COVID-19 as a catalyst for reimagining cervical cancer prevention.

Cervical cancer has killed millions of women over the past decade. In 2019 the World Health Organization launched the Cervical Cancer Elimination Strategy, which included ambitious targets for vaccination, screening, and treatment. The COVID-19 pandemic disrupted progress on the strategy, but lessons learned during the pandemic - especially in vaccination, self-administered testing, and coordinated mobilization on a global scale - may help with efforts to achieve its targets. However, we must also learn from the failure of the COVID-19 response to include adequate representation of global voices. Efforts to eliminate cervical cancer will only succeed if those countries most affected are involved from the very start of planning. In this article we summarize innovations and highlight missed opportunities in the COVID response, and make recommendations to leverage the COVID experience to accelerate the elimination of cervical cancer globally.

Quantification of impact of COVID-19 pandemic on cancer screening programmes - a case study from Argentina, Bangladesh, Colombia, Morocco, Sri Lanka, and Thailand.

It is quite well documented that the COVID-19 pandemic disrupted cancer screening services in all countries, irrespective of their resources and healthcare settings. While quantitative estimates on reduction in volume of screening tests or diagnostic evaluation are readily available from the high-income countries, very little data are available from the low- and middle-income countries (LMICs). From the CanScreen5 global cancer screening data repository we identified six LMICs through purposive sampling based on the availability of cancer screening data at least for the years 2019 and 2020. These countries represented those in high human development index (HDI) categories (Argentina, Colombia, Sri Lanka, and Thailand) and medium HDI categories (Bangladesh and Morocco). No data were available from low HDI countries to perform similar analysis. The reduction in the volume of tests in 2020 compared to the previous year ranged from 14.1% in Bangladesh to 72.9% in Argentina (regional programme) for cervical screening, from 14.2% in Bangladesh to 49.4% in Morocco for breast cancer screening and 30.7% in Thailand for colorectal cancer screening. Number of colposcopies was reduced in 2020 compared to previous year by 88.9% in Argentina, 38.2% in Colombia, 27.4% in Bangladesh, and 52.2% in Morocco. The reduction in detection rates of CIN 2 or worse lesions ranged from 20.7% in Morocco to 45.4% in Argentina. Reduction of breast cancer detection by 19.1% was reported from Morocco. No association of the impact of pandemic could be seen with HDI categories. Quantifying the impact of service disruptions in screening and diagnostic tests will allow the programmes to strategize how to ramp up services to clear the backlogs in screening and more crucially in further evaluation of screen positives. The data can be used to estimate the impact on stage distribution and avoidable mortality from these common cancers.

Predictive performance of multi-model ensemble forecasts of COVID-19 across European nations.

Background: Short-term forecasts of infectious disease burden can contribute to situational awareness and aid capacity planning. Based on best practice in other fields and recent insights in infectious disease epidemiology, one can maximise the predictive performance of such forecasts if multiple models are combined into an ensemble. Here, we report on the performance of ensembles in predicting COVID-19 cases and deaths across Europe between 08 March 2021 and 07 March 2022. Methods: We used open-source tools to develop a public European COVID-19 Forecast Hub. We invited groups globally to contribute weekly forecasts for COVID-19 cases and deaths reported by a standardised source for 32 countries over the next 1-4 weeks. Teams submitted forecasts from March 2021 using standardised quantiles of the predictive distribution. Each week we created an ensemble forecast, where each predictive quantile was calculated as the equally-weighted average (initially the mean and then from 26th July the median) of all individual models' predictive quantiles. We measured the performance of each model using the relative Weighted Interval Score (WIS), comparing models' forecast accuracy relative to all other models. We retrospectively explored alternative methods for ensemble forecasts, including weighted averages based on models' past predictive performance. Results: Over 52 weeks, we collected forecasts from 48 unique models. We evaluated 29 models' forecast scores in comparison to the ensemble model. We found a weekly ensemble had a consistently strong performance across countries over time. Across all horizons and locations, the ensemble performed better on relative WIS than 83% of participating models' forecasts of incident cases (with a total N=886 predictions from 23 unique models), and 91% of participating models' forecasts of deaths (N=763 predictions from 20 models). Across a 1-4 week time horizon, ensemble performance declined with longer forecast periods when forecasting cases, but remained stable over 4 weeks for incident death forecasts. In every forecast across 32 countries, the ensemble outperformed most contributing models when forecasting either cases or deaths, frequently outperforming all of its individual component models. Among several choices of ensemble methods we found that the most influential and best choice was to use a median average of models instead of using the mean, regardless of methods of weighting component forecast models. Conclusions: Our results support the use of combining forecasts from individual models into an ensemble in order to improve predictive performance across epidemiological targets and populations during infectious disease epidemics. Our findings further suggest that median ensemble methods yield better predictive performance more than ones based on means. Our findings also highlight that forecast consumers should place more weight on incident death forecasts than incident case forecasts at forecast horizons greater than 2 weeks. Funding: AA, BH, BL, LWa, MMa, PP, SV funded by National Institutes of Health (NIH) Grant 1R01GM109718, NSF BIG DATA Grant IIS-1633028, NSF Grant No.: OAC-1916805, NSF Expeditions in Computing Grant CCF-1918656, CCF-1917819, NSF RAPID CNS-2028004, NSF RAPID OAC-2027541, US Centers for Disease Control and Prevention 75D30119C05935, a grant from Google, University of Virginia Strategic Investment Fund award number SIF160, Defense Threat Reduction Agency (DTRA) under Contract No. HDTRA1-19-D-0007, and respectively Virginia Dept of Health Grant VDH-21-501-0141, VDH-21-501-0143, VDH-21-501-0147, VDH-21-501-0145, VDH-21-501-0146, VDH-21-501-0142, VDH-21-501-0148. AF, AMa, GL funded by SMIGE - Modelli statistici inferenziali per governare l'epidemia, FISR 2020-Covid-19 I Fase, FISR2020IP-00156, Codice Progetto: PRJ-0695. AM, BK, FD, FR, JK, JN, JZ, KN, MG, MR, MS, RB funded by Ministry of Science and Higher Education of Poland with grant 28/WFSN/2021 to the University of Warsaw. BRe, CPe, JLAz funded by Ministerio de Sanidad/ISCIII. BT, PG funded by PERISCOPE European H2020 project, contract number 101016233. CP, DL, EA, MC, SA funded by European Commission - Directorate-General for Communications Networks, Content and Technology through the contract LC-01485746, and Ministerio de Ciencia, Innovacion y Universidades and FEDER, with the project PGC2018-095456-B-I00. DE., MGu funded by Spanish Ministry of Health / REACT-UE (FEDER). DO, GF, IMi, LC funded by Laboratory Directed Research and Development program of Los Alamos National Laboratory (LANL) under project number 20200700ER. DS, ELR, GG, NGR, NW, YW funded by National Institutes of General Medical Sciences (R35GM119582; the content is solely the responsibility of the authors and does not necessarily represent the official views of NIGMS or the National Institutes of Health). FB, FP funded by InPresa, Lombardy Region, Italy. HG, KS funded by European Centre for Disease Prevention and Control. IV funded by Agencia de Qualitat i Avaluacio Sanitaries de Catalunya (AQuAS) through contract 2021-021OE. JDe, SMo, VP funded by Netzwerk Universitatsmedizin (NUM) project egePan (01KX2021). JPB, SH, TH funded by Federal Ministry of Education and Research (BMBF; grant 05M18SIA). KH, MSc, YKh funded by Project SaxoCOV, funded by the German Free State of Saxony. Presentation of data, model results and simulations also funded by the NFDI4Health Task Force COVID-19 (https://www.nfdi4health.de/task-force-covid-19-2) within the framework of a DFG-project (LO-342/17-1). LP, VE funded by Mathematical and Statistical modelling project (MUNI/A/1615/2020), Online platform for real-time monitoring, analysis and management of epidemic situations (MUNI/11/02202001/2020); VE also supported by RECETOX research infrastructure (Ministry of Education, Youth and Sports of the Czech Republic: LM2018121), the CETOCOEN EXCELLENCE (CZ.02.1.01/0.0/0.0/17-043/0009632), RECETOX RI project (CZ.02.1.01/0.0/0.0/16-013/0001761). NIB funded by Health Protection Research Unit (grant code NIHR200908). SAb, SF funded by Wellcome Trust (210758/Z/18/Z).

Reducing societal impacts of SARS-CoV-2 interventions through subnational implementation.

To curb the initial spread of SARS-CoV-2, many countries relied on nation-wide implementation of non-pharmaceutical intervention measures, resulting in substantial socio-economic impacts. Potentially, subnational implementations might have had less of a societal impact, but comparable epidemiological impact. Here, using the first COVID-19 wave in the Netherlands as a case in point, we address this issue by developing a high-resolution analysis framework that uses a demographically stratified population and a spatially explicit, dynamic, individual contact-pattern based epidemiology, calibrated to hospital admissions data and mobility trends extracted from mobile phone signals and Google. We demonstrate how a subnational approach could achieve similar level of epidemiological control in terms of hospital admissions, while some parts of the country could stay open for a longer period. Our framework is exportable to other countries and settings, and may be used to develop policies on subnational approach as a better strategic choice for controlling future epidemics.

Study of efficacy and longevity of immune response to third and fourth doses of COVID-19 vaccines in patients with cancer: A single arm clinical trial.

Background: Cancer patients show increased morbidity with COVID-19 and need effective immunization strategies. Many healthcare regulatory agencies recommend administering 'booster' doses of COVID-19 vaccines beyond the standard two-dose series, for this group of patients. Therefore, studying the efficacy of these additional vaccine doses against SARS-CoV-2 and variants of concern is of utmost importance in this immunocompromised patient population. Methods: We conducted a prospective single arm clinical trial enrolling patients with cancer that had received two doses of mRNA or one dose of AD26.CoV2.S vaccine and administered a third dose of mRNA vaccine. We further enrolled patients that had no or low responses to three mRNA COVID vaccines and assessed the efficacy of a fourth dose of mRNA vaccine. Efficacy was assessed by changes in anti-spike antibody, T-cell activity, and neutralization activity, which were again assessed at baseline and 4 weeks. Results: We demonstrate that a third dose of COVID-19 vaccine leads to seroconversion in 57% of patients that were seronegative after primary vaccination series. The immune response is durable as assessed by anti-SARS-CoV-2 (anti-S) antibody titers, T-cell activity, and neutralization activity against wild-type (WT) SARS-CoV2 and BA1.1.529 at 6 months of follow-up. A subset of severely immunocompromised hematologic malignancy patients that were unable to mount an adequate immune response (titer <1000 AU/mL) after the third dose and were treated with a fourth dose in a prospective clinical trial which led to adequate immune boost in 67% of patients. Low baseline IgM levels and CD19 counts were associated with inadequate seroconversion. Booster doses induced limited neutralization activity against the Omicron variant. Conclusions: These results indicate that third dose of COVID vaccine induces durable immunity in cancer patients and an additional dose can further stimulate immunity in a subset of patients with inadequate response. Funding: Leukemia Lymphoma Society, National Cancer Institute. Clinical trial number: NCT05016622.

People with cancer have a higher risk of death or severe complications from COVID-19. As a result, vaccinating cancer patients against COVID-19 is critical. But patients with cancer, particularly blood or lymphatic system cancers, are less likely to develop protective immunity after COVID-19 vaccination. Immune suppression caused by cancer or cancer therapies may explain the poor vaccine response. Booster doses of the vaccine may improve the vaccine response in patients with cancer. But limited information is available about how well booster doses protect patients with cancer against COVID-19. Thakkar et al. show that a third dose of a COVID-19 vaccine can induce a protective immune response in half of the patients with cancer with no immunity after the first two doses. In the experiments, Thakkar et al. tracked the immune reaction to COVID-19 booster shots in 106 cancer patients. A third booster dose protected patients for up to four to six months and reduced breakthrough infection rates to low levels. Eighteen patients with blood cancers and severe immune suppression had an inadequate immune response after three doses of the vaccine; a fourth dose boosted the immune response for two-thirds of them, which for some included neutralization of variants such as Omicron. The experiments show that booster doses can increase COVID-19 vaccine protection for patients with cancer, even those who do not respond to the initial vaccine series. Thakkar et al. also show that pre-vaccine levels of two molecules linked to the immune system, (immunoglobin M and the CD19 antigen) predicted the patients' vaccine response, which might help physicians identify which individuals would benefit from booster doses.

The impact of the COVID-19 pandemic on Italian population-based cancer screening activities and test coverage: Results from national cross-sectional repeated surveys in 2020.

Background: In Italy, regions have the mandate to implement population-based screening programs for breast, cervical, and colorectal cancer. From March to May 2020, a severe lockdown was imposed due to the COVID-19 pandemic by the Italian Ministry of Health, with the suspension of screening programs. This paper describes the impact of the pandemic on Italian screening activities and test coverage in 2020 overall and by socioeconomic characteristics. Methods: The regional number of subjects invited and of screening tests performed in 2020 were compared with those in 2019. Invitation and examination coverage were also calculated. PASSI surveillance system, through telephone interviews, collects information about screening test uptake by test provider (public screening and private opportunistic). Test coverage and test uptake in the last year were computed by educational attainment, perceived economic difficulties, and citizenship. Results: A reduction of subjects invited and tests performed, with differences between periods and geographical macro areas, was observed in 2020 vs. 2019. The reduction in examination coverage was larger than that in invitation coverage for all screening programs. From the second half of 2020, the trend for test coverage showed a decrease in all the macro areas for all the screening programs. Compared with the pre-pandemic period, there was a greater difference according to the level of education in the odds of having had a test last year vs. never having been screened or not being up to date with screening tests. Conclusions: The lockdown and the ongoing COVID-19 emergency caused an important delay in screening activities. This increased the preexisting individual and geographical inequalities in access. The opportunistic screening did not mitigate the impact of the pandemic. Funding: This study was partially supported by Italian Ministry of Health - Ricerca Corrente Annual Program 2023 and by the Emilian Region DGR 839/22.

The SARS-CoV-2 accessory protein Orf3a is not an ion channel, but does interact with trafficking proteins.

The severe acute respiratory syndrome associated coronavirus 2 (SARS-CoV-2) and SARS-CoV-1 accessory protein Orf3a colocalizes with markers of the plasma membrane, endocytic pathway, and Golgi apparatus. Some reports have led to annotation of both Orf3a proteins as viroporins. Here, we show that neither SARS-CoV-2 nor SARS-CoV-1 Orf3a form functional ion conducting pores and that the conductances measured are common contaminants in overexpression and with high levels of protein in reconstitution studies. Cryo-EM structures of both SARS-CoV-2 and SARS-CoV-1 Orf3a display a narrow constriction and the presence of a positively charged aqueous vestibule, which would not favor cation permeation. We observe enrichment of the late endosomal marker Rab7 upon SARS-CoV-2 Orf3a overexpression, and co-immunoprecipitation with VPS39. Interestingly, SARS-CoV-1 Orf3a does not cause the same cellular phenotype as SARS-CoV-2 Orf3a and does not interact with VPS39. To explain this difference, we find that a divergent, unstructured loop of SARS-CoV-2 Orf3a facilitates its binding with VPS39, a HOPS complex tethering protein involved in late endosome and autophagosome fusion with lysosomes. We suggest that the added loop enhances SARS-CoV-2 Orf3a's ability to co-opt host cellular trafficking mechanisms for viral exit or host immune evasion.

Nationwide participation in FIT-based colorectal cancer screening in Denmark during the COVID-19 pandemic: An observational study.

Background: Worldwide, most colorectal cancer screening programmes were paused at the start of the COVID-19 pandemic, while the Danish faecal immunochemical test (FIT)-based programme continued without pausing. We examined colorectal cancer screening participation and compliance with subsequent colonoscopy in Denmark throughout the pandemic. Methods: We used data from the Danish Colorectal Cancer Screening Database among individuals aged 50-74 years old invited to participate in colorectal cancer screening from 2018 to 2021 combined with population-wide registries. Using a generalised linear model, we estimated prevalence ratios (PRs) and 95% confidence intervals (CIs) of colorectal cancer screening participation within 90 days since invitation and compliance with colonoscopy within 60 days since a positive FIT test during the pandemic in comparison with the previous years adjusting for age, month and year of invitation. Results: Altogether, 3,133,947 invitations were sent out to 1,928,725 individuals and there were 94,373 positive FIT tests (in 92,848 individuals) during the study period. Before the pandemic, 60.7% participated in screening within 90 days. A minor reduction in participation was observed at the start of the pandemic (PR = 0.95; 95% CI: 0.94-0.96 in pre-lockdown and PR = 0.85; 95% CI: 0.85-0.86 in first lockdown) corresponding to a participation rate of 54.9% during pre-lockdown and 53.0% during first lockdown. This was followed by a 5-10% increased participation in screening corresponding to a participation rate of up to 64.9%. The largest increase in participation was observed among 55-59 years old and among immigrants. The compliance with colonoscopy within 60 days was 89.9% before the pandemic. A slight reduction was observed during first lockdown (PR = 0.96; 95% CI: 0.93-0.98), where after it resumed to normal levels. Conclusions: Participation in the Danish FIT-based colorectal cancer screening programme and subsequent compliance to colonoscopy after a positive FIT result was only slightly affected by the COVID-19 pandemic. Funding: The study was funded by the Danish Cancer Society Scientific Committee (Grant number R321-A17417) and the Danish regions.

Participation in the nationwide cervical cancer screening programme in Denmark during the COVID-19 pandemic: An observational study.

Background: In contrast to most of the world, the cervical cancer screening programme continued in Denmark throughout the COVID-19 pandemic. We examined the cervical cancer screening participation during the pandemic in Denmark. Methods: We included all women aged 23-64 y old invited to participate in cervical cancer screening from 2015 to 2021 as registered in the Cervical Cancer Screening Database combined with population-wide registries. Using a generalised linear model, we estimated prevalence ratios (PRs) and 95% CIs of cervical cancer screening participation within 90, 180, and 365 d since invitation during the pandemic in comparison with the previous years adjusting for age, year, and month of invitation. Results: Altogether, 2,220,000 invited women (in 1,466,353 individuals) were included in the study. Before the pandemic, 36% of invited women participated in screening within 90 d, 54% participated within 180 d, and 65% participated within 365 d. At the start of the pandemic, participation in cervical cancer screening within 90 d was lower (pre-lockdown PR = 0.58; 95% CI: 0.56-0.59 and first lockdown PR = 0.76; 95% CI: 0.75-0.77) compared with the previous years. A reduction in participation within 180 d was also seen during pre-lockdown (PR = 0.89; 95% CI: 0.88-0.90) and first lockdown (PR = 0.92; 95% CI: 0.91-0.93). Allowing for 365 d to participation, only a slight reduction (3%) in participation was seen with slightly lower participation in some groups (immigrants, low education, and low income). Conclusions: The overall participation in cervical cancer screening was reduced during the early phase of the pandemic. However, the decline almost diminished with longer follow-up time. Funding: The study was funded by the Danish Cancer Society Scientific Committee (grant number R321-A17417) and the Danish regions.

Revealing druggable cryptic pockets in the Nsp1 of SARS-CoV-2 and other ß-coronaviruses by simulations and crystallography.

Non-structural protein 1 (Nsp1) is a main pathogenicity factor of α- and ß-coronaviruses. Nsp1 of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suppresses the host gene expression by sterically blocking 40S host ribosomal subunits and promoting host mRNA degradation. This mechanism leads to the downregulation of the translation-mediated innate immune response in host cells, ultimately mediating the observed immune evasion capabilities of SARS-CoV-2. Here, by combining extensive molecular dynamics simulations, fragment screening and crystallography, we reveal druggable pockets in Nsp1. Structural and computational solvent mapping analyses indicate the partial crypticity of these newly discovered and druggable binding sites. The results of fragment-based screening via X-ray crystallography confirm the druggability of the major pocket of Nsp1. Finally, we show how the targeting of this pocket could disrupt the Nsp1-mRNA complex and open a novel avenue to design new inhibitors for other Nsp1s present in homologous ß-coronaviruses.

Gastrointestinal helminths increase Bordetella bronchiseptica shedding and host variation in supershedding.

Co-infected hosts, individuals that carry more than one infectious agent at any one time, have been suggested to facilitate pathogen transmission, including the emergence of supershedding events. However, how the host immune response mediates the interactions between co-infecting pathogens and how these affect the dynamics of shedding remains largely unclear. We used laboratory experiments and a modeling approach to examine temporal changes in the shedding of the respiratory bacterium Bordetella bronchiseptica in rabbits with one or two gastrointestinal helminth species. Experimental data showed that rabbits co-infected with one or both helminths shed significantly more B. bronchiseptica, by direct contact with an agar petri dish, than rabbits with bacteria alone. Co-infected hosts generated supershedding events of higher intensity and more frequently than hosts with no helminths. To explain this variation in shedding an infection-immune model was developed and fitted to rabbits of each group. Simulations suggested that differences in the magnitude and duration of shedding could be explained by the effect of the two helminths on the relative contribution of neutrophils and specific IgA and IgG to B. bronchiseptica neutralization in the respiratory tract. However, the interactions between infection and immune response at the scale of analysis that we used could not capture the rapid variation in the intensity of shedding of every rabbit. We suggest that fast and local changes at the level of respiratory tissue probably played a more important role. This study indicates that co-infected hosts are important source of variation in shedding, and provides a quantitative explanation into the role of helminths to the dynamics of respiratory bacterial infections.

A model-based analysis of the health impacts of COVID-19 disruptions to primary cervical screening by time since last screen for current and future disruptions.

We evaluated how temporary disruptions to primary cervical cancer (CC) screening services may differentially impact women due to heterogeneity in their screening history and test modality. We used three CC models to project the short- and long-term health impacts assuming an underlying primary screening frequency (i.e., 1, 3, 5, or 10 yearly) under three alternative COVID-19-related screening disruption scenarios (i.e., 1-, 2-, or 5-year delay) versus no delay in the context of both cytology-based and human papillomavirus (HPV)-based screening. Models projected a relative increase in symptomatically detected cancer cases during a 1-year delay period that was 38% higher (Policy1-Cervix), 80% higher (Harvard), and 170% higher (MISCAN-Cervix) for underscreened women whose last cytology screen was 5 years prior to the disruption period compared with guidelines-compliant women (i.e., last screen 3 years prior to disruption). Over a woman's lifetime, temporary COVID-19-related delays had less impact on lifetime risk of developing CC than screening frequency and test modality; however, CC risks increased disproportionately the longer time had elapsed since a woman's last screen at the time of the disruption. Excess risks for a given delay period were generally lower for HPV-based screeners than for cytology-based screeners. Our independent models predicted that the main drivers of CC risk were screening frequency and screening modality, and the overall impact of disruptions from the pandemic on CC outcomes may be small. However, screening disruptions disproportionately affect underscreened women, underpinning the importance of reaching such women as a critical area of focus, regardless of temporary disruptions.

COVID-19 pandemic dynamics in South Africa and epidemiological characteristics of three variants of concern (Beta, Delta, and Omicron).

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) have been key drivers of new coronavirus disease 2019 (COVID-19) pandemic waves. To better understand variant epidemiologic characteristics, here we apply a model-inference system to reconstruct SARS-CoV-2 transmission dynamics in South Africa, a country that has experienced three VOC pandemic waves (i.e. Beta, Delta, and Omicron BA.1) by February 2022. We estimate key epidemiologic quantities in each of the nine South African provinces during March 2020 to February 2022, while accounting for changing detection rates, infection seasonality, nonpharmaceutical interventions, and vaccination. Model validation shows that estimated underlying infection rates and key parameters (e.g. infection-detection rate and infection-fatality risk) are in line with independent epidemiological data and investigations. In addition, retrospective predictions capture pandemic trajectories beyond the model training period. These detailed, validated model-inference estimates thus enable quantification of both the immune erosion potential and transmissibility of three major SARS-CoV-2 VOCs, that is, Beta, Delta, and Omicron BA.1. These findings help elucidate changing COVID-19 dynamics and inform future public health planning.

Mental health in medical and biomedical doctoral students during the 2020 COVID-19 pandemic and racial protests.

Concerns about the mental health of students, trainees and staff at universities and medical schools have been growing for many years. Recently, these have been exacerbated by the COVID-19 pandemic and a period of heightened reckoning and protests about systemic racism in the United States in 2020. To better understand the mental health of medical students and biomedical doctoral students at the University of North Carolina at Chapel Hill during this challenging period, we performed a cross-sectional study (n=957) using institutional annual survey data on measures of depression, anxiety, hazardous alcohol use, problems related to substance use, and suicidal ideation. These data were collected in 2019 and 2020, and were analyzed by type of training program, race/ethnicity, gender, sexual orientation, and survey year. Results indicated significant differences for rates of depression, anxiety, and suicidal ideation, with biomedical doctoral students showing greater incidence than medical students, and historically excluded students (e.g., people of color, women, LGBQ+ trainees) showing greater incidence compared to their peers. Of note, mental health remained poor for biomedical doctoral students in 2020 and declined for those belonging to historically excluded populations. The high rates of depression, anxiety, and suicidal ideation reported suggest that training environments need to be improved and support for mental health increased.

Surveying the experience of postdocs in the United States before and during the COVID-19 pandemic.

In the interest of advocating for the postdoctoral community in the United States (US), we compared the results of surveys of postdocs carried out in 2019 and in late 2020. We found that respondents' mental health and wellness were significantly impacted by the pandemic irrespective of their gender, race, citizenship, or other identities. Career trajectories and progression were also affected, as respondents reported being less confident about achieving career goals, and having more negative perceptions of the job market compared to before the pandemic. Postdocs working in the US on temporary visas reported experiencing increased stress levels due to changes in immigration policy. Access to institutional Postdoctoral Offices or Associations positively impacted well-being and helped mitigate some of the personal and professional stresses caused by the pandemic.

Adding a One Health approach to a research framework for minority health and health disparities.

The National Institute on Minority Health and Health Disparities (NIMHD) has developed a framework to guide and orient research into health disparities and minority health. The framework depicts different domains of influence (such as biological and behavioral) and different levels of influence (such as individual and interpersonal). Here, influenced by the "One Health" approach, we propose adding two new levels of influence - interspecies and planetary - to this framework to reflect the interconnected nature of human, animal, and environmental health. Extending the framework in this way will help researchers to create new avenues of inquiry and encourage multidisciplinary collaborations. We then use the One Health approach to discuss how the COVID-19 pandemic has exacerbated health disparities, and show how the expanded framework can be applied to research into health disparities related to antimicrobial resistance and obesity.

Author-level data confirm the widening gender gap in publishing rates during COVID-19.

Publications are essential for a successful academic career, and there is evidence that the COVID-19 pandemic has amplified existing gender disparities in the publishing process. We used longitudinal publication data on 431,207 authors in four disciplines - basic medicine, biology, chemistry and clinical medicine - to quantify the differential impact of COVID-19 on the annual publishing rates of men and women. In a difference-in-differences analysis, we estimated that the average gender difference in publication productivity increased from -0.26 in 2019 to -0.35 in 2020; this corresponds to the output of women being 17% lower than the output of men in 2109, and 24% lower in 2020. An age-group comparison showed a widening gender gap for both early-career and mid-career scientists. The increasing gender gap was most pronounced among highly productive authors and in biology and clinical medicine. Our study demonstrates the importance of reinforcing institutional commitments to diversity through policies that support the inclusion and retention of women in research.

Building a community to engineer synthetic cells and organelles from the bottom-up.

Employing concepts from physics, chemistry and bioengineering, 'learning-by-building' approaches are becoming increasingly popular in the life sciences, especially with researchers who are attempting to engineer cellular life from scratch. The SynCell2020/21 conference brought together researchers from different disciplines to highlight progress in this field, including areas where synthetic cells are having socioeconomic and technological impact. Conference participants also identified the challenges involved in designing, manipulating and creating synthetic cells with hierarchical organization and function. A key conclusion is the need to build an international and interdisciplinary research community through enhanced communication, resource-sharing, and educational initiatives.

Data mining methodology for response to hypertension symptomology-application to COVID-19-related pharmacovigilance.

Background: Potential therapy and confounding factors including typical co-administered medications, patient's disease states, disease prevalence, patient demographics, medical histories, and reasons for prescribing a drug often are incomplete, conflicting, missing, or uncharacterized in spontaneous adverse drug event (ADE) reporting systems. These missing or incomplete features can affect and limit the application of quantitative methods in pharmacovigilance for meta-analyses of data during randomized clinical trials. Methods: Data from patients with hypertension were retrieved and integrated from the FDA Adverse Event Reporting System; 134 antihypertensive drugs out of 1131 drugs were filtered and then evaluated using the empirical Bayes geometric mean (EBGM) of the posterior distribution to build ADE-drug profiles with an emphasis on the pulmonary ADEs. Afterward, the graphical least absolute shrinkage and selection operator (GLASSO) captured drug associations based on pulmonary ADEs by correcting hidden factors and confounder misclassification. Selected drugs were then compared using the Friedman test in drug classes and clusters obtained from GLASSO. Results: Following multiple filtering stages to exclude insignificant and noise-driven reports, we found that drugs from antihypertensives agents, urologicals, and antithrombotic agents (macitentan, bosentan, epoprostenol, selexipag, sildenafil, tadalafil, and beraprost) form a similar class with a significantly higher incidence of pulmonary ADEs. Macitentan and bosentan were associated with 64% and 56% of pulmonary ADEs, respectively. Because these two medications are prescribed in diseases affecting pulmonary function and may be likely to emerge among the highest reported pulmonary ADEs, in fact, they serve to validate the methods utilized here. Conversely, doxazosin and rilmenidine were found to have the least pulmonary ADEs in selected drugs from hypertension patients. Nifedipine and candesartan were also found by signal detection methods to form a drug cluster, shown by several studies an effective combination of these drugs on lowering blood pressure and appeared an improved side effect profile in comparison with single-agent monotherapy. Conclusions: We consider pulmonary ADE profiles in multiple long-standing groups of therapeutics including antihypertensive agents, antithrombotic agents, beta-blocking agents, calcium channel blockers, or agents acting on the renin-angiotensin system, in patients with hypertension associated with high risk for coronavirus disease 2019 (COVID-19). We found that several individual drugs have significant differences between their drug classes and compared to other drug classes. For instance, macitentan and bosentan from endothelin receptor antagonists show major concern while doxazosin and rilmenidine exhibited the least pulmonary ADEs compared to the outcomes of other drugs. Using techniques in this study, we assessed and confirmed the hypothesis that drugs from the same drug class could have very different pulmonary ADE profiles affecting outcomes in acute respiratory illness. Funding: GJW and MJD accepted funding from BioNexus KC for funding on this project, but BioNexus KC had no direct role in this article.

Social contact patterns and implications for infectious disease transmission - a systematic review and meta-analysis of contact surveys.

Background: Transmission of respiratory pathogens such as SARS-CoV-2 depends on patterns of contact and mixing across populations. Understanding this is crucial to predict pathogen spread and the effectiveness of control efforts. Most analyses of contact patterns to date have focused on high-income settings. Methods: Here, we conduct a systematic review and individual-participant meta-analysis of surveys carried out in low- and middle-income countries and compare patterns of contact in these settings to surveys previously carried out in high-income countries. Using individual-level data from 28,503 participants and 413,069 contacts across 27 surveys, we explored how contact characteristics (number, location, duration, and whether physical) vary across income settings. Results: Contact rates declined with age in high- and upper-middle-income settings, but not in low-income settings, where adults aged 65+ made similar numbers of contacts as younger individuals and mixed with all age groups. Across all settings, increasing household size was a key determinant of contact frequency and characteristics, with low-income settings characterised by the largest, most intergenerational households. A higher proportion of contacts were made at home in low-income settings, and work/school contacts were more frequent in high-income strata. We also observed contrasting effects of gender across income strata on the frequency, duration, and type of contacts individuals made. Conclusions: These differences in contact patterns between settings have material consequences for both spread of respiratory pathogens and the effectiveness of different non-pharmaceutical interventions. Funding: This work is primarily being funded by joint Centre funding from the UK Medical Research Council and DFID (MR/R015600/1).

Infectious diseases, particularly those caused by airborne pathogens like SARS-CoV-2, spread by social contact, and understanding how people mix is critical in controlling outbreaks. To explore these patterns, researchers typically carry out large contact surveys. Participants are asked for personal information (such as gender, age and occupation), as well as details of recent social contacts, usually those that happened in the last 24 hours. This information includes, the age and gender of the contact, where the interaction happened, how long it lasted, and whether it involved physical touch. These kinds of surveys help scientists to predict how infectious diseases might spread. But there is a problem: most of the data come from high-income countries, and there is evidence to suggest that social contact patterns differ between places. Therefore, data from these countries might not be useful for predicting how infections spread in lower-income regions. Here, Mousa et al. have collected and combined data from 27 contact surveys carried out before the COVID-19 pandemic to see how baseline social interactions vary between high- and lower-income settings. The comparison revealed that, in higher-income countries, the number of daily contacts people made decreased with age. But, in lower-income countries, younger and older individuals made similar numbers of contacts and mixed with all age groups. In higher-income countries, more contacts happened at work or school, while in low-income settings, more interactions happened at home and people were also more likely to live in larger, intergenerational households. Mousa et al. also found that gender affected how long contacts lasted and whether they involved physical contact, both of which are key risk factors for transmitting airborne pathogens. These findings can help researchers to predict how infectious diseases might spread in different settings. They can also be used to assess how effective non-medical restrictions, like shielding of the elderly and workplace closures, will be at reducing transmissions in different parts of the world.