HLA Alleles, COVID-19 Vaccine Antibody Response and Real-World Breakthrough Outcomes (preprint)

The rapid development, approval, and global distribution of COVID-19 vaccines represent an unprecedented intervention in public health history, with over 13 billion doses administered worldwide in two years. However, our understanding of the HLA genetic underpinnings of COVID-19 vaccine-induced antibody responses and their clinical implications for breakthrough outcomes remain limited. To bridge this knowledge gap, we designed and performed a series of genetic and epidemiological analyses among 368,098 vaccinated individuals, and a subset of 194,371 participants who had antibody serology tests. Firstly, we corroborated earlier findings that SNPs associated with antibody response were predominantly located in Major Histocompatibility Complex region, and that the expansive HLA-DQB1*06 allele family was linked to better antibody responses. However, our findings contest the claim that DQB1*06 alleles alone significantly impact breakthrough risks. Additionally, our results suggest that the specific DQB1*06:04 subtype could be the true causal allele, as opposed to the previously reported DQB1*06:02. Secondly, we identified and validated six new functional HLA alleles that independently contribute to vaccine-induced antibody responses. Moreover, we unravelled additive effects of variations across multiple HLA genes that, concurrently, change the risk of clinically relevant breakthrough COVID-19 outcomes. Finally, we detangled the overall vaccine effectiveness and showed that antibody positivity accounts for approximately 20% protection against breakthrough infection and 50% against severe outcomes. These novel findings provide robust population evidence demonstrating how variations within HLA genes strongly, collectively, and causally influence vaccine-induced antibody responses, and the risk of COVID-19 breakthrough infection and related outcomes, with implications for subsequent functional research and personalised vaccination.

Risk of SARS-CoV-2 reinfection during multiple Omicron variant waves in the UK general population (preprint)

SARS-CoV-2 reinfections increased substantially after Omicron variants emerged. Large-scale community-based comparisons across multiple Omicron waves of reinfection characteristics, risk factors, and protection afforded by previous infection and vaccination, are limited, especially after widespread national testing stopped. We studied 245,895 adults >=18y in the UK's national COVID-19 Infection Survey with at least one infection (identified from positive swab tests done within the study, linked from national testing programmes, or self-reported by participants, up to their last study assessment). We quantified the risk of reinfection in multiple infection waves, including those driven by BA.1, BA.2, BA.4/5, and most recently BQ.1/CH.1.1/XBB.1.5 variants, in which most reinfections occurred. Reinfections had higher cycle threshold (Ct) values (lower viral load) and lower percentages self-reporting symptoms compared with first infections. Across multiple Omicron waves, protection against reinfection was significantly higher in those previously infected with more recent than earlier variants, even at the same time from previous infection. Protection against Omicron reinfections decreased over time from the most recent infection if this was the previous or penultimate variant (generally within the preceding year), but did not change or even slightly increased over time if this was with an even earlier variant (generally >1 year previously). Those 14-180 days after receiving their most recent vaccination had a lower risk of reinfection with all Omicron variants except BA.2 than those >180 days from their most recent vaccination. Reinfection risk was independently higher in those aged 30-45 years, and with either low or high Ct values in their most recent previous infection. Overall, the risk of Omicron reinfection is high, but with lower severity than first infections; reinfection risk is likely driven as much by viral evolution as waning immunity.

Local travel behaviour under continuing COVID-19 waves- A proxy for pandemic fatigue?

COVID-19 continues to threaten the world. Relaxing local travel behaviours on preventing the spread of COVID-19, may increase the infection risk in subsequent waves of SARS-CoV-2 transmission. In this study, we analysed changes in the travel behaviour of different population groups (adult, child, student, elderly) during four pandemic waves in Hong Kong before January 2021, by 4-billion second-by-second smartcard records of subway. A significant continuous relaxation in human travel behaviour was observed during the four waves of SARS-CoV-2 transmission. Residents sharply reduced their local travel by 51.9%, 50.1%, 27.6%, and 20.5% from the first to fourth pandemic waves, respectively. The population flow in residential areas, workplaces, schools, shopping areas, amusement areas and border areas, decreased on average by 30.3%, 33.5%, 41.9%, 58.1%, 85.4% and 99.6%, respectively, during the pandemic weeks. We also found that many other cities around the world experienced a similar relaxation trend in local travel behaviour, by comparing traffic congestion data during the pandemic with data from the same period in 2019. The quantitative pandemic fatigue in local travel behaviour could help governments partially predicting personal protective behaviours, and thus to suggest more accurate interventions during subsequent waves, especially for highly infectious virus variants such as Omicron.

Fever with atypical lymphocytosis: pearls and pitfalls in Epstein-Barr virus serology.

The heterophile antibody (also known as the Monospot) test is a useful screening tool for infectious mononucleosis (IM) resulting from primary Epstein-Barr virus (EBV) infection. However, up to 10% of patients with IM are heterophile negative. Heterophile-negative patients who have lymphocytosis or atypical lymphocytes on peripheral blood smear should be further tested for EBV serologies, which include testing for specific IgM and IgG antibodies against viral capsid antigens, early antigens and EBV nuclear antigen proteins. A diagnostic dilemma arises when the patient has clinical and laboratory features of IM, but is both heterophile negative and seronegative for IM, as illustrated in this case presentation. To avoid missed diagnoses of IM, misdiagnosis of mononucleosis-like illnesses and unnecessary testing, knowledge of test characteristics and the evolving course of EBV serologies is important to assure and inform both the physician and the patient.

Impacts of emotional regulation, adaptive selling and customer-oriented behavior on sales performance: the moderating role of job resourcefulness

PurposeGiven the increasing intensity of highly competitive markets, this study aims to evaluate the effect of salespeople's emotional regulation, adaptive selling and customer-oriented behavior on sales performance.Design/methodology/approachA research model was tested by using a sample of 288 respondents from the logistics industry in Taiwan. Structural equation modeling was used to examine the relationships between emotional regulation, adaptive selling, job resourcefulness, customer-oriented behavior and sales performance.FindingsThe results indicate that emotional regulation, adaptive selling and job resourcefulness can improve customer-oriented behavior, and that customer-oriented behavior and job resourcefulness can enhance sales performance. By highlighting the role of job resourcefulness, the authors find a positive moderating effect among these four dimensions.Originality/valueThe findings can help salespeople integrate customer-oriented behaviors into strategic changes to regulate their own emotions and those of others to productively address and resolve difficult business conditions. The theoretical and managerial implications of this work's contributions to international logistics are also discussed.

Randomized Trial of BCG Vaccine to Protect against Covid-19 in Health Care Workers.

BACKGROUND: The bacille Calmette-Guérin (BCG) vaccine has immunomodulatory "off-target" effects that have been hypothesized to protect against coronavirus disease 2019 (Covid-19). METHODS: In this international, double-blind, placebo-controlled trial, we randomly assigned health care workers to receive the BCG-Denmark vaccine or saline placebo and followed them for 12 months. Symptomatic Covid-19 and severe Covid-19, the primary outcomes, were assessed at 6 months; the primary analyses involved the modified intention-to-treat population, which was restricted to participants with a negative test for severe acute respiratory syndrome coronavirus 2 at baseline. RESULTS: A total of 3988 participants underwent randomization; recruitment ceased before the planned sample size was reached owing to the availability of Covid-19 vaccines. The modified intention-to-treat population included 84.9% of the participants who underwent randomization: 1703 in the BCG group and 1683 in the placebo group. The estimated risk of symptomatic Covid-19 by 6 months was 14.7% in the BCG group and 12.3% in the placebo group (risk difference, 2.4 percentage points; 95% confidence interval [CI], -0.7 to 5.5; P = 0.13). The risk of severe Covid-19 by 6 months was 7.6% in the BCG group and 6.5% in the placebo group (risk difference, 1.1 percentage points; 95% CI, -1.2 to 3.5; P = 0.34); the majority of participants who met the trial definition of severe Covid-19 were not hospitalized but were unable to work for at least 3 consecutive days. In supplementary and sensitivity analyses that used less conservative censoring rules, the risk differences were similar but the confidence intervals were narrower. There were five hospitalizations due to Covid-19 in each group (including one death in the placebo group). The hazard ratio for any Covid-19 episode in the BCG group as compared with the placebo group was 1.23 (95% CI, 0.96 to 1.59). No safety concerns were identified. CONCLUSIONS: Vaccination with BCG-Denmark did not result in a lower risk of Covid-19 among health care workers than placebo. (Funded by the Bill and Melinda Gates Foundation and others; BRACE ClinicalTrials.gov number, NCT04327206.).

Changes on local travel behaviors under travel reduction-related interventions during COVID-19 pandemic: a case study in Hong Kong

The emerging Omicron variant poses a serious threat to human health. Public transports play a critical role in infection spread. Based on the data of nearly 4 billion smartcard uses, between January 1, 2019 and January 31, 2021 from the Mass Transit Railway Corporation of Hong Kong, we analyzed the subway travel behavior of different population groups (adults, children, students and senior citizens) due to the COVID-19 pandemic and human travel behavior under different interventions (e.g. work suspension, school closure). Due to the pandemic, the number of MTR passengers (the daily number of passengers in close proximity in subway carriages) decreased by 37.4% (40.8%) for adults, 80.3% (78.5%) for children, 71.6% (71.6%) for students, and 33.5% (36.1%) for senior citizens. Due to work from home (school suspension), the number of contacted adults (students/children) in the same carriage during the rush hours decreased by 39.6% (38.6%/43.2%). If all workers, students, and children were encouraged to commute avoiding rush hours, the possible repeated contacts during rush hour of adults, children and students decreased by 73.3%, 77.9% and 79.5%, respectively. Since adults accounted for 87.3% of the total number of subway passengers during the pandemic, work from home and staggered shift pattern of workers can reduce the infection risk effectively. Our objective is to find the changes of local travel behavior due to the pandemic. From the perspective of public transports, the results provide a scientific support for COVID-19 prevention and control in cities. Supplementary Information The online version contains supplementary material available at 10.1007/s44213-023-00006-z.

Development of a multiplex qRT-PCR assay for the detection of porcine epidemic diarrhea virus, porcine transmissible gastroenteritis virus and porcine Deltacoronavirus.

Currently, porcine coronaviruses are prevalent in pigs, and due to the outbreak of COVID-19, porcine coronaviruses have become a research hotspot. porcine epidemic diarrhea virus (PEDV), Transmissible Gastroenteritis Virus (TGEV), and Porcine Deltacoronavirus (PDCoV) mentioned in this study mainly cause diarrhea in pigs. These viruses cause significant economic losses and pose a potential public health threat. In this study, specific primers and probes were designed according to the M gene of PEDV, the S gene of TGEV, and the M gene of PDCoV, respectively, and TaqMan probe-based multiplex real-time quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was developed for the simultaneous detection of PEDV, TGEV, and PDCoV. This method has high sensitivity and specificity, and the detection limit of each virus can reach 2.95 × 100 copies/µl. An assay of 160 clinical samples from pigs with diarrhea showed that the positive rates of PEDV, TGEV, and PDCoV were 38.13, 1.88, and 5.00%; the coinfection rates of PEDV+TGEV, PEDV+PDCoV, TGEV+PDCoV, PEDV+TGEV+PDCoV were 1.25, 1.25, 0, 0.63%, respectively. The positive coincidence rates of the multiplex qRT-PCR and single-reaction qRT-PCR were 100%. This method is of great significance for clinical monitoring of the porcine enteric diarrhea virus and helps reduce the loss of the breeding industry and control the spread of the disease.

Co-incidence of BA.1 and BA.2 at the start of Singapore's Omicron wave revealed by Community and University Campus wastewater surveillance.

Wastewater surveillance (WWS) has been globally recognised to be a useful tool in quantifying SARS-CoV-2 RNA at the community and residential levels without biases associated with case-reporting. The emergence of variants of concern (VOCs) have given rise to an unprecedented number of infections even though populations are increasingly vaccinated. This is because VOCs have been reported to possess higher transmissibility and can evade host immune responses. The B.1.1.529 lineage (Omicron) has severely disrupted global plans to return to normalcy. In this study, we developed an allele-specific (AS) RT-qPCR assay which simultaneously targets the stretch of deletions and mutations in the spike protein from position 24-27 for quantitative detection of Omicron BA.2. Together with previous assays that detect mutations associated with Omicron BA.1 (deletion at position 69 and 70) and all Omicron (mutation at position 493 and 498), we report the validation and time series of these assays from September 2021 to May 2022 using influent samples from two wastewater treatment plants and across four University campus sites in Singapore. Viral RNA concentrations at the treatment plants corroborate with locally reported clinical cases, AS RT-qPCR assays revealed co-incidence of Omicron BA.1 and BA.2 on 12 January 2022, almost two months after initial BA.1 detection in South Africa and Botswana. BA.2 became the dominant variant by the end of January 2022 and completely displaced BA.1 by mid-March 2022. University campus sites were similarly positive for BA.1 and/or BA.2 in the same week as first detection at the treatment plants, where BA.2 became rapidly established as the dominant lineage within three weeks. These results corroborate clinical incidence of the Omicron lineages in Singapore and indicate minimal silent circulation prior to January 2022. The subsequent simultaneous spread of both variant lineages followed strategic relaxation of safe management measures upon meeting nationwide vaccination goals.

Airborne antibiotic resistome and human health risk in railway stations during COVID-19 pandemic.

Antimicrobial resistance is recognized as one of the greatest public health concerns. It is becoming an increasingly threat during the COVID-19 pandemic due to increasing usage of antimicrobials, such as antibiotics and disinfectants, in healthcare facilities or public spaces. To explore the characteristics of airborne antibiotic resistome in public transport systems, we assessed distribution and health risks of airborne antibiotic resistome and microbiome in railway stations before and after the pandemic outbreak by culture-independent and culture-dependent metagenomic analysis. Results showed that the diversity of airborne antibiotic resistance genes (ARGs) decreased following the pandemic, while the relative abundance of core ARGs increased. A total of 159 horizontally acquired ARGs, predominantly confering resistance to macrolides and aminoglycosides, were identified in the airborne bacteria and dust samples. Meanwhile, the abundance of horizontally acquired ARGs hosted by pathogens increased during the pandemic. A bloom of clinically important antibiotic (tigecycline and meropenem) resistant bacteria was found following the pandemic outbreak. 251 high-quality metagenome-assembled genomes (MAGs) were recovered from 27 metagenomes, and 86 genera and 125 species were classified. Relative abundance of ARG-carrying MAGs, taxonomically assigned to genus of Bacillus, Pseudomonas, Acinetobacter, and Staphylococcus, was found increased during the pandemic. Bayesian source tracking estimated that human skin and anthropogenic activities were presumptive resistome sources for the public transit air. Moreover, risk assessment based on resistome and microbiome data revealed elevated airborne health risks during the pandemic.

Development of a multiplex RT-PCR method for the detection of four porcine enteric coronaviruses.

Porcine enteric coronaviruses are pathogens that cause viral diarrhea in pigs and are widely prevalent worldwide. Moreover, studies have shown that some porcine enteric coronaviruses can infect humans and poultry. In order to effectively monitor these viruses, it is necessary to establish a multiple detection method to understand their prevalence and conduct in-depth research. Common porcine enteric coronaviruses include Porcine epidemic diarrhea virus (PEDV), Porcine transmissible gastroenteritis virus (TGEV), Porcine delta coronavirus (PDCoV), and Swine acute diarrhea syndrome coronavirus (SADS-CoV). Pigs infected with these viruses have the common clinical symptoms that are difficult to distinguish. A quadruplex RT-PCR (reverse transcription-polymerase chain reaction) method for the simultaneous detection of PEDV, PDCoV, TGEV and SADS-CoV was developed. Four pairs of specific primers were designed for the PEDV M gene, PDCoV N gene, TGEV S gene and SADS-CoV RdRp gene. Multiplex RT-PCR results showed that the target fragments of PDCoV, SADS-CoV, PEDV and TGEV could be amplified by this method. and the specific fragments with sizes of 250 bp, 368 bp, 616 bp and 801 bp were amplified, respectively. This method cannot amplify any fragment of nucleic acids of Seneca Valley virus (SVV), Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) and Atypical Porcine Pestivirus (APPV), and has good specificity. The lowest detection limits of PDCoV, PEDV, TGEV and SADS-CoV were 5.66 × 105 copies/µL, 6.48 × 105 copies/µL, 8.54 × 105 copies/µL and 7.79 × 106 copies/µL, respectively. A total of 94 samples were collected from pig farms were analyzed using this method. There were 15 positive samples for PEDV, 3 positive samples for mixed infection of PEDV and PDCoV, 2 positive samples for mixed infection of PEDV and TGEV, and 1 positive sample for mixed infection of PEDV, TGEV, and PDCoV. Multiplex RT-PCR method could detect four intestinal coronaviruses (PEDV, PDCoV, TGEV, and SADS-CoV) in pigs efficiently, cheaply and accurately, which can be used for clinical large-scale epidemiological investigation and diagnosis.

Correlates of protection against SARS-CoV-2 Omicron variant and anti-spike antibody responses after a third/booster vaccination or breakthrough infection in the UK general population (preprint)

Following primary SARS-CoV-2 vaccination, understanding the relative extent of protection against SARS-CoV-2 infection from boosters or from breakthrough infections (i.e. infection in the context of previous vaccination) has important implications for vaccine policy. In this study, we investigated correlates of protection against Omicron BA.4/5 infections and anti-spike IgG antibody trajectories after a third/booster vaccination or breakthrough infection following second vaccination in 154,149 adults [≥]18y from the United Kingdom general population. We found that higher anti-spike IgG antibody levels were associated with increased protection against Omicron BA.4/5 infection and that breakthrough infections were associated with higher levels of protection at any given antibody level than booster vaccinations. Breakthrough infections generated similar antibody levels to third/booster vaccinations, and the subsequent declines in antibody levels were similar to or slightly slower than those after third/booster vaccinations. Taken together our findings show that breakthrough infection provides longer lasting protection against further infections than booster vaccinations. For example, considering antibody levels associated with 67% protection against infection, a third/booster vaccination did not provide long-lasting protection, while a Delta/Omicron BA.1 breakthrough infection could provide 5-10 months of protection against Omicron BA.4/5 reinfection. 50-60% of the vaccinated UK population with a breakthrough infection would still be protected by the end of 2022, compared to <15% of the triple-vaccinated UK population without previous infection. Although there are societal impacts and risks to some individuals associated with ongoing transmission, breakthrough infection could be an efficient immune-boosting mechanism for subgroups of the population, including younger healthy adults, who have low risks of adverse consequences from infection.

Performance of antigen lateral flow devices in the United Kingdom during the Alpha, Delta, and Omicron waves of the SARS-CoV-2 pandemic (preprint)

Background Antigen lateral flow devices (LFDs) have been widely used to control SARS-CoV-2. Changes in LFD sensitivity and detection of infectious individuals during the pandemic with successive variants, vaccination, and changes in LFD use are incompletely understood. Methods Paired LFD and PCR tests were collected from asymptomatic and symptomatic participants, across multiple settings in the UK between 04-November-2020 and 21-March-2022. Multivariable logistic regression was used to analyse LFD sensitivity and specificity, adjusting for viral load, LFD manufacturer, setting, age, sex, assistance, symptoms, vaccination, and variant. National contact tracing data were used to estimate the proportion of transmitting index cases (with [≥]1 PCR/LFD-positive contact) potentially detectable by LFDs over time, accounting for viral load, variant, and symptom status. Findings 4131/75,382 (5.5%) participants were PCR-positive. Sensitivity vs. PCR was 63.2% (95%CI 61.7-64.6%) and specificity 99.71% (99.66-99.74%). Increased viral load was independently associated with being LFD-positive. There was no evidence LFD sensitivity differed between Delta vs. Alpha/pre-Alpha infections, but Omicron infections were more likely to be LFD positive. Sensitivity was higher in symptomatic participants, 68.7% (66.9-70.4%) than in asymptomatic participants, 52.8% (50.1-55.4%). 79.4% (68.6-81.3%) of index cases resulting in probable onward transmission with were estimated to have been detectable using LFDs, this proportion was relatively stable over time/variants, but lower in asymptomatic vs. symptomatic cases. Interpretation LFDs remained able to detect most SARS-CoV-2 infections throughout vaccine roll-out and different variants. LFDs can potentially detect most infections that transmit to others and reduce risks. However, performance is lower in asymptomatic compared to symptomatic individuals. Funding UK Government.

Individual heterogeneity and airborne infection: Effect of non-uniform air distribution

The classical Wells–Riley equation assumes homogeneity of susceptible individuals and environments to airborne exposure. However, individual susceptibility to infection is mostly heterogeneous, and exposure variability could arise from differences in inhalation rate, spatiotemporal non-uniformity of infectious aerosol concentrations, and the exposure trajectory and time. Non-uniform air distribution results in spatial non-uniformity of infectious aerosol concentrations. The non-uniformity effect is essentially a problem of individual infection probability. Here, we derived a general dose-response equation and a heterogeneous Wells–Riley equation accounting for individual variability in infection probability. The heterogeneous Wells-Riley equation shows the potential of the zone air distribution effectiveness to consider spatial non-uniformity under steady-state conditions. An existing quanta generation rate formula was theoretically justified. The new equation was then applied to a restaurant reporting an outbreak of coronavirus disease 2019, with spatial and/or temporal heterogeneity of infectious aerosol concentrations. Our results show the need to include spatial non-uniformity in outbreak investigations. A hypothetical two-zone setup was used to demonstrate how the inter-zonal distribution of clean air and the inter-zonal exchange flow affect airborne infections. An infector in a poorly diluted zone with the greatest number of susceptible individuals would result in the most secondary infections, whereas an infector in a well-ventilated zone with few susceptible individuals would result in the least secondary infections.

Exposure and respiratory infection risk via the short-range airborne route.

Leading health authorities have suggested short-range airborne transmission as a major route of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). However, there is no simple method to assess the short-range airborne infection risk or identify its governing parameters. We proposed a short-range airborne infection risk assessment model based on the continuum model and two-stage jet model. The effects of ventilation, physical distance and activity intensity on the short-range airborne exposure were studied systematically. The results suggested that increasing physical distance and ventilation reduced short-range airborne exposure and infection risk. However, a diminishing return phenomenon was observed when the ventilation rate or physical distance was beyond a certain threshold. When the infectious quantum concentration was less than 1 quantum/L at the mouth, our newly defined threshold distance and threshold ventilation rate were independent of quantum concentration. We estimated threshold distances of 0.59, 1.1, 1.7 and 2.6 m for sedentary/passive, light, moderate and intense activities, respectively. At these distances, the threshold ventilation was estimated to be 8, 20, 43, and 83 L/s per person, respectively. The findings show that both physical distancing and adequate ventilation are essential for minimising infection risk, especially in high-intensity activity or densely populated spaces.

[Mahuang (herbaceous stem of Ephedra spp.): chemistry, pharmacodynamics, and pharmacokinetics].

The Chinese medicinal herb Mahuang is herbaceous stem of Ephedra sinica, E. intermedia, or E. equisetina(Family, Ephedraceae). In China, Mahuang has been used, all the way over a millennium, as a key component herb of many herbal medicines for management of epidemics of acute respiratory illness and is also used in officially recommended herbal medicines for COVID-19. Mahuang is the first-line medicinal herb for cold and wheezing and also an effective diuretic herb for edema. However, Mahuang can also exert significant adverse effects. The key to safety and effectiveness is rational and precise use of the herb. In this review article, we comprehensively summarize chemical composition of Mahuang and associated differences in pharmacognosy, pharmacodynamics and pharmacokinetics of Mahuang compounds, along with the adverse effects of Mahuang compounds and products. Based on full understanding of how Mahuang is used in Chinese traditional medicine, systematic research on Mahuang in line with contemporary standards of pharmaceutical sciences will facilitate promoting Chinese herbal medicines to become more efficient in management of epidemic illnesses, such as COVID-19. To this end, we recommend research on Mahuang of two aspects, i.e., pharmacological investigation for its multicompound-involved therapeutic effects and toxicological investigation for clinical manifestation of the adverse effects, chemicals responsible for the adverse effects, and conditions for safe use of the herb and the herb-containing medicines.

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.

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 and 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 Guidelines. 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 main medical center and the COVID-19 pandemic were 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.

Role of Neuroimmune Interactions in COVID-19-related Cardiovascular Damage.

Coronavirus disease 2019 (COVID-19) has caused a global pandemic impacting over 200 countries/regions and more than 200 million patients worldwide. Among the infected patients, there is a high prevalence of COVID-19-related cardiovascular injuries. However, the specific mechanisms linking cardiovascular damage and COVID-19 remain unclear. The COVID-19 pandemic also has exacerbated the mental health burden of humans. Considering the close association between neuroimmune interactions and cardiovascular disease, this review assessed the complex pathophysiological mechanisms connecting neuroimmune interactions and cardiovascular disease. It was revealed that the mental health burden might be a pivotal accomplice causing COVID-19-associated cardiovascular damage. Specifically, the proinflammatory status of patients with a terrible mood state is closely related to overdrive of the hypothalamus-pituitary-adrenal (HPA) axis, sympathovagal imbalance, and endothelial dysfunction, which lead to an increased risk of developing cardiovascular injury during COVID-19. Therefore, during the prevention and treatment of cardiovascular complications in COVID-19 patients, particular attention should be given to relieve the mental health burden of these patients.