Androgen receptor blockade promotes response to BRAF/MEK-targeted therapy.

Treatment with therapy targeting BRAF and MEK (BRAF/MEK) has revolutionized care in melanoma and other cancers; however, therapeutic resistance is common and innovative treatment strategies are needed1,2. Here we studied a group of patients with melanoma who were treated with neoadjuvant BRAF/MEK-targeted therapy ( NCT02231775 , n = 51) and observed significantly higher rates of major pathological response (MPR; ≤10% viable tumour at resection) and improved recurrence-free survival (RFS) in female versus male patients (MPR, 66% versus 14%, P = 0.001; RFS, 64% versus 32% at 2 years, P = 0.021). The findings were validated in several additional cohorts2-4 of patients with unresectable metastatic melanoma who were treated with BRAF- and/or MEK-targeted therapy (n = 664 patients in total), demonstrating improved progression-free survival and overall survival in female versus male patients in several of these studies. Studies in preclinical models demonstrated significantly impaired anti-tumour activity in male versus female mice after BRAF/MEK-targeted therapy (P = 0.006), with significantly higher expression of the androgen receptor in tumours of male and female BRAF/MEK-treated mice versus the control (P = 0.0006 and P = 0.0025). Pharmacological inhibition of androgen receptor signalling improved responses to BRAF/MEK-targeted therapy in male and female mice (P = 0.018 and P = 0.003), whereas induction of androgen receptor signalling (through testosterone administration) was associated with a significantly impaired response to BRAF/MEK-targeted therapy in male and female patients (P = 0.021 and P < 0.0001). Together, these results have important implications for therapy.

PKCε promotes oncogenic functions of ATF2 in the nucleus while blocking its apoptotic function at mitochondria.

The transcription factor ATF2 elicits oncogenic activities in melanoma and tumor suppressor activities in nonmalignant skin cancer. Here, we identify that ATF2 tumor suppressor function is determined by its ability to localize at the mitochondria, where it alters membrane permeability following genotoxic stress. The ability of ATF2 to reach the mitochondria is determined by PKCε, which directs ATF2 nuclear localization. Genotoxic stress attenuates PKCε effect on ATF2; enables ATF2 nuclear export and localization at the mitochondria, where it perturbs the HK1-VDAC1 complex; increases mitochondrial permeability; and promotes apoptosis. Significantly, high levels of PKCε, as seen in melanoma cells, block ATF2 nuclear export and function at the mitochondria, thereby attenuating apoptosis following exposure to genotoxic stress. In melanoma tumor samples, high PKCε levels associate with poor prognosis. Overall, our findings provide the framework for understanding how subcellular localization enables ATF2 oncogenic or tumor suppressor functions.

Pandemic fatigue impedes mitigation of COVID-19 in Hong Kong.

Hong Kong has implemented stringent public health and social measures (PHSMs) to curb each of the four COVID-19 epidemic waves since January 2020. The third wave between July and September 2020 was brought under control within 2 m, while the fourth wave starting from the end of October 2020 has taken longer to bring under control and lasted at least 5 mo. Here, we report the pandemic fatigue as one of the potential reasons for the reduced impact of PHSMs on transmission in the fourth wave. We contacted either 500 or 1,000 local residents through weekly random-digit dialing of landlines and mobile telephones from May 2020 to February 2021. We analyze the epidemiological impact of pandemic fatigue by using the large and detailed cross-sectional telephone surveys to quantify risk perception and self-reported protective behaviors and mathematical models to incorporate population protective behaviors. Our retrospective prediction suggests that an increase of 100 daily new reported cases would lead to 6.60% (95% CI: 4.03, 9.17) more people worrying about being infected, increase 3.77% (95% CI: 2.46, 5.09) more people to avoid social gatherings, and reduce the weekly mean reproduction number by 0.32 (95% CI: 0.20, 0.44). Accordingly, the fourth wave would have been 14% (95% CI%: -53%, 81%) smaller if not for pandemic fatigue. This indicates the important role of mitigating pandemic fatigue in maintaining population protective behaviors for controlling COVID-19.

Estimation of the Time-Varying Effective Reproductive Number of COVID-19 Based on Multivariate Time Series of Severe Health Outcomes.

The time-varying effective reproduction number (Rt at time t) measures the transmissibility of SARS-CoV-2 and is conventionally based on daily case counts, which may suffer from time-varying ascertainment. We analyzed Rt estimates from case counts and severe COVID-19 (intensive care unit admissions, severe or critical cases, and mortality) across 2022 in Hong Kong's fifth and sixth waves of infection. Within the fifth wave, the severe disease-based Rt (3.5) was significantly higher than the case-based Rt (2.4) but not in the sixth wave. During periods with fluctuating underreporting, data based on severe diseases may provide more reliable Rt estimates.

Circulating metabolomic markers linking diabetic kidney disease and incident cardiovascular disease in type 2 diabetes: analyses from the Hong Kong Diabetes Biobank.

AIMS/HYPOTHESIS: The aim of this study was to describe the metabolome in diabetic kidney disease (DKD) and its association with incident CVD in type 2 diabetes, and identify prognostic biomarkers. METHODS: From a prospective cohort of individuals with type 2 diabetes, baseline sera (N=1991) were quantified for 170 metabolites using NMR spectroscopy with median 5.2 years of follow-up. Associations of chronic kidney disease (CKD, eGFR<60 ml/min per 1.73 m2) or severely increased albuminuria with each metabolite were examined using linear regression, adjusted for confounders and multiplicity. Associations between DKD (CKD or severely increased albuminuria)-related metabolites and incident CVD were examined using Cox regressions. Metabolomic biomarkers were identified and assessed for CVD prediction and replicated in two independent cohorts. RESULTS: At false discovery rate (FDR)<0.05, 156 metabolites were associated with DKD (151 for CKD and 128 for severely increased albuminuria), including apolipoprotein B-containing lipoproteins, HDL, fatty acids, phenylalanine, tyrosine, albumin and glycoprotein acetyls. Over 5.2 years of follow-up, 75 metabolites were associated with incident CVD at FDR<0.05. A model comprising age, sex and three metabolites (albumin, triglycerides in large HDL and phospholipids in small LDL) performed comparably to conventional risk factors (C statistic 0.765 vs 0.762, p=0.893) and adding the three metabolites further improved CVD prediction (C statistic from 0.762 to 0.797, p=0.014) and improved discrimination and reclassification. The 3-metabolite score was validated in independent Chinese and Dutch cohorts. CONCLUSIONS/INTERPRETATION: Altered metabolomic signatures in DKD are associated with incident CVD and improve CVD risk stratification.

Comparison of Bivalent and Monovalent mRNA Vaccine Boosters.

In this cohort study conducted in Hong Kong where both bivalent and monovalent formulations of BNT162b2 were available, there were no significant differences in the mortality or hospitalization between those who received bivalent and monovalent mRNA as second boosters. Bivalent and monovalent mRNA boosters appear equally protective against clinical outcomes.

Effectiveness of Vaccines and Antiviral Drugs in Preventing Severe and Fatal COVID-19, Hong Kong.

We compared the effectiveness and interactions of molnupiravir and nirmatrelvir/ritonavir and 2 vaccines, CoronaVac and Comirnaty, in a large population of inpatients with COVID-19 in Hong Kong. Both the oral antiviral drugs and vaccines were associated with lower risks for all-cause mortality and progression to serious/critical/fatal conditions (study outcomes). No significant interaction effects were observed between the antiviral drugs and vaccinations; their joint effects were additive. If antiviral drugs were prescribed within 5 days of confirmed COVID-19 diagnosis, usage was associated with lower risks for the target outcomes for patients >60, but not <60, years of age; no significant clinical benefit was found if prescribed beyond 5 days. Among patients >80 years of age, 3-4 doses of Comirnaty vaccine were associated with significantly lower risks for target outcomes. Policies should encourage COVID-19 vaccination, and oral antivirals should be made accessible to infected persons within 5 days of confirmed diagnosis.

Public Health Impact of Paxlovid as Treatment for COVID-19, United States.

We evaluated the population-level benefits of expanding treatment with the antiviral drug Paxlovid (nirmatrelvir/ritonavir) in the United States for SARS-CoV-2 Omicron variant infections. Using a multiscale mathematical model, we found that treating 20% of symptomatic case-patients with Paxlovid over a period of 300 days beginning in January 2022 resulted in life and cost savings. In a low-transmission scenario (effective reproduction number of 1.2), this approach could avert 0.28 million (95% CI 0.03-0.59 million) hospitalizations and save US $56.95 billion (95% CI US $2.62-$122.63 billion). In a higher transmission scenario (effective reproduction number of 3), the benefits increase, potentially preventing 0.85 million (95% CI 0.36-1.38 million) hospitalizations and saving US $170.17 billion (95% CI US $60.49-$286.14 billion). Our findings suggest that timely and widespread use of Paxlovid could be an effective and economical approach to mitigate the effects of COVID-19.

A novel electronic health record-based, machine-learning model to predict severe hypoglycemia leading to hospitalizations in older adults with diabetes: A territory-wide cohort and modeling study.

BACKGROUND: Older adults with diabetes are at high risk of severe hypoglycemia (SH). Many machine-learning (ML) models predict short-term hypoglycemia are not specific for older adults and show poor precision-recall. We aimed to develop a multidimensional, electronic health record (EHR)-based ML model to predict one-year risk of SH requiring hospitalization in older adults with diabetes. METHODS AND FINDINGS: We adopted a case-control design for a retrospective territory-wide cohort of 1,456,618 records from 364,863 unique older adults (age ≥65 years) with diabetes and at least 1 Hong Kong Hospital Authority attendance from 2013 to 2018. We used 258 predictors including demographics, admissions, diagnoses, medications, and routine laboratory tests in a one-year period to predict SH events requiring hospitalization in the following 12 months. The cohort was randomly split into training, testing, and internal validation sets in a 7:2:1 ratio. Six ML algorithms were evaluated including logistic-regression, random forest, gradient boost machine, deep neural network (DNN), XGBoost, and Rulefit. We tested our model in a temporal validation cohort in the Hong Kong Diabetes Register with predictors defined in 2018 and outcome events defined in 2019. Predictive performance was assessed using area under the receiver operating characteristic curve (AUROC), area under the precision-recall curve (AUPRC) statistics, and positive predictive value (PPV). We identified 11,128 SH events requiring hospitalization during the observation periods. The XGBoost model yielded the best performance (AUROC = 0.978 [95% CI 0.972 to 0.984]; AUPRC = 0.670 [95% CI 0.652 to 0.688]; PPV = 0.721 [95% CI 0.703 to 0.739]). This was superior to an 11-variable conventional logistic-regression model comprised of age, sex, history of SH, hypertension, blood glucose, kidney function measurements, and use of oral glucose-lowering drugs (GLDs) (AUROC = 0.906; AUPRC = 0.085; PPV = 0.468). Top impactful predictors included non-use of lipid-regulating drugs, in-patient admission, urgent emergency triage, insulin use, and history of SH. External validation in the HKDR cohort yielded AUROC of 0.856 [95% CI 0.838 to 0.873]. Main limitations of this study included limited transportability of the model and lack of geographically independent validation. CONCLUSIONS: Our novel-ML model demonstrated good discrimination and high precision in predicting one-year risk of SH requiring hospitalization. This may be integrated into EHR decision support systems for preemptive intervention in older adults at highest risk.

1-year weight change after diabetes diagnosis and long-term incidence and sustainability of remission of type 2 diabetes in real-world settings in Hong Kong: An observational cohort study.

BACKGROUND: Clinical trials have demonstrated that remission of type 2 diabetes can be achieved following sustained weight loss. However, the feasibility of achieving diabetes remission through weight management in real-world settings remains unclear. In this study, we aimed to examine the association of weight change at 1 year after diabetes diagnosis with long-term incidence and sustainability of type 2 diabetes remission in real-world settings in Hong Kong. METHODS AND FINDINGS: This was a population-based observational cohort study. The territory-wide Risk Assessment and Management Programme for Diabetes Mellitus (RAMP-DM) provides regular comprehensive assessments of metabolic control and complication screening for people with diabetes in Hong Kong. We included 37,326 people with newly diagnosed type 2 diabetes who were enrolled in the RAMP-DM between 2000 and 2017, followed until 2019. Diabetes remission was defined as 2 consecutive HbA1c <6.5% measurements at least 6 months apart in the absence of glucose-lowering drugs (GLDs) and with no record of GLDs at least 3 months before these measurements. During a median follow-up of 7.9 years, 6.1% (2,279) of people achieved diabetes remission, with an incidence rate of 7.8 (95% CI: 7.5, 8.1) per 1,000 person-years. After adjusting for age at diabetes diagnosis, sex, assessment year, body mass index, other metabolic indices, smoking, alcohol drinking, and medication use, the hazard ratio (HR) for diabetes remission was 3.28 (95% CI: 2.75, 3.92; p < 0.001) for people with ≥10% weight loss within 1 year of diagnosis, 2.29 (95% CI: 2.03, 2.59; p < 0.001) for those with 5% to 9.9% weight loss, and 1.34 (95% CI: 1.22, 1.47; p < 0.001) for those with 0% to 4.9% weight loss compared to people with weight gain. During a median follow-up of 3.1 years, 67.2% (1,531) of people who had achieved diabetes remission returned to hyperglycaemia, with an incidence rate of 184.8 (95% CI: 175.5, 194.0) per 1,000 person-years. The adjusted HR for returning to hyperglycaemia was 0.52 (95% CI: 0.41, 0.65; p < 0.001) for people with ≥10% weight loss, 0.78 (95% CI: 0.68, 0.92; p = 0.002) for those with 5% to 9.9% weight loss, and 0.90 (95% CI: 0.80, 1.01; p = 0.073) for those with 0% to 4.9% weight loss compared to people with weight gain. Diabetes remission was associated with a 31% (HR: 0.69, 95% CI: 0.52, 0.93; p = 0.014) decreased risk of all-cause mortality. The main limitation of the study is that the reliability of HbA1c used to define diabetes remission can be affected by other medical conditions. Furthermore, we did not have data on bariatric surgery. CONCLUSIONS: In this study, greater weight loss within the first year of diabetes diagnosis was associated with an increased likelihood of achieving diabetes remission and a decreased risk of returning to hyperglycaemia among those who had achieved diabetes remission. However, both the incidence of diabetes remission and the probability of its long-term sustainability were low with conventional management in real-world settings, in an era when the importance of weight loss was not fully appreciated. Our study provides evidence for policymakers to design and implement early weight management interventions and diabetes remission initiatives.

Early treatment with dipeptidyl-peptidase 4 inhibitors reduces glycaemic variability and delays insulin initiation in type 2 diabetes: A propensity score-matched cohort study.

AIMS: To examine whether early treatment intensification using dipeptidyl-peptidase 4 inhibitors (DPP4i) delays insulin initiation in Chinese patients diagnosed with type 2 diabetes for less than 5 years. MATERIALS AND METHODS: In a territory-wide prospective cohort study, patients with type 2 diabetes initiating DPP4i at diabetes duration <2 years (early intensification) and 3-5 years (late intensification) were matched using 1:1 propensity-score matching (n = 908 in each arm). We used Cox regression to compare the risk of insulin initiation between the two groups. We explored the interactive and mediation effects of glycated haemoglobin (HbA1c) variability score (HVS), defined as the percentage of HbA1c varying by ≥0.5% compared with preceding values. RESULTS: Of 1816 patients (60.7% men, mean age 54.4 ± 11.9 years), 92.4% and 71.9% were treated with metformin and sulphonylureas respectively at DPP4i initiation. Early DPP4i intensification [hazard ratio (HR) 0.71, (95% CI 0.58-0.68)] and low HVS (<50%) (HR = 0.40, 0.33-0.50) were associated with delayed insulin initiation during a median 4.08 years of follow-up. Early intensification with low HVS had the lowest risk versus late intensification with high HVS (HR = 0.30, 0.22-0.40) (pinteraction  = 0.013). HVS mediated 19.5% of the total effect of early DPP4i intensification on delaying insulin initiation. The late and early intensification groups had similar HbA1c at month 0 (8.4 ± 1.3% vs. 8.4 ± 1.5%) and month 3 (7.6 ± 1.2% vs. 7.6 ± 1.3%) after DPP4i initiation. By month 12, HbA1c in the late intensification group deteriorated (7.9 ± 1.4%) but remained stable in the early intensification group (7.6 ± 1.4%, p = 0.001) with persistent between-group difference over 72 months (8.2 ± 1.7% vs. 7.7 ± 1.6%, p = 0.001). CONCLUSIONS: In type 2 diabetes, early DPP4i intensification delayed insulin initiation, partially explained by reduced glycaemic variability.

Monogenic diabetes in a Chinese population with young-onset diabetes: A 17-year prospective follow-up study in Hong Kong.

AIMS: Asians have a high prevalence of young-onset diabetes, but the pattern of monogenic diabetes is unknown. We aimed to determine the prevalence of monogenic diabetes in Chinese patients with young-onset diabetes and compare the clinical characteristics and outcome between patients with and without monogenic diabetes. MATERIALS AND METHODS: We sequenced a targeted panel of 33 genes related to monogenic diabetes in 1021 Chinese patients with non-type 1 diabetes diagnosed at age ≤40 years. Incident complications including cardiovascular disease (CVD), end-stage kidney disease (ESKD) and all-cause death were captured since enrolment (1995-2012) until 2019. RESULTS: In this cohort (mean ± SD age at diagnosis: 33.0 ± 6.0 years, median[IQR] diabetes duration 7.0[1.0-15.0] years at baseline, 44.9% men), 22(2.2%, 95% confidence interval[CI] 1.4%-3.2%) had monogenic diabetes. Pathogenic (P) or likely pathogenic (LP) variants were detected in GCK (n = 6), HNF1A (n = 9), HNF4A (n = 1), PLIN1 (n = 1) and PPARG (n = 2), together with copy number variations in HNF1B (n = 3). Over a median follow-up of 17.1 years, 5(22.7%) patients with monogenic diabetes (incidence rate 12.3[95% CI 5.1-29.4] per 1000 person-years) versus 254(25.4%) without monogenic diabetes (incidence rate 16.7[95% CI 14.8-18.9] per 1000 person-years) developed the composite outcome of CVD, ESKD and/or death (p = 0.490). The multivariable Cox model did not show any difference in hazards for composite events between groups. CONCLUSIONS: In Chinese with young-onset non-type 1 diabetes, at least 2% of cases were contributed by monogenic diabetes, over 80% of which were accounted for by P/LP variants in common MODY genes. The incidence of diabetes complications was similar between patients with and without monogenic diabetes.

Association of dipeptidyl peptidase-4 inhibitor initiation at glycated haemoglobin <7.5% with reduced major clinical events mediated by low glycated haemoglobin variability.

AIM: Therapeutic inertia, hypoglycaemia and poor treatment persistence can lead to glycaemic fluctuation and poor outcomes in type 2 diabetes (T2D). We compared glycated haemoglobin (HbA1c) variability, insulin initiation, severe hypoglycaemia and clinical events in patients with T2D initiated dipeptidyl peptidase-4 inhibitors (DPP4is) at low versus high HbA1c thresholds. METHODS: Using territory-wide electronic medical records in Hong Kong, we curated a propensity score-matched cohort of patients initiated DPP4i at HbA1c <7.5% versus ≥7.5% in 2007-2019. We expressed the HbA1c variability score (HVS) as a proportion of HbA1c varied by ≥0.5% compared with preceding values. We used the Cox model to compare the risks of insulin initiation and clinical outcomes, adjusted for time-varying variables between the two groups. Mediation analysis estimated the effects of HbA1c variability on outcomes. RESULTS: Among 6874 insulin-naïve patients who initiated DPP4i, 88.7% were treated with metformin and 79.6% with sulphonylureas at baseline (54.9% men; mean age 65.2 ± 11.4 years). After a median follow-up of 4.6 years, compared with the high-threshold plus high-HVS group (≥50%), the low-threshold plus low-HVS (<50%) group had reduced hazard ratios (95% confidence interval) of insulin initiation (0.35, 0.31-0.40), severe hypoglycaemia (0.38, 0.34-0.44), major adverse cardiovascular endpoints (0.76, 0.66-0.88), heart failure (0.42, 0.36-0.49), end-stage kidney disease (0.65, 0.36-0.49) and mortality (0.45, 0.35-0.57). Reduced HbA1c variability explained 31.1%-81.2% of the effect size of DPP4i initiation at HbA1c <7.5% versus ≥7.5% on outcomes. CONCLUSIONS: In Chinese patients with T2D, avoiding therapeutic inertia with intensified glycaemic control at HbA1c <7.5% using drugs with low risk of hypoglycaemia and good tolerability, such as DPP4i, delayed insulin treatment, reduced HbA1c variability and improved clinical events.

Decreased risk of non-influenza respiratory infection after influenza B virus infection in children.

Previous studies suggest that influenza virus infection may provide temporary non-specific immunity and hence lower the risk of non-influenza respiratory virus infection. In a randomized controlled trial of influenza vaccination, 1 330 children were followed-up in 2009-2011. Respiratory swabs were collected when they reported acute respiratory illness and tested against influenza and other respiratory viruses. We used Poisson regression to compare the incidence of non-influenza respiratory virus infection before and after influenza virus infection. Based on 52 children with influenza B virus infection, the incidence rate ratio (IRR) of non-influenza respiratory virus infection after influenza virus infection was 0.47 (95% confidence interval: 0.27-0.82) compared with before infection. Simulation suggested that this IRR was 0.87 if the temporary protection did not exist. We identified a decreased risk of non-influenza respiratory virus infection after influenza B virus infection in children. Further investigation is needed to determine if this decreased risk could be attributed to temporary non-specific immunity acquired from influenza virus infection.

Investigation of the Impact of Childhood Immune Imprinting on Birth Year-Specific Risk of Clinical Infection During Influenza A Virus Epidemics in Hong Kong.

Influenza imprinting reduces risks of influenza A virus clinical infection by 40%-90%, estimated from surveillance data in western countries. We analyzed surveillance data from 2010 to 2019 in Hong Kong. Based on the best model, which included hemagglutinin group-level imprinting, we estimated that individuals imprinted to H1N1 or H2N2 had a 17% (95% confidence interval [CI], 3%-28%) lower risk of H1N1 clinical infection, and individuals imprinted to H3N2 would have 12% (95% CI, -3% to 26%) lower risk of H3N2 clinical infection. These estimated imprinting protections were weaker than estimates in western countries. Identifying factors affecting imprinting protections is important for control policies and disease modeling.

Intrinsic and Effective Severity of Coronavirus Disease 2019 Cases Infected With the Ancestral Strain and Omicron BA.2 Variant in Hong Kong.

BACKGROUND: Understanding severity of infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants is crucial to inform public health measures. Here we used coronavirus disease 2019 (COVID-19) patient data from Hong Kong to characterize the severity profile of COVID-19. METHODS: Time-varying and age-specific effective severity measured by case hospitalization risk and hospitalization fatality risk was estimated with all individual COVID-19 case data collected in Hong Kong from 23 January 2020 through 26 October 2022 over 6 epidemic waves. The intrinsic severity of Omicron BA.2 was compared with the estimate for the ancestral strain with the data from unvaccinated patients without previous infections. RESULTS: With 32 222 COVID-19 hospitalizations and 9669 deaths confirmed over 6 epidemic waves, the time-varying hospitalization fatality risk dramatically increased from <10% before the largest fifth wave of Omicron BA.2 to 41% during the peak of the fifth wave when hospital resources were severely constrained. The age-specific fatality risk in unvaccinated hospitalized Omicron cases was comparable to the estimates for unvaccinated cases with the ancestral strain. During epidemics predominated by Omicron BA.2, fatality risk was highest among older unvaccinated patients. CONCLUSIONS: Omicron has comparable intrinsic severity to the ancestral Wuhan strain, although the effective severity is substantially lower in Omicron cases due to vaccination.

Residential Clustering of Coronavirus Disease 2019 Cases and Efficiency of Building-Wide Compulsory Testing Notices as a Transmission Control Measure in Hong Kong.

We described the frequency of residential case clusters and the efficiency of compulsory testing in identifying cases using buildings targeted in compulsory testing and locally infected coronavirus disease 2019 (COVID-19) cases matched by residence in Hong Kong. Most of the buildings (4246 of 7688, 55.2%) with COVID-19 cases identified had only 1 reported case, and 13% of the daily reported cases were detected through compulsory testing. Compulsory testing notices could be essential in attempting to eliminate infections ("zero COVID") and have an impact early in an epidemic, but they appear to be relatively inefficient in response to sustained community transmission.

Effects of School-Based Preventive Measures on COVID-19 Incidence, Hong Kong, 2022.

We show that school closures reduced COVID-19 incidence rates in children by 31%-46% in Hong Kong in 2022. After school reopening accompanied by mask mandates, daily rapid testing, and vaccination requirements, school-reported cases correlated with community incidence rates. Safe school reopening is possible when appropriate preventive measures are used.

Convergent dysbiosis of upper aerodigestive microbiota between patients with esophageal and oral cavity squamous cell carcinoma.

The bidirectional association between primary esophageal squamous cell carcinoma (ESCC) and oral cavity squamous cell carcinoma (OSCC) suggests common risk factors and oncogenic molecular processes but it is unclear whether these two cancers display similar patterns of dysbiosis in their upper aerodigestive microbiota (UADM). We conducted a case-control study to characterize the microbial communities in esophageal lavage samples from 49 ESCC patients and oral rinse samples from 91 OSCC patients using 16S rRNA V3-V4 amplicon sequencing. Compared with their respective non-SCC controls from the same anatomical sites, 32 and 45 discriminative bacterial genera were detected in ESCC and OSCC patients, respectively. Interestingly, 20 of them were commonly enriched or depleted in both types of cancer, suggesting a convergent niche adaptation of upper aerodigestive SCC-associated bacteria that may play important roles in the pathogenesis of malignancies. Notably, Fusobacterium, Selenomonas, Peptoanaerobacter and Peptostreptococcus were enriched in both ESCC and OSCC, whereas Streptococcus and Granulicatelia were commonly depleted. We further identified Fusobacterium nucleatum as the most abundant species enriched in the upper aerodigestive SCC microenvironment, and the higher relative abundances of Selenomonas danae and Treponema maroon were positively correlated with smoking. In addition, predicted functional analysis revealed several depleted (eg, lipoic acid and pyruvate metabolism) and enriched (eg, RNA polymerase and nucleotide excision repair) pathways common to both cancers. Our findings reveal a convergent dysbiosis in the UADM between patients with ESCC and OSCC, suggesting a shared niche adaptation of host-microbiota interactions in the pathogenesis of upper aerodigestive tract malignancies.