Protection against SARS-CoV-2 Omicron BA.4/5 variant following booster vaccination or breakthrough infection in the UK.

Following primary SARS-CoV-2 vaccination, whether boosters or breakthrough infections provide greater protection against SARS-CoV-2 infection is incompletely understood. Here we investigated SARS-CoV-2 antibody correlates of protection against new Omicron BA.4/5 (re-)infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults ≥18 y from the United Kingdom general population. Higher antibody levels were associated with increased protection against Omicron BA.4/5 infection and breakthrough infections were associated with higher levels of protection at any given antibody level than boosters. Breakthrough infections generated similar antibody levels to boosters, and the subsequent antibody declines were slightly slower than after boosters. Together our findings show breakthrough infection provides longer-lasting protection against further infections than booster vaccinations. Our findings, considered alongside the risks of severe infection and long-term consequences of infection, have important implications for vaccine policy.

Therapeutic potency of compound RMY-205 for pulmonary fibrosis induced by SARS-CoV-2 nucleocapsid protein.

Pulmonary fibrosis is a typical sequela of coronavirus disease 2019 (COVID-19), which is linked with a poor prognosis for COVID-19 patients. However, the underlying mechanism of pulmonary fibrosis induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is unclear. Here, we demonstrated that the nucleocapsid (N) protein of SARS-CoV-2 induced pulmonary fibrosis by activating pulmonary fibroblasts. N protein interacted with the transforming growth factor ß receptor I (TßRI), to disrupt the interaction of TßRI-FK506 Binding Protein12 (FKBP12), which led to activation of TßRI to phosphorylate Smad3 and boost expression of pro-fibrotic genes and secretion of cytokines to promote pulmonary fibrosis. Furthermore, we identified a compound, RMY-205, that bound to Smad3 to disrupt TßRI-induced Smad3 activation. The therapeutic potential of RMY-205 was strengthened in mouse models of N protein-induced pulmonary fibrosis. This study highlights a signaling pathway of pulmonary fibrosis induced by N protein and demonstrates a novel therapeutic strategy for treating pulmonary fibrosis by a compound targeting Smad3.

Performance of antigen lateral flow devices in the UK during the alpha, delta, and omicron waves of the SARS-CoV-2 pandemic: a diagnostic and observational study.

BACKGROUND: Antigen lateral flow devices (LFDs) have been widely used to control SARS-CoV-2. We aimed to improve understanding of LFD performance with changes in variant infections, vaccination, viral load, and LFD use, and in the detection of infectious individuals. METHODS: In this diagnostic study, paired LFD and RT-PCR test results were prospectively collected from asymptomatic and symptomatic participants in the UK between Nov 4, 2020, and March 21, 2022, to support the National Health Service (NHS) England's Test and Trace programme. The LFDs evaluated were the Innova SARS-CoV-2 Antigen Rapid Qualitative Test, the Orient Gene Rapid Covid-19 (Antigen) Self-Test, and the Acon Flowflex SARS-CoV-2 Antigen Rapid Test (Self-Testing). Test results were collected across various community testing settings, including predeployment testing sites, routine testing centres, homes, schools, universities, workplaces, targeted community testing, and from health-care workers. We used multivariable logistic regression to analyse LFD sensitivity and specificity using RT-PCR as a reference standard, adjusting for viral load, LFD manufacturer, test setting, age, sex, test assistance, symptom status, vaccination status, and SARS-CoV-2 variant. National contact tracing data from NHS Test and Trace (Jan 1, 2021, to Jan 11, 2022) were used to estimate the proportion of transmitting index patients (with ≥1 RT-PCR-positive or LFD-positive contact) potentially detectable by LFDs (specifically Innova, as the most widely used LFD) with time, accounting for index viral load, variant, and symptom status. FINDINGS: We assessed 75 382 pairs of LFD and RT-PCR tests. Of these, 4131 (5·5%) were RT-PCR-positive. LFD sensitivity versus RT-PCR was 63·2% (95% CI 61·7-64·6) and specificity was 99·71% (95% CI 99·66-99·74). Increased viral load was independently associated with being LFD positive (adjusted odds ratio [aOR] 2·85 [95% CI 2·66-3·06] per 1 log10 copies per mL increase; p<0·0001). There was no evidence that LFD sensitivity differed for delta (B.1.617.2) infections versus alpha (B.1.1.7) or pre-alpha (B.1.177) infections (aOR 1·00 [0·69-1·45]; p=0·99), whereas omicron (BA.1 or BA.2) infections appeared more likely to be LFD positive (aOR 1·63 [1·02-2·59]; p=0·042). Sensitivity was higher in symptomatic participants (68·7% [95% CI 66·9-70·4]) than in asymptomatic participants (52·8% [50·1-55·4]). Among 347 374 unique index patients with probable onward transmission, 78·3% (95% CI 75·3-81·2) were estimated to have been detectable with LFDs (Innova), and this proportion was mostly stable with time and for successive variants. Overall, the estimated proportion of infectious index patients detectable by the Innova LFD was lower in asymptomatic patients (57·6% [53·6-61·9]) versus symptomatic patients (79·7% [76·7-82·5]). INTERPRETATION: LFDs remained able to detect most SARS-CoV-2 infections throughout vaccine roll-out and across different viral variants. LFDs can potentially detect most infections that transmit to others and reduce the risk of transmission. However, performance is lower in asymptomatic individuals than in symptomatic individuals. FUNDING: UK Health Security Agency, the UK Government Department of Health and Social Care, National Institute for Health Research (NIHR) Health Protection Research Unit in Healthcare Associated Infections and Antimicrobial Resistance, and the University of Oxford NIHR Biomedical Research Centre.

Micronutrient perspective on COVID-19: Umbrella review and reanalysis of meta-analyses.

INTRODUCTION: Micronutrients are clinically important in managing COVID-19, and numerous studies have been conducted, but inconsistent findings exist. OBJECTIVE: To explore the association between micronutrients and COVID-19. METHODS: PubMed, Web of Science, Embase, Cochrane Library and Scopus for study search on July 30, 2022 and October 15, 2022. Literature selection, data extraction and quality assessment were performed in a double-blinded, group discussion format. Meta-analysis with overlapping associations were reconsolidated using random effects models, and narrative evidence was performed in tabular presentations. RESULTS: 57 reviews and 57 latest original studies were included. 21 reviews and 53 original studies were of moderate to high quality. Vitamin D, vitamin B, zinc, selenium, and ferritin levels differed between patients and healthy people. Vitamin D and zinc deficiencies increased COVID-19 infection by 0.97-fold/0.39-fold and 1.53-fold. Vitamin D deficiency increased severity 0.86-fold, while low vitamin B and selenium levels reduced severity. Vitamin D and calcium deficiencies increased ICU admission by 1.09 and 4.09-fold. Vitamin D deficiency increased mechanical ventilation by 0.4-fold. Vitamin D, zinc, and calcium deficiencies increased COVID-19 mortality by 0.53-fold, 0.46-fold, and 5.99-fold, respectively. CONCLUSION: The associations between vitamin D, zinc, and calcium deficiencies and adverse evolution of COVID-19 were positive, while the association between vitamin C and COVID-19 was insignificant.REGISTRATION: PROSPERO CRD42022353953.

Immunogenicity, durability, and safety of an mRNA and three platform-based COVID-19 vaccines as a third dose following two doses of CoronaVac in China: A randomised, double-blinded, placebo-controlled, phase 2 trial.

Background: More effective vaccine candidates against variants of concern as a booster dose are needed in people primed with two-dose inactivated COVID-19 vaccines. Methods: This randomised, double-blinded, investigator-initiated phase 2 trial aims to evaluate immunogenicity, durability, and safety of an mRNA vaccine candidate (RQ3013) and three other platform vaccines (an adenovirus-vectored vaccine candidate [ChAdTS-S], a recombinant protein vaccine candidate [ZR202-CoV], and an inactivated vaccine [CoronaVac]) as a booster. 250 eligible volunteers, who had received a prime two-dose CoronaVac (3 to 5 weeks apart) vaccination 100-270 days before, were randomly assigned in a 1:1:1:1:1 ratio to receive a third dose of RQ3013 (30 µg mRNA per 0.15 mL), ChAdTS-S (5×1010 viral particles per 0.5 mL), ZR202-CoV (25 µg prefusion-stabilized Spike ectodomain trimer per 0.5 mL), CoronaVac (3 µg inactivated CN02 strain of SARS-CoV-2 per 0.5 mL) or placebo (0.5 mL of 0.9% sodium chloride solution) via intramuscular injection into the upper arm at a single clinical site in Kunming, China. Participants, investigators, and immunogenicity laboratory were masked to group assignment. The primary immunogenicity outcomes were geometric mean titres (GMTs) of neutralising antibodies against live SARS-CoV-2 (wild-type, delta and omicron) virus at day 0 (before vaccination), day 7, day 14 and day 28 after vaccination, as analysed in a modified intention-to-treat (mITT) population (all participants who completed their booster doses and had at least one post-dose immunogenicity data). Secondary outcomes include T cell responses against the wild-type and omicron SARS-CoV-2 Spike protein. The primary safety outcome was incidence of adverse events within 14 days after the booster vaccination. This trial is registered with ChiCTR.org.cn, ChiCTR2200057758. Findings: Between January 1, 2022, and February 28, 2022, 235 eligible participants were enrolled and vaccinated, and the primary analysis included 234 participants. At baseline, neutralising antibodies against wild-type virus, the delta, or omicron variants were low or undetectable in all groups. After the booster vaccination, GMTs of neutralising antibodies ranged from 75.4 (95% confidence interval [CI] 61.4-92.5) in CoronaVac to 950.1 (95% CI 785.4-1149.3) in RQ3013 against live wild-type SARS-CoV-2, and from 8.1 (95% CI: 6.1-10.7) in CoronaVac to 247.0 (95% CI 194.1-314.3) in RQ3013 against the omicron variant at day 14. Immunogenicities of all heterologous regimens were superior to that of homologous regimen in neutralisation against all tested SARS-CoV-2 strains, with RQ3013 showing the highest geometric mean ratios (GMRs) of 12.6, 14.7, and 31.3 against the wild-type, the delta variant and the omicron variant compared to CoronaVac at day 14 post-vaccination, respectively. Durability analysis at day 90 showed that >90% of participants in RQ3013 and ZR202-CoV were seropositive for the omicron variant while ZR202-CoV with adjuvants containing CpG showed a slightly better durability than RQ3013. T cell responses specific to the omicron variant were similar to that of the wild-type, with RQ3013 showing the highest boosting effect. Any solicited injection site or systemic adverse events reported within 14 days after vaccination were most commonly observed in RQ3013 (47/47, 100%), followed by ZR202-CoV (46/47, 97.9%) and ChAdTS-S (43/48, 89.6%), and then CoronaVac (37/46, 80.4%) and placebo (21/47, 44.7%). More than 90% of the adverse events were grade 1 (mild) or 2 (moderate) with a typical resolution time of 3 days. No grade 4 adverse events or serious adverse events were reported by study vaccines. Interpretation: Although all study vaccines boosted neutralising antibodies with no safety concerns, RQ3013 showed much stronger cross-neutralisation and cellular responses, adding more effective vaccine candidates against the omicron variant. Funding: Yunnan Provincial Science and Technology Department China (202102AA100051 and 202003AC100010), the Double First-class University funding to Yunnan University, National Natural Science Foundation of China (81960116, 82060368 and 82170711), Yunnan Natural Science Foundation (202001AT070085), High-level Health Technical Personnel Project of Yunnan Province (H-2018102) and Spring City Plan: The High-level Talent Promotion and Training Project of Kunming.

Retrospective study of the immunogenicity and safety of the CoronaVac SARS-CoV-2 vaccine in people with underlying medical conditions.

BACKGROUND: People living with chronic disease, particularly seniors (≥60 years old), made up of most severe symptom and death cases among SARS-CoV-2 infected patients. However, they are lagging behind in the national COVID-19 vaccination campaign in China due to the uncertainty of vaccine safety and effectiveness. Safety and immunogenicity data of COVID-19 vaccines in people with underlying medical conditions are needed to address the vaccine hesitation in this population. METHODS: We included participants (≥40 years old) who received two doses of CoronaVac inactivated vaccines (at a 3-5 week interval) and were healthy or had at least one of 6 common chronic diseases. The incidence of adverse events after vaccination was monitored. Vaccine immunogenicity was studied by determining neutralizing antibodies and SARS-CoV-2-specific T cell responses post vaccination. RESULTS: Here we show that chronic diseases are associated with a higher rate of mild fatigue following the first dose of CoronaVac. By day 14-28 post vaccination, the neutralizing antibody level shows no significant difference between disease groups and healthy controls, except for people with coronary artery disease (p = 0.0287) and chronic respiratory disease (p = 0.0416), who show moderate reductions. Such differences diminish by day 90 and 180. Most people show detectable SARS-CoV-2-specific T cell responses at day 90 and day 180 without significant differences between disease groups and healthy controls. CONCLUSIONS: Our results highlight the comparable safety, immunogenicity and cellular immunity memory of CoronaVac in seniors and people living with chronic diseases. This data should reduce vaccine hesitancy in this population.

People living with chronic diseases, particularly those over the age of 60, are more likely to have severe symptoms and die following SARS-CoV-2 infection. However, many have not been vaccinated during the national COVID-19 vaccination campaign in China due to concerns about vaccine safety and effectiveness. Here we show that the inactivated COVID-19 vaccine, CoronaVac, is as safe in older people with chronic diseases as it is for healthy people. Also, only slightly differences are seen in the immune response of people with diseases compared to healthy people. Overall, our results highlight that the CoronaVac vaccine is safe and effective in people living with chronic diseases.

SARS-CoV-2 antibody responses post-vaccination in UK healthcare workers with pre-existing medical conditions: a cohort study.

OBJECTIVES: To examine antibody responses after the second vaccination in healthcare workers (HCWs) with underlying health conditions. DESIGN: Cohort study. SETTING: Oxford University Hospitals in the United Kingdom. PARTICIPANTS: Healthcare workers who had SARS-CoV-2 serological data available and received two SARS-CoV- 2 vaccinations. PRIMARY OUTCOME: Peak SARS-CoV-2 anti-spike IgG responses after the second vaccination and associations with underlying health conditions and the estimated risk of severe COVID-19 using an occupational health risk assessment tool. METHODS: We used univariable and multivariable linear regression models to investigate associations between antibody levels and demographics (age, sex, ethnicity), healthcare role, body mass index, underlying health conditions, vaccination status, prior infection and the Association of Local Authority Medical Advisors COVID-age risk score. RESULTS: 1635 HCWs had anti-spike IgG measurements 14-84 days after second vaccination and data on any underlying health conditions. Only five HCWs (0.3%), all on immunosuppressive treatment, (including four organ transplant recipients), did not seroconvert after second vaccination. Antibody levels were independently lower with older age, diabetes, immunosuppression, respiratory disorders other than asthma and markedly so in organ transplant recipients. Levels were independently lower in ChAdOx1 versus BNT162b2 recipients and higher following previous infection. HCWs with 'very high' COVID-age risk scores had lower median antibody levels than those with 'low', 'medium' or 'high' risk scores; 4379 AU/mL, compared with 12 337 AU/mL, 9430 AU/mL and 10 524 AU/mL, respectively. CONCLUSIONS: Two vaccine doses are effective in generating antibody responses among HCWs, including those with a high occupational risk. However, HCWs with underlying health conditions, especially diabetes, immunosuppression and organ transplant, had lower antibody levels, and vaccine response monitoring may be needed.

Exploring multigenerational co-residence in the United States

Purpose This paper aims to investigate the increasing trend of multigenerational co-living in the USA and to research the socioeconomic and cultural determinants of such decision. Design/methodology/approach This study uses the 2017 American Housing Survey data to run descriptive and regression analysis. Findings The authors find household income appears consistently to be the most significant factor determining multigenerational co-residence decision across all household compositions. Latino households are most likely to co-reside with multiple generations, followed by Asian and African American households. Immigrants tend to live in multigenerational co-residential housing units with smaller sizes and more impoverished neighborhoods, but show greater flexibility in making residential arrangements once they gain better education. In addition, older householders or female householders are significantly more likely to co-reside with multiple generations. Living in metropolitan areas has no impact on co-residence choice, although some evidence suggests that multigenerational co-residential families tend to live in inferior neighborhoods. Research limitations/implications This study provides updated evidence on multigenerational co-residence choice in the contemporary United States. The findings provide evidence on how households make residential choices in response to financial hardships and contribute to the theoretical understanding of the variations of such decisions among immigrants and different ethnic and aging groups. Practical implications This study on multigenerational co-residence choice imposes important practical implications. The unprecedented COVID-19 pandemic creates ideal research setting to study how households cope with the tremendous uncertainties in the job markets and financial markets. Although multigenerational co-living may work well for some households with lower or moderate-income for financial reasons, it is not an attractive option for every family. Social implications Sharing a home with multiple generations can be challenging. Policymakers should design policies and programs to provide households with guidance on how to live peacefully in multigenerational settings and make multigenerational co-living an appealing and cost-effective housing option for American families of all means. Originality/value This study contributes to the existing literature by providing new evidence on the determinants of multigenerational co-residence decision. This study's findings are fundamental to guide policymakers in carrying out policies and programs aimed at providing a more appealing and cost-effective housing arrangement for American families. The evidence on the senior and minority subsamples are especially meaningful as the vast majority of the baby boom generation in the USA is aging and substantial growth is expected in multigenerational households over the next several decades. Understanding the increasing burden of old-age depression in aging societies will help policymakers prioritize public resources in city planning to address the needs of this rapidly growing population.

ISARIC-COVID-19 dataset: A Prospective, Standardized, Global Dataset of Patients Hospitalized with COVID-19.

The International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC) COVID-19 dataset is one of the largest international databases of prospectively collected clinical data on people hospitalized with COVID-19. This dataset was compiled during the COVID-19 pandemic by a network of hospitals that collect data using the ISARIC-World Health Organization Clinical Characterization Protocol and data tools. The database includes data from more than 705,000 patients, collected in more than 60 countries and 1,500 centres worldwide. Patient data are available from acute hospital admissions with COVID-19 and outpatient follow-ups. The data include signs and symptoms, pre-existing comorbidities, vital signs, chronic and acute treatments, complications, dates of hospitalization and discharge, mortality, viral strains, vaccination status, and other data. Here, we present the dataset characteristics, explain its architecture and how to gain access, and provide tools to facilitate its use.

SARS-CoV-2 antibody trajectories after a single COVID-19 vaccination with and without prior infection.

Given high SARS-CoV-2 incidence, coupled with slow and inequitable vaccine roll-out in many settings, there is a need for evidence to underpin optimum vaccine deployment, aiming to maximise global population immunity. We evaluate whether a single vaccination in individuals who have already been infected with SARS-CoV-2 generates similar initial and subsequent antibody responses to two vaccinations in those without prior infection. We compared anti-spike IgG antibody responses after a single vaccination with ChAdOx1, BNT162b2, or mRNA-1273 SARS-CoV-2 vaccines in the COVID-19 Infection Survey in the UK general population. In 100,849 adults median (50 (IQR: 37-63) years) receiving at least one vaccination, 13,404 (13.3%) had serological/PCR evidence of prior infection. Prior infection significantly boosted antibody responses, producing higher peak levels and/or longer half-lives after one dose of all three vaccines than those without prior infection receiving one or two vaccinations. In those with prior infection, the median time above the positivity threshold was >1 year after the first vaccination. Single-dose vaccination targeted to those previously infected may provide at least as good protection to two-dose vaccination among those without previous infection.

Research progress on association between COVID-19 and herpes zoster

The infection caused by SARS-CoV-2 may result in a series of skin damages. In addition, some patients report the re-activation of the varicella-zoster virus, which might be related to T cell immune dysfunction caused by SARS-CoV-2 infection. Recently, studies reported herpes zoster occurrence after inoculating the COVID-19 vaccine. At present, the mechanism of interaction between COVID-19, COVID-19 vaccine and herpes zoster remains unclear, and more high-quality studies are required to further define the relationship.

Contribution of CD4+ T cell-mediated inflammation to diarrhea in patients with COVID-19.

OBJECTIVES: This study aimed to explore the role of CD4+ T cells in the mechanisms of COVID-19 related diarrhea. METHODS: We analyzed lymphocyte subsets in patients with COVID-19 and the expression of angiotensin-converting enzyme 2 (ACE2), the transmembrane protease serine 2, and CD4+ T cell-related indicators in the colon were compared between patients with and without diarrhea. Correlation analyses were performed for ACE2 and other indicators to identify the relationship between SARS-CoV-2 infection and CD4+ mediated inflammation. The expression and distribution of CD4+ T cell-associated chemokines and their receptors were detected to determine the possibility of migration of CD4+ T cells to inflammation sites. RESULTS: The CD4+ T cell counts and percentages and CD4/CD8 ratio showed the most significant differences between the 2 groups. The diarrhea group expressed higher levels of ACE2, T-box expressed in T cells (Tbet), and tumor necrosis factor-alpha (TNFα) at both the mRNA and protein levels, with no difference from the nondiarrhea group for the percentage of ACE2+TNFα+ cells, indicating an indirect association between ACE2 and TNFα. The mRNA expression of CXCL10, CXCL11, and CXCR3 and the number of CD4+CXCR3+T cells were increased in the diarrhea group. CONCLUSIONS: CD4+ T cell-mediated inflammation may contribute to COVID-19 related diarrhea. CXCR3+ mediated migration of CD4+ T cells into the gut may perpetuate inflammation.

Gender Modifies the Association of Cognition With Age-Related Hearing Impairment in the Health and Retirement Study.

Introduction: Despite growing recognition of hearing loss as a risk factor for late life cognitive disorders, sex and gender analysis of this association has been limited. Elucidating this is one means to advocate for holistic medicine by considering the psychosocial attributes of people. With a composite Gender Score (GS), we aimed to assess this among aging participants (50+) from the 2016 Health and Retirement Study (HRS) cohort. Methods: The GS was derived from gender-related variables in HRS by factor analyses and logistic regression, ranging from 0 (toward masculinity) to 100 (toward femininity). GS tertiles were also used to indicate three gender types (GS tertile 1: lower GS indicates masculinity; GS tertile 2: middle GS indicates androgyny; GS tertile 3: higher GS indicates femininity). Univariate followed by multiple logistic regressions were used to estimate the Odds Ratio (OR) and 95% confidence intervals (CI) of cognitive impairment (assessed by adapted Telephone Interview for Cognitive Status) from hearing acuity, as well as to explore the interactions of sex and gender with hearing acuity. The risk of cognitive impairment among hearing-impaired participants was assessed using multivariable models including sex and gender as exposure variables. Results: Five variables (taking risks, loneliness, housework, drinking, and depression) were retained to compute the GS for each participant. The distribution of GS between sexes partly overlapped. After adjusting for confounding factors, the OR for cognitive impairment associated with hearing impairment was significantly higher (OR = 1.65, 95% CI: 1.26, 2.15), and this association was not modified by female sex (OR = 0.77, 95% CI: 0.46, 1.27), but by androgynous gender (OR = 0.44, 95% CI: 0.24, 0.81). In the multivariable models for participants with hearing impairment, androgynous and feminine gender, as opposed to female sex, was associated with lower odds of cognitive impairment (OR of GS tertile 2 = 0.59, 95% CI: 0.41, 0.84; OR of GS tertile 3 = 0.60, 95% CI: 0.41, 0.87; OR of female sex = 0.78, 95% CI: 0.57, 1.08). Conclusions: Hearing impairment was associated with cognitive impairment among older people, and this association may be attenuated by a more feminine GS.

Clinical characteristics, socioeconomic factors and COVID-19 were associated with delayed surgery in children with hypospadias: a retrospective study of 4439 cases in a single center (preprint)

Background Hypospadias is one of the most common congenital diseases of the genitourinary system in children. The European Association of Urology (EAU) Guidelines recommend that children undergoing hypospadias surgery should be between 6-18 months. In China, where many children have hypospadias, it remains unknown whether clinical characteristics, socioeconomic factors and COVID-19 were associated with delayed surgery in children with hypospadias.Methods We retrospectively analyzed children with hypospadias who underwent primary surgery at the Department of Pediatric Urology in Guangzhou Women and Children’s Medical Center between January 2010 and October 2021. Patients who had two-stage surgery or a second round of surgery due to complications were excluded to eliminate data duplication. The clinical characteristics and demographic information were collected. We defined delayed surgery as primary surgery performed after 18 months following the EAU guideline.Results A total of 4439 children diagnosed with hypospadias were included in the study. The median age (29.1±16.7 months) of surgery for hypospadias in our study was much higher than the recommended age reported in the EAU guidelines, and 76.6% of the children underwent surgery after the age of 18 months. Children without comorbidities including cryptorchidism (odds ratio [OR]=1.562; 95% confidence interval [CI]1.199-2.034; p=0.001), prostatic cyst (OR=2.613; 95% CI 1.579-4.324; p<0.001), penile hypoplasia (OR=1.778; 95% CI 1.225-2.580; p=0.002), inguinal hernia (OR=2.070; 95% CI 1.394-3.075; p<0.001), and penoscrotal transposition (OR=4.125; 95% CI 1.250-13.619; p=0.020) were more likely to receive delayed surgery. Living in a low economic area (OR=1.731; 95% CI 1.068-2.806; p=0.026) or not close to a main medical center (OR=1.580; 95% CI 1.370-1.824; p<0.001) was highly associated with delayed surgery. The proportion of children undergoing delayed surgery and the median age of surgery during the COVID-19 pandemic were significantly higher than those before the COVID-19 pandemic (p=0.004 and < 0.001, respectively).Conclusions Most children with hypospadias received delayed surgery (surgical age >18 months). Comorbidities, living in a low economic area, too far from a major city medical center and the COVID-19 pandemic were also highly associated with delayed surgery. It is vital to improve the public awareness of hypospadias and strengthen the re-education of primary community doctors to reduce delayed surgery. Trial registration Not applicable. 

Causal influence of lung function on risk of fatality of COVID-19: a two-sample Mendelian randomization study

Objective: To investigate whether lung function was causally associated with risk of fatality of COVID-19 based on a two-sample Mendelian randomization study.