Molecular and pro-inflammatory aspects of COVID-19: The impact on cardiometabolic health

Obesity, type 2 diabetes (T2DM), hypertension (HTN), and Cardiovascular Disease (CVD) often cluster together as “Cardiometabolic Disease” (CMD). Just under 50% of patients with CMD increased the risk of morbidity and mortality right from the beginning of the COVID-19 pandemic as it has been reported in most countries affected by the SARS-CoV2 virus.One of the pathophysiological hallmarks of COVID-19 is the overactivation of the immune system with a prominent IL-6 response, resulting in severe and systemic damage involving also cytokines such as IL2, IL4, IL8, IL10, and interferon-gamma were considered strong predictors of COVID-19 severity. Thus, in this mini-review, we try to describe the inflammatory state, the alteration of the adipokine profile, and cytokine production in the obese state of infected and not infected patients by SARS-CoV2 with the final aim to find possible influences of COVID-19 on CMD and CVD.The immunological-based discussion of the molecular processes could inspire the study of promising targets for managing CMD patients and its complications during COVID-19.     

Achieving global equity for COVID-19 vaccines: Stronger international partnerships and greater advocacy and solidarity are needed

Peter Figueroa and co-authors advocate for equity in the worldwide provision of COVID-19 vaccines.

Many may not be aware of the full extent of global inequity in the rollout of Coronavirus Disease 2019 (COVID-19) vaccines in response to the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) pandemic. As of June 20, 2021, only 0.9% of those living in low-income countries and less than 10% of those in low- and middle-income countries (LMICs) had received at least 1 dose of a COVID-19 vaccine compared with 43% of the population living in high-income countries (HICs) [1] (Fig 1). Only 2.4% of the population of Africa had been vaccinated compared with 41% of North America and 38% of Europe [1,2] (S1 Fig). Primarily due to the inability to access COVID-19 vaccines, less than 10% of the population in as many as 85 LMICs had been vaccinated compared with over 60% of the population in 26 HICs [1]. Only 10 countries account for more than 75% of all COVID-19 vaccines administered [3]. This striking and ongoing inequity has occurred despite the explicit ethical principles affirming equity of access to COVID-19 vaccines articulated in WHO SAGE values framework [4,5] prepared in mid-2020, well prior to the availability of COVID-19 vaccines.Open in a separate windowFig 1Proportion of people vaccinated with at least 1 dose of COVID-19 vaccine by income (April 14 to June 23, 2021).Note: Data on China appeared on the database on June 9, hence the jump in upper middle-income countries. COVID-19, Coronavirus Disease 2019. Source: https://ourworldindata.org/covid-vaccinations.The COVID-19 pandemic highlights the grave inequity and inadequacy of the global preparedness and response to serious emerging infections. The establishment of the Coalition for Epidemic Preparedness Innovations (CEPI) in 2018, the Access to COVID-19 Tools Accelerator (ACT-A), and the COVID-19 Vaccines Global Access (COVAX) Facility in April 2020 and the rapid development of COVID-19 vaccines were all positive and extraordinary developments [6]. The COVAX Facility, as of June 2021, has delivered approximately 83 million vaccine doses to 75 countries, representing approximately 4% of the global supply, and one-fifth of this was for HICs [7]. The COVAX Facility has been challenged to meet its supply commitments to LMICs due to insufficient access to doses of COVID-19 vaccines with the prerequisite WHO emergency use listing (EUL) or, under exceptional circumstances, product approval by a stringent regulatory authority (SRA) [8,9]. Because of the anticipated insufficient COVID-19 vaccine supply through the COVAX Facility, the majority of nonvaccine-producing LMIC countries made the decision, early in the COVID-19 pandemic, to secure and use vaccines produced in China or Russia prior to receipt of WHO EUL or SRA approval. Most of the vaccines used in LMICs as of June 20, 2021 (nearly 1.5 billion doses of the 2.6 billion doses administered) were neither WHO EUL or SRA approved at the time they were given [10]. This may raise possible concerns with respect to the effectiveness, safety, and acceptability of individual vaccines used by many countries [8,9].     

COVID-19 and global equity for health: The good,the bad,and the wicked

Elvin Geng and co-authors discuss monitoring and achieving equity in provision of vaccines for COVID-19.

Many problems underscored by the Coronavirus Disease 2019 (COVID-19) pandemic, and highlighted in other papers in this collection [1], center on addressing the grossly unequal availability of vaccine around the world. The problem of equity in the public health response fits Rittel and Webber’s conceptualization of “wicked problems” [2] that describe complex issues that defy conventional scientific analyses. Wicked problems have many characteristics, but three stand out when contemplating an equitable response to the COVID-19 pandemic. First, wicked problems have no definitive problem statement because understanding the problem is the crux of the problem itself. Is an equitable response to COVID-19 the problem, or is inequity in vaccines a symptom of larger inequity in health, economic, and societal systems? And is the problem equity in distribution, or is the root problem scarcity due to unfair trade arrangements? Second, in wicked problems, the elusive problem formulation precludes a shared understanding of success, or even progress, by stakeholders. What would constitute an acceptably equitable response? How would we measure progress without a unified direction? Third, in wicked problems, the absence of a shared agenda (and measures of progress) undermines aligned and effective action. Without true consensus that a fair allocation of vaccines across countries is based on population size instead of disease burden (as proposed by COVAX), targets based on progress toward such a distribution would lack real commitment from global stakeholders. The answers are as critical as they are elusive, not only for how the COVID-19 pandemic evolves, but also for whether we learn from it to better navigate future threats.COVID-19 is not the first wicked problem evident in global public health, however, and the recent past may offer some lessons. Three decades ago, HIV presented an urgent, complex, dynamic, and wicked threat to health around the world in which global inequities were stark and unacceptable. In 2004, 39 million people were living with HIV, 4.9 million new infections occurred, and 3.1 million died of HIV (comparable to the approximately 3.1 million COVID-19 deaths by April 16, 2021) in that year, the vast majority of new infections (>95%) and deaths (>95%) occurred in lower and middle-income countries. At the time, lifesaving antiretroviral therapy was available only in high-income countries, where it was expensive, delivered by highly trained specialists, and accompanied by sophisticated monitoring requirements (e.g., quantitative HIV plasma RNA levels and genotypical analysis). Naysayers warned that providing treatment throughout the world to close these major gaps would lead to “antiretroviral anarchy” and widespread drug resistance. To make progress against HIV, and increase equitability around the world, the world faced many of the same problems that we face today. Was the crux of problem access to antiretrovirals or to medications more generally? Should the priority be on treatment or prevention? Was this a public health problem at all or actually one of poverty and extractive economic systems? Three decades later, HIV treatment is widely available around the world, mostly free of charge, delivered by a robust healthcare workforce, based on stable global financing, and supported by the highest levels of global governance. With all the flaws of the response, from the vantage point of the present, it is clear that progress and greater equity in the response to the HIV epidemic have occurred.In the HIV response, this progress toward a global response was anchored by advocates and activists who successfully put HIV at the center of political agenda and crafted a globally shared commitment to offer treatment to every person living with HIV anywhere in the world in need [3,4]. This shared formulation of the problem (and therefore shared goals) was a critical first step in the global HIV treatment response. Even though the objective to treat all who needed treatment is crystal clear in retrospect, it was one of many competing perspectives. A few advocated a larger scope (i.e., global progress on a wider range of health conditions), while many championed smaller and “more feasible” objectives, (i.e., emphasizing prevention only without treatment). Yet, the goal to treat every person was ultimately adopted by governments, civil society, and the global agencies and therefore carried legitimacy and force. The Joint United Nations Programme on HIV/AIDS (UNAIDS) was established in 1994 through a UN resolution approved by all 193 member states to provide coordinated and aligned actions on HIV at the highest levels. The Global Fund for HIV, TB, and Malaria was created in 2002 to raise, manage, and disburse billions in funding for these priority pandemics. The first Global AIDS Coordinator to oversee the US government’s investment of billions of dollars to address HIV in 2006 reported directly to the US President, elevating the visibility and prioritization of the HIV response where it was most severe.This shared agenda to treat all in need was accompanied by the emergence of a remarkable visual heuristic that provided a shared roadmap for progress:—HIV treatment cascade—a simple and immediately accessible representation of the fraction of individuals living with HIV who are diagnosed, linked to care, started on treatment, retained, and virally suppressed. While subject to a range of criticisms (e.g., the cascade does not represent time, real journeys are cyclical), the heuristic rapidly became a universal mental model of the implementation needs for success in the global treatment response for HIV. Today, this framing is shared by virtually all health officials, healthcare workers, implementers, policy makers, and even elected officials addressing HIV anywhere in the world [5]. The shared understanding of the public health approach allowed a remarkable fluency (or 95-95-95 in some places) of action and alignment of goals across the public health environment [6,7]. Comparisons of the cascade in different regions has also sharpened the focus on equity when large differences are apparent.Finally, the HIV response has used the cascade framework to define clear targets and extract commitments from elected leaders to meet those targets, thereby enabling measurable progress. The overarching UNAIDS strategy for HIV treatment, called “90–90–90," refers to targets in this cascade—that 90% of individuals living with HIV are diagnosed, 90% of diagnosed are on treatment, and 90% of those on treatment are suppressed. Today, virtually every country, state, county, and public health jurisdiction in the world is expected to know how much progress is being made toward 90–90–90 in their own jurisdictions. The International Association of Physicians in AIDS Care’s Fast-Track Cities initiative is one of a number of global policy initiatives based explicitly on obtaining commitments from political leaders and elected officials to meet 90–90–90 cascade targets [8]. The initiative has enrolled over 350 cities around the world—with the mayors of London, Paris, and other cosmopolitan cities all vocal advocates of 90–90–90. Because the cascade is reported, progress toward 90–90–90 can be widely assessed, creating some basis for accountability.Each of these 3 steps have implications for progress against the problem of an equitable global COVID-19 response. At present, the working global targets for distribution of vaccine have been put forth by COVAX, an alliance between GAVI, Coalition for Epidemic Preparedness, and WHO. COVAX seeks to allocate vaccine to cover 20% of the population in all countries. Yet, is a 20% floor targeting success or capitulating to failure? Is its distribution schema based on population fair, or, as proposed by others, should it be based on COVID-19 disease burden [9]? In order to answer these, and many other critical questions of shared global significance, the issue of equity must take center stage in the global policy making conversation at the highest levels. Ottersen and colleagues observed that “conflicts in interests and power asymmetries” between transnational actors on health (e.g., governments, corporations, and civil society) demand institutions to negotiate, articulate, and advocate for collective interests [10]. While the institutional arrangements may take various forms, a high-level UN meeting to establish a common agenda for equity in the global COVID-19 response attended by all 193 member states—as has been done before for HIV, TB, noncommunicable diseases, and antimicrobial resistance—is a minimum step.Like the HIV cascade, consensus for a more equitable COVID-19 response must be accompanied by meaningful, interpretable, publicly facing, and credible metrics that explicitly depict equity [11]. Many candidate metrics for that exist, but more work needs to be done to identify a consensus-based set. For example, the Lorenz curve, which has long been used in economics, could be used to depict the distribution of vaccine globally; as depicted in Fig 1, the Gini index has changed little over time, indicating sluggish, if any, progress toward equitable vaccine distribution. Other candidate metrics include adaptations of the Gini coefficient and/or the Palma ratio (the ratio of the richest 10% of the countries share of vaccines to the poorest 40%’s share). Measures based on Atkinson index could be promising because they would weight changes among those with less as compared to changes among those with relatively more [12]. Such shared mental models of the roadmap, in turn, can be used to demand concrete commitments from global agencies, national governments, and other actors, including from industry.Open in a separate windowFig 1Lorenz curve and Gini coefficient as examples of potential metrics explicitly depicting equity of global distribution of COVID-19 vaccine.COVID-19, Coronavirus Disease 2019; GDP, gross domestic product.Sometimes, change occurs quickly during windows when the right problems, politics, and policy converge [13]—the COVID-19 pandemic presents a critical threat but also potentially a window to catalyze international collective action that can shape the post-COVID-19 landscape and ensure that global responses to future health threats are more equitable and effective. The barriers to using these steps to achieve greater equity in the global response to COVID-19 are myriad: Not all influential actors globally prioritize equity; agreement on metrics may be elusive; low-quality data behind metrics can mislead; and mechanisms for social accountability often fail [14]. Yet, the alternative is more daunting—the absence of a conversation, metrics, and mechanisms for global equity that is commensurate with its unequivocal place at center of global stage will set a dire path for the future. Not everything in the HIV response has gone well—indeed, opportunities for progress have been missed—but the response demonstrates that wicked problems are not completely intractable, but only if we are committed enough to change them.     

The changing health impact of vaccines in the COVID-19 pandemic: A modeling study

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Education and COVID-19 excess mortality

We study the role of education during the COVID-19 epidemic in Italy. We compare excess mortality in 2020 and 2021 compared to the pre-pandemic mortality between municipalities with different shares of educated residents. We find that education initially played a strong protective role, which however quickly faded out. After pondering several alternative explanations, we tentatively interpret this finding as the outcome of the interplay between education, information and public health communication, whose availability and coherence varied along the epidemic.     

Addressing power asymmetries in global health: Imperatives in the wake of the COVID-19 pandemic

Seye Abimbola and co-authors argue for a transformation in global health research and practice in the post-COVID-19 world.

Summary points

• The Coronavirus Disease 2019 (COVID-19) pandemic, the Black Lives Matter and Women in Global Health movements, and ongoing calls to decolonise global health have all created space for uncomfortable but important conversations that reveal serious asymmetries of power and privilege that permeate all aspects of global health.
• In this article, we, a diverse, gender-balanced group of public (global) health researchers and practitioners (most currently living in the so-called global South), outline what we see as imperatives for change in a post-pandemic world.
• At the individual level (including and especially ourselves), we emphasise the need to emancipate and decolonise our own minds (from the colonial conditionings of our education), straddle and use our privilege responsibly (to empower others and avoid elite capture), and build “Southern” networks (to affirm our ownership of global health).
• At the organisational level, we call for global health organisations to practice real diversity and inclusion (in ways that go beyond the cosmetic), to localise their funding decisions (with people on the ground in the driving seat), and to progressively self-decentralise (and so, divest themselves of financial, epistemic, and political power).
• And at both the individual and organisational level, we emphasise the need to hold ourselves, our governments, and global health organisations accountable to these goals, and especially for governance structures and processes that reflect a commitment to real change.
• By putting a spotlight on coloniality and existing inequalities, the COVID-19 pandemic inspires calls for a more equitable world and for a decolonised and decentralised approach to global health research and practice, one that moves beyond tokenistic box ticking about diversity and inclusion into real and accountable commitments to transformative change.

     

Universal healthcare coverage and health service delivery before and during the COVID-19 pandemic: A difference-in-difference study of childhood immunization coverage from 195 countries

BackgroundSeveral studies have indicated that universal health coverage (UHC) improves health service utilization and outcomes in countries. These studies, however, have primarily assessed UHC’s peacetime impact, limiting our understanding of UHC’s potential protective effects during public health crises such as the Coronavirus Disease 2019 (COVID-19) pandemic. We empirically explored whether countries’ progress toward UHC is associated with differential COVID-19 impacts on childhood immunization coverage.Methods and findingsUsing a quasi-experimental difference-in-difference (DiD) methodology, we quantified the relationship between UHC and childhood immunization coverage before and during the COVID-19 pandemic. The analysis considered 195 World Health Organization (WHO) member states and their ability to provision 12 out of 14 childhood vaccines between 2010 and 2020 as an outcome. We used the 2019 UHC Service Coverage Index (UHC SCI) to divide countries into a “high UHC index” group (UHC SCI ≥80) and the rest. All analyses included potential confounders including the calendar year, countries’ income group per the World Bank classification, countries’ geographical region as defined by WHO, and countries’ preparedness for an epidemic/pandemic as represented by the Global Health Security Index 2019. For robustness, we replicated the analysis using a lower cutoff value of 50 for the UHC index. A total of 20,230 country-year observations were included in the study. The DiD estimators indicated that countries with a high UHC index (UHC SCI ≥80, n = 35) had a 2.70% smaller reduction in childhood immunization coverage during the pandemic year of 2020 as compared to the countries with UHC index less than 80 (DiD coefficient 2.70; 95% CI: 0.75, 4.65; p-value = 0.007). This relationship, however, became statistically nonsignificant at the lower cutoff value of UHC SCI <50 (n = 60). The study’s primary limitation was scarce data availability, which restricted our ability to account for confounders and to test our hypothesis for other relevant outcomes.ConclusionsWe observed that countries with greater progress toward UHC were associated with significantly smaller declines in childhood immunization coverage during the pandemic. This identified association may potentially provide support for the importance of UHC in building health system resilience. Our findings strongly suggest that policymakers should continue to advocate for achieving UHC in coming years.

In a difference-in-difference study, Sooyoung Kim and colleagues study associations between progress toward universal healthcare coverage and childhood immunizations before and during the COVID-19 pandemic.     

COVID-19 and children: medical impact and collateral damage

Children mostly experience mild SARS-CoV-2 infections, but the extent of paediatric COVID-19 disease differs between geographical regions and the distinct pandemic waves. Not all infections in children are mild, some children even show a strong inflammatory reaction resulting in a multisystem inflammatory syndrome. The assessments of paediatric vaccination depend on the efficacy of protection conferred by vaccination, the risk of adverse reactions and whether children contribute to herd immunity against COVID-19. Children were also the target of consequential public health actions such as school closure which caused substantial harm to children (educational deficits, sociopsychological problems) and working parents. It is, therefore, important to understand the transmission dynamics of SARS-CoV-2 infections by children to assess the efficacy of school closures and paediatric vaccination. The societal restrictions to contain the COVID-19 pandemic had additional negative effects on children’s health, such as missed routine vaccinations, nutritional deprivation and lesser mother–child medical care in developing countries causing increased child mortality as a collateral damage. In this complex epidemiological context, it is important to have an evidence-based approach to public health approaches. The present review summaries pertinent published data on the role of children in the pandemic, whether they are drivers or followers of the infection chains and whether they are (after elderlies) major sufferers or mere bystanders of the COVID-19 pandemic.     

Insight into the biological impact of COVID-19 and its vaccines on human health

COVID-19 (coronavirus disease-2019) is a contagious illness that has been declared a global epidemic by the World Health Organization (WHO). The coronavirus causes diseases ranging in severity from the common cold to severe respiratory diseases and death. Coronavirus primarily affects blood pressure by attaching to the angiotensin converting enzyme 2 (ACE 2) receptor. This virus has an impact on multiple organ systems, including the central nervous system, immune system, cardiovascular system, peripheral nervous system, gastrointestinal tract, endocrine system, urinary system, skin, and pregnancy. For the prevention of COVID-19, various vaccines such as viral-like particle vaccines, entire inactivated virus vaccines, viral vector vaccines, live attenuated virus vaccines, subunit vaccines, RNA vaccines, and DNA vaccines are now available. Some of the COVID-19 vaccines are reported to cause a variety of adverse effects that range from mild to severe in nature. SARS-CoV-2 replication is controlled by the RNA-Dependent RNA-Polymerase enzyme (RdRp). The availability of FDA-approved anti-RdRp drugs (Ribavirin, Remdesivir, Sofosbuvir, Galidesivir, and Tenofovir) as potent drugs against SARS-CoV-2 that tightly bind to its RdRp may aid in the treatment of patients and reduce the risk of the mysterious new form of COVID-19 viral infection. RdRp inhibitors, such as remdesivir (an anti-Ebola virus experimental drug) and favipiravir (an anti-influenza drug), inhibit RdRp and thus slow the progression of COVID-19 and associated clinical symptoms, as well as significantly shorten recovery time. Molnupiravir, an orally active RdRp inhibitor and noval broad spectrum antiviral agent, is an isopropyl pro-drug of EIDD-1931 for emergency use. Galidesivir's in vitro and in vivo activities are limited to RNA of human public health concern. Top seeds for antiviral treatments with high potential to combat the SARS-CoV-2 strain include guanosine derivatives (IDX-184), setrobuvir, and YAK. The goal of this review is to compile scattered information on available COVID-19 vaccines and other treatments for protecting the human body from their harmful effects and to provide options for making better choices in a timely manner.     

The effect of universal influenza immunization on mortality and health care use

Background

In 2000, Ontario, Canada, initiated a universal influenza immunization program (UIIP) to provide free influenza vaccines for the entire population aged 6 mo or older. Influenza immunization increased more rapidly in younger age groups in Ontario compared to other Canadian provinces, which all maintained targeted immunization programs. We evaluated the effect of Ontario''s UIIP on influenza-associated mortality, hospitalizations, emergency department (ED) use, and visits to doctors'' offices.

Methods and Findings

Mortality and hospitalization data from 1997 to 2004 for all ten Canadian provinces were obtained from national datasets. Physician billing claims for visits to EDs and doctors'' offices were obtained from provincial administrative datasets for four provinces with comprehensive data. Since outcomes coded as influenza are known to underestimate the true burden of influenza, we studied more broadly defined conditions. Hospitalizations, ED use, doctors'' office visits for pneumonia and influenza, and all-cause mortality from 1997 to 2004 were modelled using Poisson regression, controlling for age, sex, province, influenza surveillance data, and temporal trends, and used to estimate the expected baseline outcome rates in the absence of influenza activity. The primary outcome was then defined as influenza-associated events, or the difference between the observed events and the expected baseline events. Changes in influenza-associated outcome rates before and after UIIP introduction in Ontario were compared to the corresponding changes in other provinces. After UIIP introduction, influenza-associated mortality decreased more in Ontario (relative rate [RR] = 0.26) than in other provinces (RR = 0.43) (ratio of RRs = 0.61, p = 0.002). Similar differences between Ontario and other provinces were observed for influenza-associated hospitalizations (RR = 0.25 versus 0.44, ratio of RRs = 0.58, p < 0.001), ED use (RR = 0.31 versus 0.69, ratio of RRs = 0.45, p < 0.001), and doctors'' office visits (RR = 0.21 versus 0.52, ratio of RRs = 0.41, p < 0.001). Sensitivity analyses were carried out to assess consistency, specificity, and the presence of a dose-response relationship. Limitations of this study include the ecological study design, the nonspecific outcomes, difficulty in modeling baseline events, data quality and availability, and the inability to control for potentially important confounders.

Conclusions

Compared to targeted programs in other provinces, introduction of universal vaccination in Ontario in 2000 was associated with relative reductions in influenza-associated mortality and health care use. The results of this large-scale natural experiment suggest that universal vaccination may be an effective public health measure for reducing the annual burden of influenza.     

COVID-19 vaccination in Sindh Province,Pakistan: A modelling study of health impact and cost-effectiveness

BackgroundMultiple Coronavirus Disease 2019 (COVID-19) vaccines appear to be safe and efficacious, but only high-income countries have the resources to procure sufficient vaccine doses for most of their eligible populations. The World Health Organization has published guidelines for vaccine prioritisation, but most vaccine impact projections have focused on high-income countries, and few incorporate economic considerations. To address this evidence gap, we projected the health and economic impact of different vaccination scenarios in Sindh Province, Pakistan (population: 48 million).Methods and findingsWe fitted a compartmental transmission model to COVID-19 cases and deaths in Sindh from 30 April to 15 September 2020. We then projected cases, deaths, and hospitalisation outcomes over 10 years under different vaccine scenarios. Finally, we combined these projections with a detailed economic model to estimate incremental costs (from healthcare and partial societal perspectives), disability-adjusted life years (DALYs), and incremental cost-effectiveness ratio (ICER) for each scenario.We project that 1 year of vaccine distribution, at delivery rates consistent with COVAX projections, using an infection-blocking vaccine at $3/dose with 70% efficacy and 2.5-year duration of protection is likely to avert around 0.9 (95% credible interval (CrI): 0.9, 1.0) million cases, 10.1 (95% CrI: 10.1, 10.3) thousand deaths, and 70.1 (95% CrI: 69.9, 70.6) thousand DALYs, with an ICER of $27.9 per DALY averted from the health system perspective. Under a broad range of alternative scenarios, we find that initially prioritising the older (65+) population generally prevents more deaths. However, unprioritised distribution has almost the same cost-effectiveness when considering all outcomes, and both prioritised and unprioritised programmes can be cost-effective for low per-dose costs. High vaccine prices ($10/dose), however, may not be cost-effective, depending on the specifics of vaccine performance, distribution programme, and future pandemic trends.The principal drivers of the health outcomes are the fitted values for the overall transmission scaling parameter and disease natural history parameters from other studies, particularly age-specific probabilities of infection and symptomatic disease, as well as social contact rates. Other parameters are investigated in sensitivity analyses.This study is limited by model approximations, available data, and future uncertainty. Because the model is a single-population compartmental model, detailed impacts of nonpharmaceutical interventions (NPIs) such as household isolation cannot be practically represented or evaluated in combination with vaccine programmes. Similarly, the model cannot consider prioritising groups like healthcare or other essential workers. The model is only fitted to the reported case and death data, which are incomplete and not disaggregated by, e.g., age. Finally, because the future impact and implementation cost of NPIs are uncertain, how these would interact with vaccination remains an open question.ConclusionsCOVID-19 vaccination can have a considerable health impact and is likely to be cost-effective if more optimistic vaccine scenarios apply. Preventing severe disease is an important contributor to this impact. However, the advantage of prioritising older, high-risk populations is smaller in generally younger populations. This reduction is especially true in populations with more past transmission, and if the vaccine is likely to further impede transmission rather than just disease. Those conditions are typical of many low- and middle-income countries.

In a modelling study, Carl A B Pearson and coauthors investigate the health impact and cost-effectiveness of various COVID-19 vaccination scenarios in Sindh Province, Pakistan     

Early adoption of non-pharmaceutical interventions and COVID-19 mortality

To contain the spread of the COVID-19 pandemic, many countries around the globe have adopted social distancing measures. Yet, establishing the causal effect of non-pharmaceutical interventions (NPIs) is difficult because they do not occur arbitrarily. We exploit a quasi-random source of variation for identification purposes –namely, regional differences in the placement on the pandemic curve following an unexpected and nationwide lockdown. Our results reveal that regions where the outbreak had just started when the lockdown was implemented had 1.62 fewer daily deaths per 100,000 inhabitants when compared to regions for which the lockdown arrived 10+ days after the pandemic’s outbreak. As a result, a total of 4,642 total deaths (232 deaths/daily) could have been avoided by the end of our period of study –a figure representing 23% of registered deaths in Spain at the time. We rule out differential pre−COVID mortality trends and self-distancing behaviors across the compared regions prior to the swift lockdown, which was also uniformly observed nationwide. In addition, we provide supporting evidence for contagion deceleration as the main mechanism behind the effectiveness of the early adoption of NPIs in lowering the death rate, rather than an increased healthcare capacity.     

Building global health research capacity to address research imperatives following the COVID-19 pandemic

Peter Kilmarx and Roger Glass discuss strengthening health research capabilities as a response to the COVID-19 pandemic.

Research and development of new tools and interventions are necessary to improve global health, as has been made apparent by the Coronavirus Disease 2019 (COVID-19) pandemic [1]. As of mid-July 2021, there have been nearly 190 million cases reported worldwide and more than 4 million deaths; and yet, less than a year after the outbreak was first reported, in an unprecedented global effort, researchers had developed home rapid self-tests [2], established treatment protocols proven effective to improve survival [3], and discovered highly effective vaccines that are already being produced and administered at a large scale [4].The COVID-19 pandemic also illustrates the importance of having research capacity in place as a critical element of pandemic preparedness. China, with its robust research capacity, was able to rapidly sequence the novel Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) virus in January 2020 [5] and quickly share the results, thereby jumpstarting global development of diagnostic tests and vaccines. In contrast, when outbreaks have occurred in countries with less research capacity, the development of countermeasures—diagnostics, therapeutics, and vaccines—may be delayed. We examined the relationship between a country’s preexisting research capacity and the output of scientific publications in PubMed by the country’s scientists following an outbreak. In the first 2 years after the Ebola outbreak was recognized in Guinea, only 42 papers on Ebola were published with authors with a Guinean affiliation, and there were significant challenges in launching Ebola treatment and vaccine studies. From Brazil, with its strong research infrastructure, 312 publications about Zika were authored by scientists with a Brazilian affiliation in the 2 years after that outbreak was detected, and substantial progress was made in rapidly characterizing the newly recognized, diverse clinical manifestations. Finally, authors affiliated with a Chinese institution published 8,921 articles on COVID-19 since the current outbreak was recognized, with remarkable progress in developing medical countermeasures.Anticipating significant progress in controlling COVID-19 in 2021, what are the future priorities for global health research? A helpful guide is the 2019 report of the Global Burden of Diseases, Injuries, and Risk Factors Study [6]. This comprehensive synthesis showed that the largest absolute increases in number of disability-adjusted life years between 1990 and 2019 mostly included noncommunicable diseases, i.e., ischemic heart disease, diabetes, stroke, chronic kidney disease, and lung cancer. These illnesses have overlapping risk factors—hypertension, high fasting plasma glucose, high body mass index, tobacco use, and ambient air pollution—which are also highly prevalent and mostly increasing over time [7], further suggesting important areas for research. Notably, some of these diseases and risk factors are also predisposing factors for more severe COVID-19 and prolonged symptoms post-COVID-19.Many other critical COVID-19 research questions in the NIH-Wide Strategic Plan for COVID-19 Research [8] remain unanswered, and new urgent questions have arisen. These include the following: What can we learn from how genetic and other factors explain the high individual variation in the clinical course of COVID-19 to improve treatment interventions? How can diagnostic tests be optimized for home use and low-resource settings, and can testing platforms be created for rapid adaptation with new emerging pathogens? With the potential for waning immunity and immune escape variants, what strategies will be needed for COVID-19 vaccine booster doses? Lastly, how best can public health interventions and medical countermeasures be delivered to reduce poor outcomes, especially in racial/ethnic minority and other vulnerable populations?Several other important perspectives on threats to global health cut across multiple disease entities and provide useful frameworks and new imperatives for prioritizing global health research. The One Health concept encompasses interconnections between humans, animals, plants, and the environment and embraces a transdisciplinary approach to address major emerging threats including zoonotic diseases (e.g., COVID-19), vector-borne diseases, antimicrobial resistance, food safety, and environmental contamination [9]. Another framework is Planetary Health, which focuses on the already large and growing health impacts of our extensive disruptions of earth’s systems, especially climate change, but also declining biodiversity, increasing pollution, and shortages of fresh water, land, and ocean resources [10]. In addition, humanitarian crises such as armed conflicts, natural disasters, and disease outbreaks are impacting more people than ever before. New research approaches and partnerships are needed to address evidence gaps and to establish capacities for future challenges [11]. The impact of COVID-19 on routine health services is a striking current example. Lastly, implementation research on promoting the uptake of evidence-based interventions and policies into routine healthcare and public health settings is needed across each of these fields of health research to address persistent gaps between the promise of proven effective innovations and their successful implementation, especially in underserved and marginalized populations that have been more severely impacted by COVID-19 [12].We believe the greatest priority should be on building health research capacity in low- and middle-income countries (LMICs) where the health burdens and threats are greater and research capacity is often lower than in higher-income countries. Basic pillars of capacity are needed to establish a robust, responsive research environment. Foremost among these is human capacity. Over decades of experience, we have learned that developing research leaders in LMICs requires well-trained individuals with protected time to conduct research and with strong mentorship and networking with both international and local scientists. It is encouraging to see such investigators trained in other research topics such as HIV and tuberculosis now emerge as leaders in their country’s response to the COVID-19 pandemic in Asia, Africa, and the Americas [13]. Other critical capacities include laboratory testing, data management and statistical analysis, clinical trial and community research site development, behavioral and social science, community engagement, ethical review boards, and regulatory systems. A promising emerging approach is to use basic metrics of national and institutional health research capacity to help coordinate and increase efficiency of capacity building efforts, identify and support countries with lowest capacity levels, and facilitate increased research on national health priorities [14]. As we have seen with COVID-19, these capacities can also be rapidly brought to bear to address new health threats. Notably, of the 30 countries taking part in the SOLIDARITY trial of COVID-19 treatment, 16 are LMICs [15]. A critical limitation and emerging priority underscored by COVID-19 is in vaccine research, development, and manufacturing capacity, especially in Africa [16].COVID-19 has necessitated many other substantial changes in our usual practices of global health research, some of which are likely to persist. Use of digital platforms for telecommunications has exploded. In many settings, telework and distance learning are proving to be very effective and sometimes preferable to the expense and risk of face-to-face meetings. We have seen greater participation in many webinars and network meetings, especially from early-career and LMIC colleagues who did not have the time or the budget for in-person meetings [17]. Importantly, the environmental costs of these virtual meetings are also much lower. Along with increases in telemedicine, there have also been advances in teleresearch whereby participants can be enrolled or followed via their mobile phones, potentially decreasing the costs and barriers to participation and improving study retention. The speed of research, formation of collaborations, and communication of results have all increased remarkably with digital collaboration platforms and rapid publication, including publication of preprints, which are now available on PubMed [18]. International collaboration and coordination in research and regulatory processes have also been critical to the rapid development of medical countermeasures through platforms such as the Access to COVID-19 Tools (ACT) Accelerator of the World Health Organization [19] and the Accelerating COVID-19 Therapeutic Interventions and Vaccines (ACTIV) public–private partnership led by the National Institutes of Health [20].Unfortunately, there has also been an “infodemic” of misinformation (i.e., any false information) and disinformation (deliberately false or misleading information) around the source and impact of COVID-19 and the science of its prevention and treatment [21]. This is not a new phenomenon, but with the growth of digital platforms with domestic and international rivalries, a major threat has emerged requiring research to better understand and counter that threat.Finally, COVID-19 is likely to recalibrate perspectives of levels of expertise in north–south relationships among higher- and lower-income countries. At the time of this writing, the public health, healthcare system, and policy approaches in the COVID-19 response of many high-income countries in the north have greatly underperformed in comparison to some lower-income countries in the global south, especially in regard to protecting vulnerable and marginalized populations. This has increased momentum to democratize global health, with the recognition that a new sense of humility and equity will be critical to understand all of the lessons to be learned and improve global health following COVID-19. We applaud the growing role of LMIC scientists in setting the global health research agenda [22].In conclusion, while the COVID-19 pandemic has already taken a devastating global toll on global health and well-being, it has also provided a strong example of the importance of health research capacity as an essential element of pandemic preparedness. The world faces a wide range of health challenges, from chronic diseases and risk factors to emerging global threats. Building research capacity, especially in countries with lower levels, while learning the lessons of COVID-19, must become a higher priority to achieve our current shared global health goals while increasing resilience to address future health threats.     

The impact of COVID-19 on pregnancy outcomes: a systematic review and meta-analysis

Background:The impact of coronavirus disease 2019 (COVID-19) on maternal and newborn health is unclear. We aimed to evaluate the association between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during pregnancy and adverse pregnancy outcomes.METHODS:We conducted a systematic review and meta-analysis of observational studies with comparison data on SARS-CoV-2 infection and severity of COVID-19 during pregnancy. We searched for eligible studies in MEDLINE, Embase, ClinicalTrials.gov, medRxiv and Cochrane databases up to Jan. 29, 2021, using Medical Subject Headings terms and keywords for “severe acute respiratory syndrome coronavirus 2 OR SARS-CoV-2 OR coronavirus disease 2019 OR COVID-19” AND “pregnancy.” We evaluated the methodologic quality of all included studies using the Newcastle–Ottawa Scale. Our primary outcomes were preeclampsia and preterm birth. Secondary outcomes included stillbirth, gestational diabetes and other pregnancy outcomes. We calculated summary odds ratios (ORs) or weighted mean differences with 95% confidence intervals (CI) using random-effects meta-analysis.RESULTS:We included 42 studies involving 438 548 people who were pregnant. Compared with no SARS-CoV-2 infection in pregnancy, COVID-19 was associated with preeclampsia (OR 1.33, 95% CI 1.03 to 1.73), preterm birth (OR 1.82, 95% CI 1.38 to 2.39) and stillbirth (OR 2.11, 95% CI 1.14 to 3.90). Compared with mild COVID-19, severe COVID-19 was strongly associated with preeclampsia (OR 4.16, 95% CI 1.55 to 11.15), preterm birth (OR 4.29, 95% CI 2.41 to 7.63), gestational diabetes (OR 1.99, 95% CI 1.09 to 3.64) and low birth weight (OR 1.89, 95% CI 1.14 to 3.12).INTERPRETATION:COVID-19 may be associated with increased risks of preeclampsia, preterm birth and other adverse pregnancy outcomes.

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and was declared a global pandemic in March 2020.¹ Pregnant people and infants may be particularly susceptible to COVID-19 because the physiologic changes of pregnancy involve cardiorespiratory and immune systems, which may result in an altered response to SARS-CoV-2 infection in pregnancy. ² Fetuses may be exposed to SARS-CoV-2 during critical periods of fetal development.³ The nature of the association between COVID-19 and pregnancy outcomes remains unclear, and meta-analyses involving patients with COVID-19 who are pregnant are limited. Previous reviews have focused mostly on prevalence estimates from case reports or case series that are difficult to interpret and potentially biased.^4,5 A 2020 systematic review suggested that people who are pregnant did not have an increased risk of SARS-CoV-2 infection or symptomatic COVID-19, but they were at risk of severe COVID-19 compared with those who were not pregnant.⁵ However, this review included suspected COVID-19 cases in addition to confirmed cases.⁵ Although some recent observational studies have suggested that people with confirmed asymptomatic and symptomatic COVID-19,^6–15 as well as mild and severe infections,^{6,8,9,15–22} may be at risk of adverse pregnancy outcomes, we are unaware of any systematic reviews that have comprehensively evaluated these data.We performed a systematic review and meta-analysis of maternal, fetal and neonatal outcomes among pregnant patients with COVID-19. We aimed to determine the association between SARS-CoV-2 infection and adverse pregnancy outcomes, including preeclampsia, preterm birth and stillbirth.     

The COVID-19 outbreak in Sichuan,China: Epidemiology and impact of interventions

In January 2020, a COVID-19 outbreak was detected in Sichuan Province of China. Six weeks later, the outbreak was successfully contained. The aim of this work is to characterize the epidemiology of the Sichuan outbreak and estimate the impact of interventions in limiting SARS-CoV-2 transmission. We analyzed patient records for all laboratory-confirmed cases reported in the province for the period of January 21 to March 16, 2020. To estimate the basic and daily reproduction numbers, we used a Bayesian framework. In addition, we estimated the number of cases averted by the implemented control strategies. The outbreak resulted in 539 confirmed cases, lasted less than two months, and no further local transmission was detected after February 27. The median age of local cases was 8 years older than that of imported cases. We estimated R₀ at 2.4 (95% CI: 1.6–3.7). The epidemic was self-sustained for about 3 weeks before going below the epidemic threshold 3 days after the declaration of a public health emergency by Sichuan authorities. Our findings indicate that, were the control measures be adopted four weeks later, the epidemic could have lasted 49 days longer (95% CI: 31–68 days), causing 9,216 more cases (95% CI: 1,317–25,545).