Prepandemic cross-reactive humoral immunity to SARS-CoV-2 in Africa: Systematic review and meta-analysis.

OBJECTIVES: To assess the evidence on the presence of antibodies cross-reactive with SARS-CoV-2 antigens in prepandemic samples from African populations. METHODS: We performed a systematic review and meta-analysis of studies evaluating prepandemic African samples using pre-set assay-specific thresholds for SARS-CoV-2 seropositivity. RESULTS: In total, 26 articles with 156 datasets were eligible, including 3437 positives among 29,923 measurements (11.5%) with large between-dataset heterogeneity. Positivity was similar for anti-nucleocapsid (14%) and anti-spike antibodies (11%), higher for anti-spike1 (23%), and lower for anti-receptor-binding domain antibodies (7%). Positivity was similar, on average, for immunoglobulin M and immunoglobulin G. Positivity was seen prominently in countries where malaria transmission occurs throughout and in datasets enriched in malaria cases (14%, 95% confidence interval, 12-15% vs 2%, 95% confidence interval 1-2% in other datasets). Substantial SARS-CoV-2 reactivity was seen in high malaria burden with or without high dengue burden (14% and 12%, respectively), and not without high malaria burden (2% and 0%, respectively). Lower SARS-CoV-2 cross-reactivity was seen in settings of high HIV seroprevalence. More sparse individual-level data showed associations of higher SARS-CoV-2 cross-reactivity with Plasmodium parasitemia and lower SARS-CoV-2 cross-reactivity with HIV seropositivity. CONCLUSION: Prepandemic samples from Africa show high levels of anti-SARS-CoV-2 seropositivity. At the country level, cross-reactivity tracks especially with malaria prevalence.

Transparency in Infectious Disease Research: Meta-research Survey of Specialty Journals.

BACKGROUND: Infectious diseases carry large global burdens and have implications for society at large. Therefore, reproducible, transparent research is extremely important. METHODS: We evaluated transparency indicators (code and data sharing, registration, and conflict and funding disclosures) in the 5340 PubMed Central Open Access articles published in 2019 or 2021 in the 9 most cited specialty journals in infectious diseases using the text-mining R package, rtransparent. RESULTS: A total of 5340 articles were evaluated (1860 published in 2019 and 3480 in 2021 [of which 1828 were on coronavirus disease 2019, or COVID-19]). Text mining identified code sharing in 98 (2%) articles, data sharing in 498 (9%), registration in 446 (8%), conflict of interest disclosures in 4209 (79%), and funding disclosures in 4866 (91%). There were substantial differences across the 9 journals: 1%-9% for code sharing, 5%-25% for data sharing, 1%-31% for registration, 7%-100% for conflicts of interest, and 65%-100% for funding disclosures. Validation-corrected imputed estimates were 3%, 11%, 8%, 79%, and 92%, respectively. There were no major differences between articles published in 2019 and non-COVID-19 articles in 2021. In 2021, non-COVID-19 articles had more data sharing (12%) than COVID-19 articles (4%). CONCLUSIONS: Data sharing, code sharing, and registration are very uncommon in infectious disease specialty journals. Increased transparency is required.

Clinical Spectrum, Radiological Findings, and Outcomes of Severe Toxoplasmosis in Immunocompetent Hosts: A Systematic Review.

BACKGROUND: Accumulating evidence suggests that toxoplasmosis in immunocompetent hosts can be severe and life-threatening. METHODS: We performed a systematic review of severe toxoplasmosis cases in immunocompetent patients to gain insight into the epidemiology, clinical characteristics, radiological findings, and outcomes of these cases. We classified severe toxoplasmosis as cases with the symptomatic involvement of target organs (the lungs, central nervous system (CNS), and heart), disseminated disease, prolonged disease (>3 months), or a fatal outcome. Our primary analysis focused on cases published from 1985-2022 to avoid confounding with cases in AIDS patients. RESULTS: We identified 82 pertinent articles (1985-2022) with a total of 117 eligible cases; the top five countries for these cases were French Guiana (20%), France (15%), Colombia (9%), India (9%), and Brazil (7%). Overall, 44% (51/117) of cases had pulmonary involvement, 39% (46/117) CNS, 31% (36/117) cardiac, 24% (28/117) disseminated disease, 2% (2/117) had prolonged disease, and 8% (9/117) of patients died. More than one organ was involved in 26% (31/117) of cases. Eighty-four percent (98/117) of cases occurred in the context of a recent acute primary Toxoplasma infection; for the remaining, the exact timing of infection was unclear. Genotyping data were very sparse. Among those reporting genotyping data, 96% (22/23) were caused by atypical non-type II strains; one case was caused by a type-II strain. Only half of the cases reported risk factors. The most common risk factors were eating raw/undercooked meat or eating game meat (47% (28/60)), drinking untreated water (37% (22/60)), or living in a toxoplasmosis high-prevalence area (38% (23/60)). For the 51 pulmonary cases, the main clinical presentation was pneumonia or pleural effusions in 94% (48/51) and respiratory failure in 47% (24/51). For the 46 CNS cases, the main clinical presentation was encephalitis in 54% (25/46), meningitis in 13% (6/46), focal neurologic findings in 24% (11/46), cranial nerve palsies in 17% (8/46), Guillain-Barre syndrome or Miller Fisher syndrome in 7% (3/46), and Brown-Sequard syndrome in 2% (1/46) of cases; more than one clinical manifestation could also be present. Among the 41 CNS cases reporting the CNS imaging findings, 68% (28/41) had focal supratentorial lesions and 7% (3/41) had focal infratentorial lesions. Brain abscess-like/mass-like lesions were seen in 51% (21/41) of cases. For the 36 cardiac cases, the main clinical presentation was myocarditis in 75% (27/36), pericarditis in 50% (18/36), heart failure and/or cardiogenic shock in 19% (7/36), and cardiac arrhythmias in 22% (8/36); more than one manifestation could also be present. Illness was critical in 49% (44/90) of cases intensive care unit care was needed in 54% (29/54) of cases among those reporting this information, and 9 patients died. CONCLUSION: The diagnosis of severe toxoplasmosis in immunocompetent hosts can be challenging. Toxoplasmosis should be considered in the differential diagnosis of immunocompetent patients presenting with severe illness of unclear etiology with pulmonary, cardiac, CNS, or multiorgan involvement/failure, or prolonged febrile illness, even in the absence of common exposure risk factors or common manifestations of toxoplasmosis (e.g., fever, mononucleosis-like illness, lymphadenopathy, and chorioretinitis). Fatal outcomes can also rarely occur in immunocompetent patients. Prompt initiation of anti-Toxoplasma treatment can be lifesaving.

Differential COVID-19 infection rates in children, adults, and elderly: Systematic review and meta-analysis of 38 pre-vaccination national seroprevalence studies.

Background: Debate exists about whether extra protection of elderly and other vulnerable individuals is feasible in COVID-19. We aimed to assess the relative infection rates in the elderly vs the non-elderly and, secondarily, in children vs adults. Methods: We performed a systematic review and meta-analysis of seroprevalence studies conducted in the pre-vaccination era. We identified representative national studies without high risk of bias through SeroTracker and PubMed searches (last updated May 17, 2022). We noted seroprevalence estimates for children, non-elderly adults, and elderly adults, using cut-offs of 20 and 60 years (or as close to these ages, if they were unavailable) and compared them between different age groups. Results: We included 38 national seroprevalence studies from 36 different countries comprising 826 963 participants. Twenty-six of these studies also included pediatric populations and twenty-five were from high-income countries. The median ratio of seroprevalence in elderly vs non-elderly adults (or non-elderly in general, if pediatric and adult population data were not offered separately) was 0.90-0.95 in different analyses, with large variability across studies. In five studies (all in high-income countries), we observed significant protection of the elderly with a ratio of <0.40, with a median of 0.83 in high-income countries and 1.02 elsewhere. The median ratio of seroprevalence in children vs adults was 0.89 and only one study showed a significant ratio of <0.40. The main limitation of our study is the inaccuracies and biases in seroprevalence studies. Conclusions: Precision shielding of elderly community-dwelling populations before the availability of vaccines was indicated in some high-income countries, but most countries failed to achieve any substantial focused protection. Registration: Open Science Framework (available at: https://osf.io/xvupr).

Age-stratified infection fatality rate of COVID-19 in the non-elderly population.

The largest burden of COVID-19 is carried by the elderly, and persons living in nursing homes are particularly vulnerable. However, 94% of the global population is younger than 70 years and 86% is younger than 60 years. The objective of this study was to accurately estimate the infection fatality rate (IFR) of COVID-19 among non-elderly people in the absence of vaccination or prior infection. In systematic searches in SeroTracker and PubMed (protocol: https://osf.io/xvupr), we identified 40 eligible national seroprevalence studies covering 38 countries with pre-vaccination seroprevalence data. For 29 countries (24 high-income, 5 others), publicly available age-stratified COVID-19 death data and age-stratified seroprevalence information were available and were included in the primary analysis. The IFRs had a median of 0.034% (interquartile range (IQR) 0.013-0.056%) for the 0-59 years old population, and 0.095% (IQR 0.036-0.119%) for the 0-69 years old. The median IFR was 0.0003% at 0-19 years, 0.002% at 20-29 years, 0.011% at 30-39 years, 0.035% at 40-49 years, 0.123% at 50-59 years, and 0.506% at 60-69 years. IFR increases approximately 4 times every 10 years. Including data from another 9 countries with imputed age distribution of COVID-19 deaths yielded median IFR of 0.025-0.032% for 0-59 years and 0.063-0.082% for 0-69 years. Meta-regression analyses also suggested global IFR of 0.03% and 0.07%, respectively in these age groups. The current analysis suggests a much lower pre-vaccination IFR in non-elderly populations than previously suggested. Large differences did exist between countries and may reflect differences in comorbidities and other factors. These estimates provide a baseline from which to fathom further IFR declines with the widespread use of vaccination, prior infections, and evolution of new variants.

Toxoplasmosis and Schizophrenia: A Systematic Review and Meta-Analysis of Prevalence and Associations and Future Directions.

Background: A potential link between toxoplasmosis with schizophrenia (SCZ) has been extensively studied over the past 2 decades. Our study was aimed to determine whether, beyond an association, the field is primed for randomized clinical trials of anti-Toxoplasma prophylaxis in Toxoplasma seropositive patients with SCZ. Methods: We performed a methodological appraisal of toxoplasmosis-SCZ association studies, a meta-analysis, and a compilation of claims and pathophysiologic hypotheses. Results: We analyzed 66 studies with 11,540 patients with SCZ and 69,491 controls. For patients with SCZ, 54 studies targeted Toxoplasma-IgG seropositivity, 18 targeted Toxoplasma-IgG serointensity, and 17 targeted Toxoplasma-IgM seropositivity. For SCZ-phenotypes, 26 targeted Toxoplasma-IgG seropositivity, six targeted Toxoplasma-IgG serointensity, and three targeted Toxoplasma-IgM seropositivity. Two-thirds of these studies reported a positive association. Statistically significant associations with SCZ were reported in 31/54 studies, 11/18 studies, and 3/17 studies. Significant associations with SCZ-phenotypes were reported in 20/26 studies, 2/6 studies, and 0/3 studies, respectively. Toxoplasma-IgG seropositivity increased the odds of SCZ (OR = 1.91; 95% CI: 1.61-2.27). Heterogeneity across studies was large (I 2 = 80.03%). Adjusted analyses for at least age and socioeconomic status/place of residence were done in 17 studies; temporality was addressed only in 4. Conclusion: A large number of observational studies revealed a modest to large association between toxoplasmosis and SCZ. Although important methodological biases were identified, further association studies are unlikely to change this association and are not justified. It is time to test this association in randomized double-blind placebo-controlled clinical trials of first line anti-Toxoplasma prophylaxis in Toxoplasma seropositive patients with SCZ.

Multisystem Inflammatory Syndrome in Adults and Severe Toxoplasmosis: Similar Clinical Presentations, Potentially Severe Outcomes.

We report a case of a 21-year-old previously healthy man who developed severe toxoplasmosis with chorioretinitis and myositis 2 months after receiving corticosteroids for presumed multisystem inflammatory syndrome in adults, in the setting of a recently acquired acute Toxoplasma infection, likely during a trip to Latin America.

Infectious Diseases-Related Hospitalizations During Oral Polio Vaccine (OPV) and Non-OPV Immunization Periods: An Empirical Evaluation of all Hospital Discharges in California (1985-2010).

BACKGROUND: Live attenuated vaccines such as oral polio vaccine (OPV) can stimulate innate immunity and may have off-target protective effects on other pathogens. We aimed to address this hypothesis by examining changes in infectious diseases (ID)-related hospitalizations in all hospital discharges in California during OPV (1985-1996) and non-OPV immunization periods (2000-2010). METHODS: We searched the Office of Statewide Health Planning and Development database for all hospital discharges with any ID-related discharge diagnosis code during 1985-2010. We compared the proportion of ID-related hospitalizations (with at least 1 ID-related discharge diagnosis) among total hospitalizations during OPV immunization (1985-1996) versus non-OPV immunization (2000-2010) periods. RESULTS: There were 19 281 039 ID-related hospitalizations (8 464 037 with an ID-related discharge diagnosis as the principal discharge diagnosis for the hospitalization) among 98 117 475 hospitalizations in 1985-2010; 9 520 810 ID hospitalizations/43 456 484 total hospitalizations in 2000-2010 versus 7 526 957/43 472 796 in 1985-1996. The risk ratio for ID-related hospitalizations in 2000-2010 versus 1985-1996 was 1.27 (95% confidence interval [CI], 1.26-1.27) for all diagnoses and 1.15 (95% CI: 1.15-1.16) for principal diagnoses. Increases also existed in the proportion of lower respiratory and gastrointestinal infections. DISCUSSION: The proportion of ID-related hospitalizations was lower in the OPV immunization period compared to the period after OPV was discontinued. When focused only on hospitalizations with ID as the principal discharge diagnosis, the signal remained significant but was smaller. These findings require replication in additional studies.

Change in age distribution of COVID-19 deaths with the introduction of COVID-19 vaccination.

OBJECTIVES: Most countries initially deployed COVID-19 vaccines preferentially in elderly populations. We aimed to evaluate whether population-level vaccine effectiveness is heralded by an increase in the relative proportion of deaths among non-elderly populations that were less covered by vaccination programs. ELIGIBLE DATA: We collected data from 40 countries on age-stratified COVID-19 deaths during the vaccination period (1/14/2021-5/31/2021) and two control periods (entire pre-vaccination period and excluding the first wave). MAIN OUTCOME MEASURES: We meta-analyzed the proportion of deaths in different age groups in vaccination versus control periods in (1) countries with low vaccination rates; (2) countries with age-independent vaccination policies; and (3) countries with standard age-dependent vaccination policies. RESULTS: Countries that prioritized vaccination among older people saw an increasing share of deaths among 0-69 year old people in the vaccination versus the two control periods (summary proportion ratio 1.32 [95 CI% 1.24-1.41] and 1.35 [95 CI% 1.26-1.44)]. No such change was seen on average in countries with age-independent vaccination policies (1.05 [95 CI% 0.78-1.41 and 0.97 [95 CI% 0.95-1.00], respectively) and limited vaccination (0.93 [95 CI% 0.85-1.01] and 0.95 [95 CI% 0.87-1.03], respectively). Proportion ratios were associated with the difference of vaccination rates in elderly versus non-elderly people. No significant changes occurred in the share of deaths in age 0-49 among all 0-69 deaths in the vaccination versus pre-vaccination periods. CONCLUSIONS: The substantial shift in the age distribution of COVID-19 deaths in countries that rapidly implemented vaccination predominantly among elderly provides evidence for the population level-effectiveness of COVID-19 vaccination and a favorable evolution of the pandemic towards endemicity with fewer elderly deaths.

Large Pediatric Randomized Clinical Trials in ClinicalTrials.gov.

BACKGROUND: Large, randomized controlled trials (RCTs) are essential in answering pivotal questions in child health. METHODS: We created a bird's eye view of all large, noncluster, nonvaccine pediatric RCTs with ≥1000 participants registered in ClinicalTrials.gov (last search January 9, 2020). We analyzed the funding sources, countries, outcomes, publication status, and correlation with the pediatric global burden of disease (GBD) for eligible trials. RESULTS: We identified 247 large, nonvaccine, noncluster pediatric RCTs. Only 17 mega-trials with ≥5000 participants existed. Industry funding was involved in only 52 (21%) and exclusively funded 47 (19%) trials. Participants were from high-income countries (HICs) in 100 (40%) trials, from lower-middle-income countries (LMICs) in 122 (49%) trials, and from both HICs and LMICs in 19 (8%) trials; 6 trials did not report participants' country location. Of trials conducted in LMIC, 43% of investigators were from HICs. Of non-LMIC participants trials (HIC or HIC and LMIC), 39% were multicountry trials versus 11% of exclusively LMIC participants trials. Few trials (18%; 44 of 247) targeted mortality as an outcome. 35% (58 of 164) of the trials completed ≥12 months were unpublished at the time of our assessment. The number of trials per disease category correlated well with pediatric GBD overall (ρ = 0.76) and in LMICs (ρ = 0.69), but not in HICs (ρ = 0.29). CONCLUSIONS: Incentivization of investigator collaborations across diverse country settings, timely publication of results of large pediatric RCTs, and alignment with the pediatric GBD are of pivotal importance to ultimately improve child health globally.

Late Diagnosis of Congenital Toxoplasmosis with Macrocephaly in Dizygotic Twins after Incidental Detection of Leukocoria: A Case Report.

Untreated congenital toxoplasmosis remains an important cause of neurologic and ocular disease worldwide. However, congenitally infected infants may not have signs and symptoms their physicians recognize, leading to delayed diagnosis and missed opportunities for treatment. We describe a pair of twins diagnosed with congenital toxoplasmosis at 11 months of age following incidental detection of leukocoria in one twin.

Toxoplasmosis in Pediatric Hematopoietic Stem Cell Transplantation Patients.

Infection due to the protozoa Toxoplasma gondii can be life-threatening in hematopoietic stem cell transplantation (HSCT) recipients. Most cases of toxoplasmosis in HSCT recipients result from reactivation of latent infection in individuals who were Toxoplasma-seropositive before transplantation and did not receive appropriate prophylaxis. Pretransplantation screening with Toxoplasma IgG and IgM antibodies is suggested for all allogeneic HSCT recipients and their donors and all autologous HSCT recipients. Prevention of toxoplasmosis in T. gondii-seropositive HSCT recipients requires primary prophylaxis, preemptive screening, or both. Trimethoprim-sulfamethoxazole (TMP-SMX) is the preferred agent for Toxoplasma prophylaxis and should be continued for 6 months or until the patient is no longer receiving immunosuppression, whichever is longer, assuming that immune reconstitution has occurred. Preemptive weekly screening with whole blood Toxoplasma PCR should be considered for seropositive HSCT recipients if prophylaxis cannot be given or if prophylaxis other than TMP-SMX is used. The signs, symptoms, and radiographic findings of toxoplasmosis in HSCT recipients can be nonspecific, and the diagnosis requires a high degree of suspicion. Common presentations include fever, encephalopathy with mental status changes or seizures, and pneumonia. A Toxoplasma PCR analysis from whole blood (and other body fluids/tissues according to clinical symptoms) should be obtained in patients in whom there is a concern for toxoplasmosis. Treatment with oral pyrimethamine, sulfadiazine, and leucovorin for at least 6 weeks is the first-line therapy and should be followed by secondary prophylaxis. In this article, we review the published literature regarding the epidemiology, clinical presentation, treatment, and prevention of toxoplasmosis in HSCT recipients.

Toxoplasmosis Among 38 751 Hematopoietic Stem-cell Transplant Recipients: A Systematic Review of Disease Prevalence and a Compilation of Imaging and Autopsy Findings.

BACKGROUND: Toxoplasmosis in hematopoietic stem-cell transplant (HSCT) recipients can be life threatening if not promptly diagnosed and treated. METHODS: We performed a systematic review (PubMed last search March 29, 2020) of toxoplasmosis among HSCT recipients and calculated the toxoplasmosis prevalence across studies. We also created a compilation list of brain imaging, chest imaging, and autopsy findings of toxoplasmosis among HSCT recipients. RESULTS: We identified 46 eligible studies (47 datasets) with 399 toxoplasmosis cases among 38 751 HSCT recipients. There was large heterogeneity in the reported toxoplasmosis prevalence across studies, thus formal meta-analysis was not attempted. The median toxoplasmosis prevalence among 38 751 HSCT recipients was 2.14% (range 0%-66.67%). Data on toxoplasmosis among at-risk R+HSCT recipients were more limited (25 studies; 2404 R+HSCT recipients [6.2% of all HSCT recipients]), although the median number of R+HSCT recipients was 56.79% across all HSCT recipients. The median toxoplasmosis prevalence across studies among 2404 R+HSCT was 7.51% (range 0%-80%) versus 0% (range 0%-1.23%) among 7438 R-HSCT. There were limited data to allow meaningful analyses of toxoplasmosis prevalence according to prophylaxis status of R+HSCT recipients. CONCLUSIONS: Toxoplasmosis prevalence among HSCT recipients is underestimated. The majority of studies report toxoplasmosis prevalence among all HSCT recipients rather than only among the at-risk R+HSCT recipients. In fact, the median toxoplasmosis prevalence among all R+//R- HSCT recipients is 3.5-fold lower compared with the prevalence among only the at-risk R+HSCT recipients and the median prevalence among R+HSCT recipients is 7.51-fold higher than among R-HSCT recipients. The imaging findings of toxoplasmosis among HSCT recipients can be atypical. High index of suspicion is needed in R+HSCT recipients with fever, pneumonia, or encephalitis.

Assessment of transparency indicators across the biomedical literature: How open is open?

Recent concerns about the reproducibility of science have led to several calls for more open and transparent research practices and for the monitoring of potential improvements over time. However, with tens of thousands of new biomedical articles published per week, manually mapping and monitoring changes in transparency is unrealistic. We present an open-source, automated approach to identify 5 indicators of transparency (data sharing, code sharing, conflicts of interest disclosures, funding disclosures, and protocol registration) and apply it across the entire open access biomedical literature of 2.75 million articles on PubMed Central (PMC). Our results indicate remarkable improvements in some (e.g., conflict of interest [COI] disclosures and funding disclosures), but not other (e.g., protocol registration and code sharing) areas of transparency over time, and map transparency across fields of science, countries, journals, and publishers. This work has enabled the creation of a large, integrated, and openly available database to expedite further efforts to monitor, understand, and promote transparency and reproducibility in science.

Second versus first wave of COVID-19 deaths: Shifts in age distribution and in nursing home fatalities.

OBJECTIVE: To examine whether the age distribution of COVID-19 deaths and the share of deaths in nursing homes changed in the second versus the first pandemic wave. ELIGIBLE DATA: We considered all countries that had at least 4000 COVID-19 deaths occurring as of January 14, 2021, at least 200 COVID-19 deaths occurring in each of the two epidemic wave periods; and which had sufficiently detailed information available on the age distribution of these deaths. We also considered countries with data available on COVID-19 deaths of nursing home residents for the two waves. MAIN OUTCOME MEASURES: Change in the second wave versus the first wave in the proportion of COVID-19 deaths occurring in people <50 years ("young deaths") among all COVID-19 deaths and among COVID-19 deaths in people <70 years old; and change in the proportion of COVID-19 deaths in nursing home residents among all COVID-19 deaths. RESULTS: Data on age distribution were available for 14 eligible countries. Individuals <50 years old had small absolute difference in their share of the total COVID-19 deaths in the two waves across 13 high-income countries (absolute differences 0.0-0.4%). Their proportion was higher in Ukraine, but it decreased markedly in the second wave. The proportion of young deaths was lower in the second versus the first wave (summary prevalence ratio 0.81, 95% CI 0.71-0.92) with large between-country heterogeneity. The proportion of young deaths among deaths <70 years did not differ significantly across the two waves (summary prevalence ratio 0.96, 95% CI 0.86-1.06). Eligible data on nursing home COVID-19 deaths were available for 11 countries. The share of COVID-19 deaths that were accounted by nursing home residents decreased in the second wave significantly and substantially in 8 countries (prevalence ratio estimates: 0.36 to 0.78), remained the same in Denmark and Norway and markedly increased in Australia. CONCLUSIONS: In the examined countries, age distribution of COVID-19 deaths has been fairly similar in the second versus the first wave, but the contribution of COVID-19 deaths in nursing home residents to total fatalities has decreased in most countries in the second wave.

The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days.

Background: Never before have clinical trials drawn as much public attention as those testing interventions for COVID-19. We aimed to describe the worldwide COVID-19 clinical research response and its evolution over the first 100 days of the pandemic. Methods: Descriptive analysis of planned, ongoing or completed trials by April 9, 2020 testing any intervention to treat or prevent COVID-19, systematically identified in trial registries, preprint servers, and literature databases. A survey was conducted of all trials to assess their recruitment status up to July 6, 2020. Results: Most of the 689 trials (overall target sample size 396,366) were small (median sample size 120; interquartile range [IQR] 60-300) but randomized (75.8%; n=522) and were often conducted in China (51.1%; n=352) or the USA (11%; n=76). 525 trials (76.2%) planned to include 155,571 hospitalized patients, and 25 (3.6%) planned to include 96,821 health-care workers. Treatments were evaluated in 607 trials (88.1%), frequently antivirals (n=144) or antimalarials (n=112); 78 trials (11.3%) focused on prevention, including 14 vaccine trials. No trial investigated social distancing. Interventions tested in 11 trials with >5,000 participants were also tested in 169 smaller trials (median sample size 273; IQR 90-700). Hydroxychloroquine alone was investigated in 110 trials. While 414 trials (60.0%) expected completion in 2020, only 35 trials (4.1%; 3,071 participants) were completed by July 6. Of 112 trials with detailed recruitment information, 55 had recruited <20% of the targeted sample; 27 between 20-50%; and 30 over 50% (median 14.8% [IQR 2.0-62.0%]). Conclusions: The size and speed of the COVID-19 clinical trials agenda is unprecedented. However, most trials were small investigating a small fraction of treatment options. The feasibility of this research agenda is questionable, and many trials may end in futility, wasting research resources. Much better coordination is needed to respond to global health threats.

Population-level COVID-19 mortality risk for non-elderly individuals overall and for non-elderly individuals without underlying diseases in pandemic epicenters.

OBJECTIVE: To provide estimates of the relative rate of COVID-19 death in people <65 years old versus older individuals in the general population, the absolute risk of COVID-19 death at the population level during the first epidemic wave, and the proportion of COVID-19 deaths in non-elderly people without underlying diseases in epicenters of the pandemic. ELIGIBLE DATA: Cross-sectional survey of countries and US states with at least 800 COVID-19 deaths as of April 24, 2020 and with information on the number of deaths in people with age <65. Data were available for 14 countries (Belgium, Canada, France, Germany, India, Ireland, Italy, Mexico, Netherlands, Portugal, Spain, Sweden, Switzerland, UK) and 13 US states (California, Connecticut, Florida, Georgia, Illinois, Indiana, Louisiana, Maryland, Massachusetts, Michigan, New Jersey, New York, Pennsylvania). We also examined available data on COVID-19 deaths in people with age <65 and no underlying diseases. MAIN OUTCOME MEASURES: Proportion of COVID-19 deaths in people <65 years old; relative mortality rate of COVID-19 death in people <65 versus ≥65 years old; absolute risk of COVID-19 death in people <65 and in those ≥80 years old in the general population as of June 17, 2020; absolute COVID-19 mortality rate expressed as equivalent of mortality rate from driving a motor vehicle. RESULTS: Individuals with age <65 account for 4.5-11.2% of all COVID-19 deaths in European countries and Canada, 8.3-22.7% in the US locations, and were the majority in India and Mexico. People <65 years old had 30- to 100-fold lower risk of COVID-19 death than those ≥65 years old in 11 European countries and Canada, 16- to 52-fold lower risk in US locations, and less than 10-fold in India and Mexico. The absolute risk of COVID-19 death as of June 17, 2020 for people <65 years old in high-income countries ranged from 10 (Germany) to 349 per million (New Jersey) and it was 5 per million in India and 96 per million in Mexico. The absolute risk of COVID-19 death for people ≥80 years old ranged from 0.6 (Florida) to 17.5 per thousand (Connecticut). The COVID-19 mortality rate in people <65 years old during the period of fatalities from the epidemic was equivalent to the mortality rate from driving between 4 and 82 miles per day for 13 countries and 5 states, and was higher (equivalent to the mortality rate from driving 106-483 miles per day) for 8 other states and the UK. People <65 years old without underlying predisposing conditions accounted for only 0.7-3.6% of all COVID-19 deaths in France, Italy, Netherlands, Sweden, Georgia, and New York City and 17.7% in Mexico. CONCLUSIONS: People <65 years old have very small risks of COVID-19 death even in pandemic epicenters and deaths for people <65 years without underlying predisposing conditions are remarkably uncommon. Strategies focusing specifically on protecting high-risk elderly individuals should be considered in managing the pandemic.

Acute Toxoplasma infection in pregnant women worldwide: A systematic review and meta-analysis.

BACKGROUND: Acute Toxoplasma infection (ATI) during pregnancy, if left untreated, can cause severe adverse outcomes for the fetus and newborn. Here, we undertook a meta-analysis to estimate the worldwide prevalence of ATI in pregnant women. METHODS: We searched international databases for studies published between January 1988 and November 2018. We included population-based cross-sectional and prospective cohort studies that reported the prevalence of ATI in pregnant women. Data were synthesized using a random effect model to calculate the overall prevalence of ATI (with a 95% CI) in six WHO regions and globally. We also performed linear meta-regression analyses to investigate associations of maternal, socio-demographic, geographical and climate parameters with the prevalence of ATI. RESULTS: In total, 217 studies comprising 902,228 pregnant women across 74 countries were included in the meta-analysis. The overall prevalence of ATI in pregnant women globally was 1.1% (95% CI: 0.9-1.2%). In studies where more strict criteria for ATI were used, the overall prevalence was 0.6% (95% CI: 0.4-0.7%). The prevalence was highest in the Eastern Mediterranean region (2.5%; 95%CI: 1.7-3.4%) and lowest in the European region (0.5%; 95% CI: 0.4-0.7%). A significantly higher prevalence of ATI was found in countries with lower income levels (P = 0.027), lower human development indices (P = 0.04), higher temperatures (P = 0.02) and lower latitudes (P = 0.005) and longitudes (P = 0.02). CONCLUSIONS: The risk of acquiring ATI during gestation is clinically important and preventive measures to avoid exposure of pregnant women to Toxoplasma infection should be strictly applied.

Congenital microcephaly hospitalizations in California infants: 1999-2013.

INTRODUCTION: Population-level changes in microcephaly incidence risk (IR) could signal circulation of neurotropic pathogens or potential emerging teratogen exposure. METHODS: In this retrospective population cohort study, we estimated the IR of hospitalizations with a microcephaly ICD-9-CM discharge diagnosis code among infants ≤1 year over a 15-year period (1999-2013) using the Electronic Health Record (EHR) database from all hospital discharges in California from the Office of Statewide Hospital Planning and Development (OSHPD) database. We calculated the overall and yearly IRs per 10,000 live births (LBs) and per 10,000 hospitalizations in infants ≤1 year, and explored the impact in the IR estimates when children with microcephaly associated comorbidities were excluded or not. RESULTS: Among 8,860,153 hospital discharges of infants ≤1 year in the OSHPD database over this 15 year period, we identified 6,004 hospitalizations with a microcephaly discharge diagnosis code; 3,526 of those were in neonates ≤30 days. The IR of microcephaly hospitalizations for infants ≤1 year was 7.70/10,000 LB (for neonates it was 4.52/10,000 LB) and 6.78 per 10,000 hospitalizations ≤1 year. There was large heterogeneity in the yearly microcephaly IRs (I2 = 66.6%). DISCUSSION: EHR collected data could be used as a complementary approach to track epidemiologic changes in microcephaly IRs. However, standardization in the use of microcephaly discharge diagnosis code and harmonization in the types of additional comorbidities to be excluded across analyses is mandatory to allow for prompt identification of true changes in microcephaly rates over time.