follow-up. CONCLUSIONS: Post-COVID-19 parkinsonism is a very rare complication, and it is likely that this is an umbrella syndrome that includes many different etiologies. Dyskinesia due to COVID-19 vaccines is exceedingly rare and probably has the same pathophysiological basis as in other conditions with exacerbation of PD symptoms.

Safety, Tolerability, and Immunogenicity of PIKA-Adjuvanted Re-combinant SARS-CoV-2 Spike (S) Protein Subunit Vaccine in Healthy Adults: Interim results of an open-label and randomised Phase 1 clinical trial. (preprint)

Background: This COVID-19 pandemic has caused unprecedented morbidity, mortality, and global economic instability. Several approved vaccines demonstrated to be effective prevention against COVID-19. We aimed to evaluate the safety and immunogenicity of the PIKA-adjuvanted recombinant SARS-C0V-2 Spike (S) protein subunit vaccine in adults as a primary immunization and as a booster dose against SARS-C0V-2 infection. Methods: This was a Phase I, open label, dose-escalation study of 3 dose levels of the SARS-CoV-2 spike antigen administered intramuscularly in combination with a fixed dosage of PIKA adjuvant vaccine to evaluate the safety, tolerability, and immunogenicity of PIKA COVID-19 vaccine candidate in healthy adults. The study planned to have 3 arms: Arm A included subjects who had never received any Covid 19 vaccination or have had Covid 19 infection for > 6 months prior to enrolment, Arm B1 included subjects who had completed their primary series of Covid 19 vaccination with an inactivated Covid 19 vaccine and Arm B2 which included subjects whose primary series was completed with mRNA Covid 19 vaccine. The primary safety outcome was adverse events and safety laboratory parameters, and the secondary immunogenicity outcome was neutralizing antibody geometric mean titers and seroconversion rates against the wild type virus, Delta and Omicron variants. Findings: This interim analysis report presented the results of Arm A and Arm B1 who completed Day 35 for 2 doses in Arm A and Day 28 for a single booster dose in Arm B1. Safety results: Arm A: 60% of participants reported mainly solicited AEs after first and second vaccine. Most of those were local (mainly pain/tenderness) with few systemic (mainly fever and headaches). The majority of participants reported unsolicited events after vaccine which were mainly investigations in hematology/hepatobiliary/ Renal or Urine tract infection urine analysis. At least 80% of the participants reported mild AEs. There were 4 SAEs that were mild and were resolved. Also there were 2 medically attended AEs. Arm B1: Less than 50% of the participants reported solicited adverse events which were mainly local (pain and tenderness) and were mild. Also, less than half of the participants reported unsolicited events which were mainly investigations in hematology/hepatobiliary/ Renal or Urine tract infection urine analysis. There were no SAE and Medically attended AEs reported. Immunogenicity results: Arm A: The neutralizing antibody GMTs at day 35 were substantially higher than those at baseline for all dose groups and all variants. Seroconversion rates at 35 days ranged between 85.7% and 92.9% for 5microgram dose group, 92.9% and 100% for the 10microgram dose group and between 70% and 80% for the high dose group. Arm B1: Similar to Arm A, neutralizing antibody GMTs at day 28 were substantially higher than those at baseline for all dose groups and all variants. Seroconversion rates at 28 days ranged between 92.9% and 100% for 5microgram dose group, 80% and 100% for the 10microgram dose group and between 50% and 64.3% for the high dose group. Conclusion: The findings demonstrated that the PIKA Covid 19 vaccine is safe, well tolerated, immunogenic and can be used as a primary vaccination or as a booster dose in participants who had completed an inactivated Covid 19 vaccination series. A comparison of the immune responses presented in this interim analysis showed that geometric mean titer (GMTs) of neutralizing antibody against wild type of SARS-CoV-2 virus, Delta and Omicron of the 5microgram group was higher than the 10 microgram and 20 microgram, therefore the 5microgram was selected as the recommended dose for the Phase II and III clinical development of the PIKA Covid 19 vaccine.

Otologic disease among patients with primary ciliary dyskinesia - an international observational study (preprint)

ABSTRACT Importance Otologic disease is common among people with primary ciliary dyskinesia, yet little is known about its spectrum and severity. Objective We characterized otologic disease among participants with primary ciliary dyskinesia using data from the Ear-Nose-Throat Prospective International Cohort of PCD patients (EPIC-PCD). Design Cross-sectional analysis of baseline cohort data. Setting Twelve specialized primary ciliary dyskinesia centers in 10 countries. Participants We prospectively included children and adults with primary ciliary dyskinesia diagnoses, routine ENT examinations, and completed symptom questionnaires at the same visit or within 2 weeks. Exposures Potential risk factors associated with increased risk of ear disease. Main outcomes and measures We describe the prevalence and characteristics of patient-reported otologic symptoms and findings from otologic examinations; we identify potential factors associated with increased risk of ear inflammation and hearing impairment. Results We included 397 (211 males) participants with median age 15 (range 0–73). A total of 204 (51%) reported ear pain, 110 (28%) ear discharge, and 183 (46%) hearing problems. Adults reported ear pain and hearing problems more frequently when compared with children. Otitis media with effusion—usually bilateral—from otoscopy was most common among 121 (32%) of 384 participants. Retracted tympanic membrane and tympanic sclerosis were more commonly seen among adults. Tympanometry was performed on 216 participants and showed pathologic type B results for 114 (53%). Audiometry was performed on 273 participants and showed hearing impairment in at least 1 ear, most commonly mild. Season of visit was the strongest risk factor for problems related to ear inflammation (autumn compared with spring odds ratio, 95% confidence interval: 2.4, 1.5–3.8) and age 30 and older of hearing impairment (age 41–50 compared with age 10 years and younger odds ratio, 95% confidence interval: 3.3, 1.1–9.9). Conclusion and relevance Many people with primary ciliary dyskinesia suffer from ear problems yet frequency varies, highlighting disease expression differences and possible clinical phenotypes. Understanding differences in otologic disease expression and progression during lifetime may inform clinical decisions about follow-up and medical care. We recommend multidisciplinary primary ciliary dyskinesia management includes regular otologic assessments for all ages even without specific complaints. Key Points Question What are the characteristics of otologic disease among patients with primary ciliary dyskinesia (PCD)? Findings Baseline data from a large multicenter cohort of patients with PCD showed frequent reports of ear pain and reduced hearing with age as the main factor associated with hearing impairment. Otitis media with effusion was the most common otoscopic finding; adults often presented with tympanic sclerosis following history of previous ear infections. Meaning Since otologic disease is an important yet underreported part of PCD’s clinical expression, we recommend otologic assessments for all age groups as part of regular clinical follow-up.

Monitoring machine learning (ML)-based risk prediction algorithms in the presence of confounding medical interventions (preprint)

Performance monitoring of machine learning (ML)-based risk prediction models in healthcare is complicated by the issue of confounding medical interventions (CMI): when an algorithm predicts a patient to be at high risk for an adverse event, clinicians are more likely to administer prophylactic treatment and alter the very target that the algorithm aims to predict. A simple approach is to ignore CMI and monitor only the untreated patients, whose outcomes remain unaltered. In general, ignoring CMI may inflate Type I error because (i) untreated patients disproportionally represent those with low predicted risk and (ii) evolution in both the model and clinician trust in the model can induce complex dependencies that violate standard assumptions. Nevertheless, we show that valid inference is still possible if one monitors conditional performance and if either conditional exchangeability or time-constant selection bias hold. Specifically, we develop a new score-based cumulative sum (CUSUM) monitoring procedure with dynamic control limits. Through simulations, we demonstrate the benefits of combining model updating with monitoring and investigate how over-trust in a prediction model may delay detection of performance deterioration. Finally, we illustrate how these monitoring methods can be used to detect calibration decay of an ML-based risk calculator for postoperative nausea and vomiting during the COVID-19 pandemic.

Incidence and severity of SARS-CoV-2 infections in people with primary ciliary dyskinesia (preprint)

ImportanceEarly in the COVID-19 pandemic, chronic respiratory disease was considered a risk factor for severe COVID-19 disease. Studies have confirmed a higher risk of intensive care unit admission and mortality in people with chronic pulmonary obstructive disease and cystic fibrosis, but there is little data in people with primary ciliary dyskinesia (PCD). ObjectiveTo study incidence of SARS-CoV-2 and its risk factors in people with PCD from May 2020 to May 2022. We also describe the severity of COVID-19 symptoms in this population and factors associated with severity. Design, setting, and participantsWe used data from COVID-PCD, an international participatory cohort study following people with PCD through the COVID-19 pandemic. The study is based on self-reported weekly online questionnaires, available in five languages, adapted to children, adolescents, and adults. COVID-PCD invites people with PCD of any age to participate. ExposuresSARS-CoV-2 Main OutcomesIncidence of reported positive test of SARS-CoV-2 and reported severity of symptoms. ResultsBy May 2022, 728 people with PCD participated (40% male, median age 27 years; range 0-85). The median weeks of follow-up was 60 (range 1-100). Eighty-seven (12%) reported a SARS-CoV-2 infection at baseline or during follow-up and 62 people reported an incident SARS-CoV-2 infection during 716 person-years of follow-up (incidence rate 9 per 100 person years; 95%CI 7-11). Using Poisson regression, we found that age above 14 years was associated with lower risk of infection (IRR 0.42, 95%CI 0.21-0.85) but the strongest predictors were exposure to Delta (IRR 4.52, 95%CI 1.92-10.6) and Omicron variants (IRR 13.3, 95%CI 5.2-33.8) compared to the original strain. Severity of disease was mainly mild; 12 (14%) were asymptomatic and 75 (86%) had symptoms among whom 4 were hospitalized. None needed intensive care and nobody died. Using Poisson regression, we found that comorbidity (IRR 1.93, 95%CI 1.40-2.64) and being infected during the period when the Delta variant was predominant (IRR 1.43, 95%CI 1.07-1.92) were associated with more reported symptoms. Conclusion and RelevancePeople with PCD do not seem to have a higher incidence of SARS-CoV-2 infections nor higher risk of severe COVID-19 disease than people from the general population. Key PointsO_ST_ABSQuestionC_ST_ABSWhat is the incidence and severity of COVID-19 in people with primary ciliary dyskinesia and which factors are associated with reporting a SARS-CoV-2 infection and risk of severe disease? FindingsThis international cohort of 728 people with primary ciliary dyskinesia followed for two years during the COVID-19 pandemic found a low incidence of reported SARS-CoV-2 in people with primary ciliary dyskinesia and mainly mild disease. The strongest predictor of incidence and severity was virus variant. MeaningPeople with PCD do not seem to have a higher incidence of SARS-CoV-2 infections nor higher risk of severe COVID-19 disease than people from the general population.

A Qualitative Exploration of Medical Student Empathy During the COVID-19 Pandemic (preprint)

Background: There is evidence that medical student self-reported empathy may decline as one progresses through their clinical training. Due to the unprecedented changes to both patient care and medical education caused by COVID-19, it is reasonable to assume that medical student empathy may be impacted. The goal of this July 2020 study was to qualitatively explore how the COVID-19 pandemic might affect medical students’ reported experience of empathy. Method: Using a semi-structured interview, the authors interviewed 12 medical students, 6 second-year and 6 fourth-year. They selected these groups because of the distinct differences in their clinical experience. Results: Data analysis identified 5 major themes: 1) Expanded Perspective (e.g., a feeling of “we’re in this together”, increased awareness of patient vulnerability) 2) Moral Dilemmas (e.g., difficult decisions faced by students as a result of the pandemic such as weighing educational vs. family responsibilities, students risking their own health to provide the best possible care) 3) Confirmation of Values (e.g., Feeling reaffirmed in decision to enter medicine, feeling the pandemic was “what we signed up for” by entering medical school) 4) Shaping Priorities (e.g., changes in medical specialty or populations of interest) 5) Barriers to Empathy and Adaptive Strategies (e.g., COVID-19 created many physical, psychological, and social barriers to empathy for students, students presented many strategies for ameliorating these barriers). Five students (42%) reported increased empathy with no students reporting a decrease in empathy due to experiences during the pandemic. Conclusions: Participants did not report that their personal experience of empathy for patients was negatively influenced by the COVID-19 pandemic. Many reported that their empathy increased. The observed differences in responses by pre-clinical (second-year) and clinical (fourth-year) students suggests a possible shift in how empathy is experienced and practiced as one progresses through their medical education. The overwhelmingly positive responses to the semi-structured interview, emphasizing appreciation of the opportunity to discuss topics not previously openly discussed, underscores the importance of providing explicit opportunities for students to discuss their emotional/interpersonal experiences within medical education, particularly in difficult times such as the COVID-19 pandemic.

Outcomes and Risk Factors of Patients With COVID-19 and Cancer (ONCORONA): A Sub-Study of the Philippine CORONA Study (preprint)

Background and Objectives: A study conducted in China on patients with COVIID 19 revealed that cancer conferred a five times increased risk for needing intensive care admission and mortality. Furthermore, data from two big registry studies showed that the presence of active cancer was associated with mortality. No data was collected from the Philippines, a developing country with a different healthcare system. Thus, the investigators conducted a sub study on the participants of the Philippine COVID-19 Outcomes (CORONA) study with a history of cancer and their clinical outcomes (i.e. mortality, respiratory failure, and intensive care unit admission).Methodology: Multi-Center, Retrospective Cohort Design.Results: A total of 10, 881 patients were included in the study; out of which, 244 had a history of cancer. After adjusting to the different confounding variables of interest, having cancer was significantly associated with the following outcomes: have 75% increased odds of having severe/critical COVID-19 at nadir (CI 95% 1.32, 2.33; p <0.001), have 136% increased odds of in-hospital mortality (CI 95% 1.75, 3.18; p <0.001), have 109% increased odds of respiratory failure (CI 95% 1.55, 2.83; p <0.001), have 98% increased odds of being admitted to ICU (CI 95% 1.47, 2.67; p <0.001). Additionally, after adjusting to the different confounding variables of interest, having cancer was significantly associated with the following time-to-event outcomes: 72% increase in hazard of in-hospital mortality (CI 95% 1.37, 2.16; p <0.001), 65% increase in hazard of respiratory failure (CI 95% 1.31, 2.08; p <0.001), and 57% increase in hazard of being admitted to ICU (CII 95% 1.24, 1.97; p <0.001).Conclusion: A history of cancer conferred poorer clinical outcomes on adult, hospitalized patients who were infected with COVID-19. Other demographic and clinical risk factors associated with cancer patients infected with COVID-19 are; older age, female sex, multiple co-morbidities, and having more respiratory symptoms and neurologic manifestations.Clinical Trial Registration Details: The study protocol was registered in ClinicalTrials.gov (NCT04386083)Funding Information: This study has not received any grant or funding from third-party organizations.Declaration of Interests: All authors declare no conflict of interest.Ethics Approval Statement: Our protocol was mainly endorsed by the Single Joint Research Ethics Board of the Department of Health, Philippines (SJREB-2020–24) for which the following institutions were included: Cagayan Valley Medical Center, Tuguegarao City; Jose R. Reyes Memorial Medical Center, Manila; Ospital ng Makati, Makati City; Perpetual Succour Hospital, Cebu City; Philippine Heart Center, Quezon City; Southern Isabela Medical Center, Santiago City; Southern Philippines Medical Center, Davao City; Western Visayas Medical Center, Iloilo City; and Zamboanga City Medical Center, Zamboanga City. Moreover, the authors were able to receive approval from the following local institutional review boards (code): Asian Hospital and Medical Center, Muntinlupa City (2020- 010-A); Baguio General Hospital and Medical Center, Baguio City (BGHMC-ERC-2020–13); Capitol Medical Center, Quezon City; Cardinal Santos Medical Center, San Juan City (CSMC REC 2020–020); Chong Hua Hospital, Cebu City (IRB 2420–04); De La Salle Medical and Health Sciences Institute, Cavite (2020–23-02-A); Dr. Jose N. Rodriguez Memorial and Sanitarium Hospital, Caloocan City; Dr. Pablo O. Torre Memorial Hospital (Riverside Medical Center), Bacolod City; East Avenue Medical Center, Quezon City (EAMC IERB 2020- 38); Jose B. Lingad Memorial Regional Hospital, City of San Fernando, Pampanga; Lung Center of the Philippines, Quezon City (LCP-CT-010–2020); Manila Doctors Hospital, Manila (MDH IRB 2020–006); Makati Medical Center, Makati City (MMC IRB 2020–054); Medical Center Manila, Manila (MMERC 2020–09); New Era General Hospital, Quezon City; Northern Mindanao Medical Center, Cagayan de Oro City (025–2020); Quirino Memorial Medical Center, Quezon City (QMMC REB GCS 2020–28); Philippine General Hospital, Manila (2020–314-01 SJREB); Research Institute for Tropical Medicine, Muntinlupa City (RITM IRB 2020–16); San Lazaro Hospital, Manila; San Juan De Dios Educational Foundation Inc. Hospital, Pasay City (SJRIB 2020–0006); Southern Isabela Medical Center, Santiago City (2020–03); Southern Philippines Medical Center (SPMC), Davao City (P20062001); St. Luke’s Medical Center, Quezon City (SL–20116); St. Luke’s Medical Center, Bonifacio Global City, Taguig City (SL–20116); The Medical City, Pasig City; University of the East Ramon Magsaysay Memorial Medical Center, Inc, Quezon City (0835/E/2020/063); University of Santo Tomas Hospital, Manila (UST-REC-2020–04-071-MD); Veterans Memorial Medical Center, Quezon City (VMMC- 2020–025); Vicente Sotto Memorial Medical Center, Cebu City (VSMMC-REC-O-2020–048).

COVID-19 vaccinations: perceptions and behaviours in people with primary ciliary dyskinesia (preprint)

Primary ciliary dyskinesia (PCD) is a rare genetic disease that causes recurrent respiratory infections. People with PCD may be at high risk of severe COVID-19 and vaccination against SARS-CoV-2 is therefore important. We studied vaccination willingness, speed of vaccination uptake, side effects, and changes in social contact behavior after vaccination in people with PCD. We used data from COVID-PCD, an international participatory cohort study. A questionnaire was e-mailed to participants in May 2021 that asked about COVID-19 vaccinations. 423 participants from 31 countries replied (median age: 30 years; 261 (62%) female). Vaccination uptake and willingness was high with 273 of 287 adults (96%) being vaccinated or willing to be in June 2021; only 4% were hesitant. The most common reasons for hesitancy were fear of side effects (reported by 88%). Mild side effects were common but no participant reported severe side effects. Half of participants changed their social contact behaviour after vaccination by seeing friends and family more often. The high vaccination willingness in the study population might reflect the extraordinary effort taken by PCD support groups to inform people about COVID-19 vaccination. Clear and specific public information and involvement of representatives is important for high vaccine uptake.

Adverse SARS-CoV-2 Associated Outcomes Among People Experiencing Homelessness, Imprisonment, Supported Psychiatric Housing, Mental Disorders, Substance Abuse or Chronic Medical Disorders: A Population-Based Cohort Study Among 4.4 Million People (preprint)

Background: Marginalised or deprived groups may be at high risk of a serious COVID-19 outcome. We examined adverse outcomes associated with SARS-CoV-2 infection among vulnerable segments of society. Methods: Using health and administrative registers, we performed a population-based cohort study of 4.38 million Danes, 27 February 2020­ to 6 April 2021. Main predictors were experiences of 1) homelessness, 2) imprisonment, 3) supported psychiatric housing, 4) mental disorder, 5) substance abuse, and 6) chronic medical condition. COVID-19-related outcomes were: 1) hospitalisation, 2) intensive care, 3) 30-day mortality, and 4) overall mortality. PCR-confirmed SARS-CoV-2 infection and PCR-testing were also studied. Vulnerable groups were compared with the general population (using adjusted incidence and mortality rate ratios: IRRs, MRRs). Findings: Among individuals with a positive PCR-test experiencing homelessness and supported psychiatric housing, 8∙6% (95% CI 6∙9-10∙4) and 11% (7∙8-14∙7), respectively, were admitted to hospital within two weeks and 1∙8% (1∙1-2∙7) and 2∙9% (1∙4-5∙1), respectively, had died within 30 days. The probability of hospitalisation was higher for all predictors compared with the general population (p=<0∙0001). After adjustments, vulnerable housing situations, i.e. homelessness, imprisonment, and supported psychiatric housing, increased the risk of adverse outcomes 1∙7 to 3∙2-times; highest 30-day MRR after COVID-19 was for homelessness (3∙2, 95% CI 2∙0-5∙1) and supported psychiatric housing: (2∙7, 1∙4-5∙2). Mental disorder, substance abuse, and chronic medical conditions were associated with 1∙1 (mental disorder and intensive care, p=0∙37) to 2∙0-times increased risk of adverse outcomes (30-day MRR for substance abuse: 2∙0, 1∙8-2∙3). Overall mortality during the study period was increased for all predictors and highest for homelessness combined with a PCR-confirmed SARS-CoV-2 infection (MRR 22∙1, 15∙2-32∙2). Interpretation: This study highlights that pandemic preparedness should address inequalities in health, including infection prevention and vaccination of vulnerable groups. Higher awareness of people in vulnerable living situations is needed. Funding Information: This study was funded by a grant from the Novo Nordisk Foundation to MN (grant number NFF20SA0063142).Declaration of Interests: We declare no competing interests.Ethics Approval Statement: Permission was obtained from Statistics Denmark and the Danish Health Data Authority. Ethical permission was not required for this study according to Danish regulations.

Access to HIV Antiretroviral Therapy Among People Living with HIV in Melbourne During the COVID-19 Pandemic (preprint)

Background: The social measures taken to control the COVID-19 pandemic can potentially disrupt the management of HIV. The objective of this study was to examine the impact of the Australian COVID-19 lockdown restrictions on access to antiretroviral therapy (ART) for people living with HIV in Melbourne.Methods: Using data from the Melbourne Sexual Health Centre (MSHC), we assessed the changes in rates of ART postal delivery, controlled viral load, and ART dispensing from 2018 to 2020. The percentage of ART delivered by postage from MSHC pharmacy was calculated weekly. The percentage of people living with HIV with a controlled viral load (≤ 200 copies/mL) was calculated monthly. We calculated a yearly Medication Possession Ratio (MPR).Findings: The average percentage of HIV ART dispensed through postage for the years 2018, 2019, and 2020 was 3∙7% (371/10023), 3∙6% (380/10685), and 14% (1478/10765), respectively (Ptrend < 0∙0001). Of the 3115 people living with HIV, the average MPR for 2018, 2019, and 2020 was 1∙05, 1∙06, and 1∙14, respectively (Ptrend = 0.28). The average percentage of people with an HIV viral load of < 200 copies/mL for the years 2018, 2019, and 2020 were 97∙6% (2271/2327), 98∙0% (2390/2438), and 99∙2% (2048/2064), respectively (Ptrend < 0∙0001).Interpretation: This study found that the proportion of controlled viral load and access to ART of people living with HIV in Melbourne was largely unaffected by the COVID-19 lockdown restrictions. This suggests that some of the services provided by MSHC during the pandemic, such as HIV ART postal delivery, may assist long-term HIV management.Funding: Chow EPF and Ong JJ are supported by an Australian National Health and Medical Research Council (NHMRC) Emerging Leadership Investigator Grant (GNT1172873, GNT1193955). Fairley CK is supported by an Australian NHMRC Leadership Investigator Grant (GNT1172900).Declaration of Interest: The authors declare they do not have any conflicts of interest.Ethical Approval: This study was approved by the Alfred Hospital Ethics Committee, Melbourne, Australia (773/20).

Uptake and Effectiveness of Online Diabetes Continuing Education: The Perspectives of Thai General Practitioner Trainees (preprint)

Background: Despite continuing medical education (CME) programmes about evidence-based diabetes care, there remains a paucity of evidence-based best practice and actual GP practice. Online CME offers numerous benefits to general practitioners (GPs), particularly during the coronavirus disease 2019 (COVID-19) pandemic. In Thailand, CME is a voluntary process and yet to be established as mandatory. This study aimed to examine GP uptake on the online diabetes CME and its effectiveness on changes in the GPs’ attitudes and knowledge about Type 2 diabetes management.Methods: A cross-sectional study and a before-and-after study were employed with 279 GP trainees who voluntarily undertook the newly developed diabetes programme online. A follow-up survey was conducted 6 months after the GP trainees completed their training.Results: One hundred and twelve out of 279 GP trainees (40.1%) participated, of whom 37 (13.3%) enrolled in the online diabetes programme, and 20 (7.2%) completed the programme. The participants’ mean diabetes knowledge score before enrolling the programme was 61.5%. The participants’ confidence in effective insulin treatment increased significantly after the programme (95% Confident interval [CI], -0.51-0.00; P=0.05) but their knowledge scores before and after the programme were not statistically different (95% CI, -3.93-0.59; P=0.14).Conclusion: There was poor uptake for an online diabetes CME, even though effective recruitment strategies were employed, and while the online educational option is attractive and accessible during the COVID-19 pandemic. This present study emphasises not only the gap between evidence-based practice and actual GP practice but also a need for mandatory CME.Funding Information: This study was financially supported by the Faculty of Medicine, Khon Kaen University (Grant no. IN62338).Declaration of Interests: No potential conflict of interest relevant to this article was reported.Ethics Approval Statement: The study was approved by the Khon Kaen University Human Research Ethics Committee: Project number HE621379.

Intervention of resource allocation strategies on spatial spread of epidemic (preprint)

Medical resources are crucial in mitigating the epidemic, especially during pandemics such as the ongoing COVID-19. Thereby, reasonable resource deployment inevitably plays a significant role in suppressing the epidemic under limited resources. When an epidemic breaks out, people can produce resources for self-protection, or donate resources to help others. That is, the exchange of resources also affects the transmission between individuals, thus, altering the epidemic dynamics. To understand factors on resource deployment and the interplay between resource and transmission we construct a metapopulation network model with resource allocation. Our results indicate actively or promptly donating resources is not helpful to suppress the epidemic under both homogeneous population distribution (HOD) and heterogeneous population distribution (HED). Besides, strengthening the speed of resource production can significantly increase the recovery rate so that reduce the final outbreak size. These results may provide policy guidance towards epidemic containment.

Viable Medical Waste Chain Network Design by Considering Risk and Robustness (preprint)

Medical Waste Management (MWM) is an important and necessary problem in the COVID-19 situation for treatment staff. When the number of infectious patients grows up and amount of MWMs increases day by day. We present Medical Waste Chain Network Design (MWMCND) that contains Health Center (HC), Waste Segregation (WS), Waste Purchase Contractor (WPC) and landfill. We propose to locate WS to decrease waste and recover them and send them to the WPC. Recovering medical waste like metal and plastic can help the environment and return to the production cycle. Therefore, we proposed a novel Viable MWCND by a novel two-stage robust stochastic programming that considers resiliency (flexibility and network complexity) and sustainable (energy and environment) requirements. Therefore, we try to consider risks by Conditional Value at Risk (CVaR) and improve robustness and agility to demand fluctuation and network. We utilize and solve it by GAMS CPLEX solver. The results show that by increasing the conservative coefficient, the confidence level of CVaR and waste recovery coefficient increases cost function and population risk. Moreover, increasing demand and scale of the problem make to increase the cost function.

Immune Response and Safety to Inactivated COVID-19 Vaccine: A Comparison Between People Living with HIV and HIV-naïve Individuals (preprint)

Background: Multi-types COVID-19 vaccines have shown safety and efficacy against COVID-19 in healthy adults. Although current guidelines encourage people living with HIV(PLWH) to take COVID-19 vaccines, whether their immune response to COVID-19 vaccines is distinct from HIV-free individuals is still unclear.Methods: Between March to June 2021, 48 PLWH and 40 HNC, aged 18 to 59 years, were enrolled in the study. All of them received inactivated COVID-19 vaccine at day 0 and the second dose at day 28. The primary safety outcome was the combined adverse reactions within 7days after each injection. The primary immunogenicity outcomes were neutralizing antibodies (nAbs) responses by chemiluminescence and total specific IgM and IgG antibodies responses by ELISA and colloidal gold at baseline (day 0), day 14, day 28, day 42, and day 70.Findings: In total, the study included 46 PLWH and 38 HNC who finished 70 days’ follow-up. The frequency of adverse reactions to the first and second dose was not different between PLWH (30% and 11%) vs HNC (32% and 24%). NAbs responses among PLWH peaked at day 70, while among HNC peaked at day 42. At day 42, the geometric mean concentration (GMC) and seroconversion rate of nAbs among PLWH were 4.46 binding antibody units (BAU)/mL (95% CI, 3.18-5.87) and 26% (95% CI, 14-41), which were lower than that among HNC [GMC (18.28 BAU/mL, 95% CI, 10.33-32.33), seroconversion rate (63%, 95% CI, 44-79)]. IgG responses among both PLWH and HNC peaked at day 70. At day 70, the geometric mean ELISA units (GMEU) and seroconversion rate of IgG among PLWH were 0.193 ELISA units (EU)/mL (95% CI, 0.119-0.313) and 51% (95% CI, 34-69), which was lower than that among HNC [GMEU (0.379 BAU/mL, 95% CI, 0.224-0.653), seroconversion rate (86%, 95% CI, 64-97)].Interpretation: Early humoral immune response to the inactivated COVID-19 vaccine was weaker and delayed among the PLWH population than that among HNC. This observation remained consistent regardless of a high CD4 count and a low HIV viral load suppressed by ART.Funding: This work was supported by the National Key Research and Development Program of China (2017YFE0103800), the National Nature Science Foundation of China (81903371), NIMH (R34MH119963), the National Science and Technology Major Project (2018ZX10101-001-001-003), and Special Found on Prevention and Control of New Coronary Pneumonia in Guangdong Universities (2020KZDZX1047), Medical Science and Technology Innovation Platform Support Project of Zhongnan Hospital, Wuhan University (PTXM2020008), Science and Technology Innovation Cultivation Fund of Zhongnan Hospital, Wuhan University (cxpy2017043). Medical Science Advancement Program (Basic Medical Sciences) of Wuhan University (TFJC2018004).Declaration of Interest: The authors declare no conflict of interest.Ethical Approval: The study was approved by the Research and Ethics Committee of Zhongnan Hospital, Wuhan University, P. R. China (2020079K-1). Informed consent was obtained from all individuals enrolled in this study.

Deciphering the Mechanisms of COVID-19 Induced Anosmia (preprint)

SARS-CoV-2 infects less than 1% of cells in the human body, yet it can cause severe damage in a variety of organs. Thus, deciphering the non-cell autonomous effects of SARS-CoV-2 infection is imperative for understanding the cellular and molecular disruption it elicits. Neurological and cognitive defects are among the least understood symptoms of COVID-19 patients, with olfactory dysfunction being their most common sensory deficit. Here, we show that both in humans and hamsters SARS-CoV-2 infection causes widespread downregulation of olfactory receptors (OR) and of their signaling components. This non-cell autonomous effect coincides with a dramatic reorganization of the neuronal nuclear architecture, which results in dissipation of genomic OR compartments and elimination of genomic contact domains genomewide. Our data provide a novel mechanism by which SARS-CoV-2 infection alters the cellular morphology and the transcriptome of cells it cannot infect, providing insight to its systemic effects in the nervous system and beyond.Funding Information: NIDCD 3R01DC018744-01S1 (SL, JO) National Institutes of Health grant, 4D Nucleome Consortium U01DA052783 (SL) Howard Hughes Medical Institute Faculty Scholar Award (SL), Zegar Family Foundation (SL).Ethics Approval Statement: The study was approved by the ethics and Institutional Review Board of Columbia University Medical Center (IRB AAAT0689, AAAS7370). LVG Golden Syrian hamsters (Mesocricetus auratus) were treated in compliance with the rules and regulations of IACUC under protocol number PROTO202000113-20-0743.

Effect of the COVID-19 Pandemic on BMI in Children and Adolescents: A Retrospective Cohort Study (preprint)

Background: The COVID-19 pandemic created circumstances with the potential to increase rates of overweight and obesity. We aimed to assess whether there were significant increases in BMI among a sample of children and adolescents during the year 2020 compared to the two years prior to the pandemic.Methods: For this retrospective cohort study, data was obtained from the electronic medical records of 8398 children 3-17 years of age who attended 3 consecutive well visits between June 1 and October 31 in 2018, 2019 and 2020 in a single center in the Midwest. Generalized linear mixed models were used to calculate the differences in average BMI and obesity rates over the three years.Findings: Between 2019 and 2020, the mean BMI for the whole sample increased 3.2 percentile points (from the 70·5 th to the 73·7 th percentile; p < 0·001) compared to an increase of 0.8 percentile point between 2018 and 2019 (p = 0·008).The proportion of children and adolescents with obesity rose from 13% in 2019 to 15·2% in 2020 (p < 0·001) compared to no significant increase from 2018 to 2019. Significant disparities in BMI were observed between socioeconomic and ethnic groups.Interpretation: Significant increases in BMI and obesity rates occurred in 2020 in this sample. We propose that the circumstances surrounding the COVID-19 pandemic contributed significantly to these increases.Funding: No funding or grant support related to this research was obtained.Declaration of Interest: None to declare. Ethical Approval: The study protocol was approved by the Joint Pediatric Institutional Review Board of the University of Nebraska Medical Center and Children’s Hospital Medical Center.