Publications by authors named "Albert Ko"

304 Publications

Heterogeneous development of children with Congenital Zika Syndrome-associated microcephaly.

PLoS One 2021 15;16(9):e0256444. Epub 2021 Sep 15.

Instituto de Saúde Coletiva, Universidade Federal da Bahia, Salvador, BA, Brazil.

Objective: To describe the neurological and neurodevelopmental outcomes of children with Congenital Zika Syndrome (CZS) associated microcephaly beyond 2 years of age.

Method: We followed children with CZS-associated microcephaly in an outpatient clinic in Salvador, Brazil. Neurological and neurodevelopmental assessments were performed using the Hammersmith Infant Neurological Examination (HINE) and Bayley Scales of Infant and Toddler Neurodevelopment (Bayley-III) respectively.

Results: Of the 42 children included, 19 were male (45.2%); median (interquartile range) age at neurological evaluation was 28 (25-32) months, and 36 (85.7%) had severe microcephaly. HINE and Bayley-III results were completed for 35/42 (83.3%) and 33/42 (78.5%) children respectively. Bayley-III identified a severe developmental delay in 32/33 (97.0%) children while 1/33 (3.0%) had only a mild delay. In the multivariable analysis, we found that Bayley-III and HINE scores were correlated. Better HINE scores were associated with higher Bayley-III cognitive raw scores (β = 0.29; CI 95% = 0.02-0.57) and motor raw scores (β = 0.43; CI 95% = 0.04-0.82) after adjusting for head circumference, prematurity, and age at neurodevelopmental evaluation. Furthermore, we found that greater head circumference at follow up was associated with higher cognitive (β = 1.27; CI 95% = 0.01-2.53) and motor raw scores (β = 2.03; CI 95% = 0.25-3.81).

Conclusion: Children with CZS-associated microcephaly demonstrate severe neurodevelopmental delays and slower growth rates than their peers over time. Still, they have remarkably heterogeneous neurodevelopmental profiles according to neurological exam scores which correlate with their long-term outcomes. We found that HINE scores effectively captured the heterogeneity of neurological capabilities among these children and could be predictive of cognitive and motor development progress.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0256444PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443077PMC
September 2021

Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study.

BMJ 2021 08 20;374:n2015. Epub 2021 Aug 20.

Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA

Objective: To estimate the effectiveness of the inactivated whole virus vaccine, CoronaVac (Sinovac Biotech), against symptomatic covid-19 in the elderly population of São Paulo state, Brazil during widespread circulation of the gamma variant.

Design: Test negative case-control study.

Setting: Community testing for covid-19 in São Paulo state, Brazil.

Participants: 43 774 adults aged ≥70 years who were residents of São Paulo state and underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 from 17 January to 29 April 2021. 26 433 cases with symptomatic covid-19 and 17 622 test negative controls with covid-19 symptoms were formed into 13 283 matched sets, one case with to up to five controls, according to age, sex, self-reported race, municipality of residence, previous covid-19 status, and date of RT-PCR test (±3 days).

Intervention: Vaccination with a two dose regimen of CoronaVac.

Main Outcome Measures: RT-PCR confirmed symptomatic covid-19 and associated hospital admissions and deaths.

Results: Adjusted vaccine effectiveness against symptomatic covid-19 was 24.7% (95% confidence interval 14.7% to 33.4%) at 0-13 days and 46.8% (38.7% to 53.8%) at ≥14 days after the second dose. Adjusted vaccine effectiveness against hospital admissions was 55.5% (46.5% to 62.9%) and against deaths was 61.2% (48.9% to 70.5%) at ≥14 days after the second dose. Vaccine effectiveness ≥14 days after the second dose was highest for the youngest age group (70-74 years)-59.0% (43.7% to 70.2%) against symptomatic disease, 77.6% (62.5% to 86.7%) against hospital admissions, and 83.9% (59.2% to 93.7%) against deaths-and declined with increasing age.

Conclusions: Vaccination with CoronaVac was associated with a reduction in symptomatic covid-19, hospital admissions, and deaths in adults aged ≥70 years in a setting with extensive transmission of the gamma variant. Vaccine protection was, however, low until completion of the two dose regimen, and vaccine effectiveness was observe to decline with increasing age among this elderly population.
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http://dx.doi.org/10.1136/bmj.n2015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8377801PMC
August 2021

Effectiveness of CoronaVac among healthcare workers in the setting of high SARS-CoV-2 Gamma variant transmission in Manaus, Brazil: A test-negative case-control study.

Lancet Reg Health Am 2021 Sep 25;1:100025. Epub 2021 Jul 25.

Department of Epidemiology of Microbial Diseases, Yale School of Public Health, New Haven, CT, USA.

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Gamma, emerged in the city of Manaus in late 2020 during a large resurgence of coronavirus disease (COVID-19), and has spread throughout Brazil. The effectiveness of vaccines in settings with widespread Gamma variant transmission has not been reported.

Methods: We performed a matched test-negative case-control study to estimate the effectiveness of an inactivated vaccine, CoronaVac, in healthcare workers (HCWs) in Manaus, where the Gamma variant accounted for 86% of genotyped SARS-CoV-2 samples at the peak of its epidemic. We performed an early analysis of effectiveness following administration of at least one vaccine dose and an analysis of effectiveness of the two-dose schedule. The primary outcome was symptomatic SARS-CoV-2 infection.

Findings: For the early at-least-one-dose and two-dose analyses the study population was, respectively, 53,176 and 53,153 HCWs residing in Manaus and aged 18 years or older, with complete information on age, residence, and vaccination status. Among 53,153 HCWs eligible for the two-dose analysis, 47,170 (89%) received at least one dose of CoronaVac and 2,656 individuals (5%) underwent RT-PCR testing from 19 January, 2021 to 13 April, 2021. Of 3,195 RT-PCR tests, 885 (28%) were positive. 393 and 418 case-control pairs were selected for the early and two-dose analyses, respectively, matched on calendar time, age, and neighbourhood. Among those who had received both vaccine doses before the RT-PCR sample collection date, the average time from second dose to sample collection date was 14 days (IQR 7-24). In the early analysis, vaccination with at least one dose was associated with a 0.50-fold reduction (adjusted vaccine effectiveness (VE), 49.6%, 95% CI 11.3 to 71.4) in the odds of symptomatic SARS-CoV-2 infection during the period 14 days or more after receiving the first dose. However, we estimated low effectiveness (adjusted VE 36.8%, 95% CI -54.9 to 74.2) of the two-dose schedule against symptomatic SARS-CoV-2 infection during the period 14 days or more after receiving the second dose. A finding that vaccinated individuals were much more likely to be infected than unvaccinated individuals in the period 0-13 days after first dose (aOR 2.11, 95% CI 1.36-3.27) suggests that unmeasured confounding led to downward bias in the vaccine effectiveness estimate.

Interpretation: Evidence from this test-negative study of the effectiveness of CoronaVac was mixed, and likely affected by bias in this setting. Administration of at least one vaccine dose showed effectiveness against symptomatic SARS-CoV-2 infection in the setting of epidemic Gamma variant transmission. However, the low estimated effectiveness of the two-dose schedule underscores the need to maintain non-pharmaceutical interventions while vaccination campaigns with CoronaVac are being implemented.

Funding: Fundação Oswaldo Cruz (Fiocruz); Municipal Health Secretary of Manaus; Fundação de Vigilância em Saúde do Amazonas.
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http://dx.doi.org/10.1016/j.lana.2021.100025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310555PMC
September 2021

Gut microbiome dysbiosis during COVID-19 is associated with increased risk for bacteremia and microbial translocation.

Res Sq 2021 Jul 27. Epub 2021 Jul 27.

The microbial populations in the gut microbiome have recently been associated with COVID-19 disease severity. However, a causal impact of the gut microbiome on COVID-19 patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. Antibiotics and other treatments during COVID-19 can potentially confound microbiome associations. We therefore first demonstrate that the gut microbiome is directly affected by SARS-CoV-2 infection in a dose-dependent manner in a mouse model, causally linking viral infection and gut microbiome dysbiosis. Comparison with stool samples collected from 97 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, paralleling our observations in the animal model. Specifically, we observed blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species in hospitalized COVID-19 patients. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data obtained from these patients suggest that bacteria translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID 19.
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http://dx.doi.org/10.21203/rs.3.rs-726620/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8328072PMC
July 2021

Social determinants associated with Zika virus infection in pregnant women.

PLoS Negl Trop Dis 2021 Jul 30;15(7):e0009612. Epub 2021 Jul 30.

Instituto de Saúde Coletiva, Universidade Federal da Bahia, Salvador, Brazil.

This study aims to describe the sociodemographic determinants associated with exposure to Zika Virus (ZIKV) in pregnant women during the 2015-2016 epidemic in Salvador, Brazil.

Methods: We recruited women who gave birth between October 2015 and January 2016 to a cross-sectional study at a referral maternity hospital in Salvador, Brazil. We collected information on their demographic, socioeconomic, and clinical characteristics, and evaluated their ZIKV exposure using a plaque reduction neutralization test. Logistic regression was then used to assess the relationship between these social determinants and ZIKV exposure status.

Results: We included 469 pregnant women, of whom 61% had a positive ZIKV result. Multivariate analysis found that lower education (adjusted Prevalence Rate [aPR] 1.21; 95%CI 1.04-1.35) and food insecurity (aPR 1.17; 95%CI 1.01-1.30) were positively associated with ZIKV exposure. Additionally, age was negatively associated with the infection risk (aPR 0.99; 95%CI 0.97-0.998).

Conclusion: Eve after controlling for age, differences in key social determinants, as education and food security, were associated with the risk of ZIKV infection among pregnant women in Brazil. Our findings elucidate risk factors that can be targeted by future interventions to reduce the impact of ZIKV infection in this vulnerable population.
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http://dx.doi.org/10.1371/journal.pntd.0009612DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323902PMC
July 2021

Maternal outcomes and risk factors for COVID-19 severity among pregnant women.

Sci Rep 2021 07 6;11(1):13898. Epub 2021 Jul 6.

Department of Obstetrics & Gynecology, University of Campinas, Campinas, Brazil.

Pregnant women may be at higher risk of severe complications associated with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which may lead to obstetrical complications. We performed a case control study comparing pregnant women with severe coronavirus disease 19 (cases) to pregnant women with a milder form (controls) enrolled in the COVI-Preg international registry cohort between March 24 and July 26, 2020. Risk factors for severity, obstetrical and immediate neonatal outcomes were assessed. A total of 926 pregnant women with a positive test for SARS-CoV-2 were included, among which 92 (9.9%) presented with severe COVID-19 disease. Risk factors for severe maternal outcomes were pulmonary comorbidities [aOR 4.3, 95% CI 1.9-9.5], hypertensive disorders [aOR 2.7, 95% CI 1.0-7.0] and diabetes [aOR2.2, 95% CI 1.1-4.5]. Pregnant women with severe maternal outcomes were at higher risk of caesarean section [70.7% (n = 53/75)], preterm delivery [62.7% (n = 32/51)] and newborns requiring admission to the neonatal intensive care unit [41.3% (n = 31/75)]. In this study, several risk factors for developing severe complications of SARS-CoV-2 infection among pregnant women were identified including pulmonary comorbidities, hypertensive disorders and diabetes. Obstetrical and neonatal outcomes appear to be influenced by the severity of maternal disease.
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http://dx.doi.org/10.1038/s41598-021-92357-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260739PMC
July 2021

Kynurenic acid may underlie sex-specific immune responses to COVID-19.

Sci Signal 2021 07 6;14(690). Epub 2021 Jul 6.

Department of Environmental Health Sciences, Yale School of Public Health, New Haven, CT 06510, USA.

Coronavirus disease 2019 (COVID-19) has poorer clinical outcomes in males than in females, and immune responses underlie these sex-related differences. Because immune responses are, in part, regulated by metabolites, we examined the serum metabolomes of COVID-19 patients. In male patients, kynurenic acid (KA) and a high KA-to-kynurenine (K) ratio (KA:K) positively correlated with age and with inflammatory cytokines and chemokines and negatively correlated with T cell responses. Males that clinically deteriorated had a higher KA:K than those that stabilized. KA inhibits glutamate release, and glutamate abundance was lower in patients that clinically deteriorated and correlated with immune responses. Analysis of data from the Genotype-Tissue Expression (GTEx) project revealed that the expression of the gene encoding the enzyme that produces KA, kynurenine aminotransferase, correlated with cytokine abundance and activation of immune responses in older males. This study reveals that KA has a sex-specific link to immune responses and clinical outcomes in COVID-19, suggesting a positive feedback between metabolites and immune responses in males.
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http://dx.doi.org/10.1126/scisignal.abf8483DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8432948PMC
July 2021

Reducing Lung ATP Levels and Alleviating Asthmatic Airway Inflammation through Adeno-Associated Viral Vector-Mediated CD39 Expression.

Biomedicines 2021 Jun 8;9(6). Epub 2021 Jun 8.

Department of Microbiology and Immunology, Graduate Institute of Biomedical Sciences, College of Medicine, Chang Gung University, Taoyuan 33302, Taiwan.

Asthma is a chronic respiratory inflammatory disease. Patients usually suffer long-term symptoms and high medical expenses. Extracellular ATP (eATP) has been identified as a danger signal in innate immunity and serves as a potent inflammatory mediator for asthma. Hydrolyzing eATP in lungs might be a potential approach to alleviate asthmatic inflammation. Recombinant adeno-associated virus (rAAV) vectors that contain tissue-specific cap protein have been demonstrated to efficiently transfer exogenous genes into the lung tissues. To test anti-inflammation efficacy of rAAV-mediated CD39 gene transfer, rAAV-CD39 was generated and applied to OVA-mediated asthmatic mice. BALB/c mice were sensitized intraperitoneally and challenged intratracheally with OVA and treated with rAAV-CD39. At the end of procedure, some inflammatory features were examined. rAAV-CD39 treatment downregulated the levels of pulmonary eATP by the rescued expression of CD39. Several asthmatic features, such as airway hyperresponsiveness, eosinophilia, mucin deposition, and IL-5/IL-13 production in the lungs were decreased in the rAAV-CD39-treated mice. Reduced IL-5/IL-13 production and increased frequency of CD4FoxP3 regulatory T cells were detected in draining lymph nodes of rAAV-CD39 treated mice. This evidence suggested that rAAV-mediated CD39 gene transfer attenuated the asthmatic airway inflammation locally. The results suggest that rAAV-CD39 might have therapeutic potential for asthma.
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http://dx.doi.org/10.3390/biomedicines9060656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8228057PMC
June 2021

Rapid, reliable, and reproducible cell fusion assay to quantify SARS-Cov-2 spike interaction with hACE2.

PLoS Pathog 2021 06 24;17(6):e1009683. Epub 2021 Jun 24.

Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, Connecticut, United States of America.

COVID-19 is a global crisis of unimagined dimensions. Currently, Remedesivir is only fully licensed FDA therapeutic. A major target of the vaccine effort is the SARS-CoV-2 spike-hACE2 interaction, and assessment of efficacy relies on time consuming neutralization assay. Here, we developed a cell fusion assay based upon spike-hACE2 interaction. The system was tested by transient co-transfection of 293T cells, which demonstrated good correlation with standard spike pseudotyping for inhibition by sera and biologics. Then established stable cell lines were very well behaved and gave even better correlation with pseudotyping results, after a short, overnight co-incubation. Results with the stable cell fusion assay also correlated well with those of a live virus assay. In summary we have established a rapid, reliable, and reproducible cell fusion assay that will serve to complement the other neutralization assays currently in use, is easy to implement in most laboratories, and may serve as the basis for high throughput screens to identify inhibitors of SARS-CoV-2 virus-cell binding and entry.
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http://dx.doi.org/10.1371/journal.ppat.1009683DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8263067PMC
June 2021

Genetic evidence for a potential environmental pathway to spillover infection of rat-borne leptospirosis.

J Infect Dis 2021 Jun 17. Epub 2021 Jun 17.

Yale School of Public Health, New Haven, Connecticut, USA.

In this study, we genotyped samples from environmental reservoirs (surface water and soil), colonized rat specimens and cases of human severe leptospirosis from an endemic urban slum in Brazil, to determine the molecular epidemiology of pathogenic Leptospira and identify pathways of leptospirosis infection. We identified a well-stablished population of Leptospira interrogans serovar Copenhageni common to human leptospirosis cases, and animal and environmental reservoirs. This finding provides genetic evidence for a potential environmental spillover pathway for rat-borne leptospirosis through the environment in this urban community and highlights the importance of environmental and social interventions to reduce spillover infections.
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http://dx.doi.org/10.1093/infdis/jiab323DOI Listing
June 2021

Long noncoding RNA HAR1A regulates oral cancer progression through the alpha-kinase 1, bromodomain 7, and myosin IIA axis.

J Mol Med (Berl) 2021 Sep 7;99(9):1323-1334. Epub 2021 Jun 7.

Environment-Omics-Disease Research Center, China Medical University Hospital, China Medical University, No. 2 Yude Road, Taichung, 40447, Taiwan.

Studies suggested that long noncoding HAR1A RNA may be a tumor suppressor, but its association with oral cancer remains unclear. Here, we show the functional role and mechanisms of HAR1A in oral cancer progression. Microarray analysis was performed to screen the related candidates of long noncoding RNA (lncRNA) in human monocytes. Following lncRNA HAR1A, the regulation of HAR1A, ALPK1, myosin IIA, and BRD7 was tested using reverse-transcription quantitative polymerase chain reaction (RT-qPCR) in oral cancer cells. The inflammatory and epithelial-to-mesenchymal transition marker expressions were analyzed using enzyme-linked immunosorbent assay and western blot. Phenotypic experiments were verified by colony formation assay, transwell migration assay, and Annexin V-apoptotic assay. In the nuclei of cancer cells, HAR1A functions upstream of signaling pathways and knockdown of HAR1A promoted ALPK1 expression and downregulated BRD7 resulting in inflammation and oral cancer progression. In monocytes, the expressions of TNF-α and CCL2 were increased following HAR1A knockdown and reduced following ALPK1 knockdown. HAR1A knockdown upregulated the expression of ALPK1, slug, vimentin, fibronectin, and N-cadherin but reduced the expression of E-cadherin in oral cancer cells. Myosin IIA was primarily located in the cytoplasm and that its decrease in the nuclei of oral cancer cells was likely to demonstrate suppressive ability in late-stage cancer. Our findings suggest that the HAR1A, BRD7, and myosin IIA are tumor suppressors while ALPK1 has oncogene-like property in the nucleus and is involved in inflammation and oral cancer progression. More research for HAR1A activators or ALPK1 inhibitors is required to develop potential therapeutic agents for advanced oral cancer. KEY MESSAGES: lncRNA HAR1A, BRD7, and myosin IIA are tumor suppressors whereas ALPK1 has an oncogenic-like property in the nucleus. lncRNA HAR1A/ALPK1/BRD7/myosin IIA axis plays a critical role in the progression of oral cancer. lncRNA HAR1A localizes upstream of signaling pathways to inhibit ALPK1 expression and then upregulated BRD7. lncRNA HAR1A and ALPK1 are involved in cancer progression via epithelial-to-mesenchymal transition regulations. ALPK1 inhibitors are potential kinase-targeted therapeutic agents for patients with advanced oral cancer.
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http://dx.doi.org/10.1007/s00109-021-02095-xDOI Listing
September 2021

infection induces cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein.

medRxiv 2021 May 12. Epub 2021 May 12.

Individuals with acute malaria infection generated high levels of antibodies that cross-react with the SARS-CoV-2 Spike protein. Cross-reactive antibodies specifically recognized the sialic acid moiety on N-linked glycans of the Spike protein and do not neutralize SARS-CoV-2. Sero-surveillance is critical for monitoring and projecting disease burden and risk during the pandemic; however, routine use of Spike protein-based assays may overestimate SARS-CoV-2 exposure and population-level immunity in malaria-endemic countries.
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http://dx.doi.org/10.1101/2021.05.10.21256855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132281PMC
May 2021

Accuracy of Computable Phenotyping Approaches for SARS-CoV-2 Infection and COVID-19 Hospitalizations from the Electronic Health Record.

medRxiv 2021 May 13. Epub 2021 May 13.

Objective: Real-world data have been critical for rapid-knowledge generation throughout the COVID-19 pandemic. To ensure high-quality results are delivered to guide clinical decision making and the public health response, as well as characterize the response to interventions, it is essential to establish the accuracy of COVID-19 case definitions derived from administrative data to identify infections and hospitalizations.

Methods: Electronic Health Record (EHR) data were obtained from the clinical data warehouse of the Yale New Haven Health System (Yale, primary site) and 3 hospital systems of the Mayo Clinic (validation site). Detailed characteristics on demographics, diagnoses, and laboratory results were obtained for all patients with either a positive SARS-CoV-2 PCR or antigen test or ICD-10 diagnosis of COVID-19 (U07.1) between April 1, 2020 and March 1, 2021. Various computable phenotype definitions were evaluated for their accuracy to identify SARS-CoV-2 infection and COVID-19 hospitalizations.

Results: Of the 69,423 individuals with either a diagnosis code or a laboratory diagnosis of a SARS-CoV-2 infection at Yale, 61,023 had a principal or a secondary diagnosis code for COVID-19 and 50,355 had a positive SARS-CoV-2 test. Among those with a positive laboratory test, 38,506 (76.5%) and 3449 (6.8%) had a principal and secondary diagnosis code of COVID-19, respectively, while 8400 (16.7%) had no COVID-19 diagnosis. Moreover, of the 61,023 patients with a COVID-19 diagnosis code, 19,068 (31.2%) did not have a positive laboratory test for SARS-CoV-2 in the EHR. Of the 20 cases randomly sampled from this latter group for manual review, all had a COVID-19 diagnosis code related to asymptomatic testing with negative subsequent test results. The positive predictive value (precision) and sensitivity (recall) of a COVID-19 diagnosis in the medical record for a documented positive SARS-CoV-2 test were 68.8% and 83.3%, respectively. Among 5,109 patients who were hospitalized with a principal diagnosis of COVID-19, 4843 (94.8%) had a positive SARS-CoV-2 test within the 2 weeks preceding hospital admission or during hospitalization. In addition, 789 hospitalizations had a secondary diagnosis of COVID-19, of which 446 (56.5%) had a principal diagnosis consistent with severe clinical manifestation of COVID-19 (e.g., sepsis or respiratory failure). Compared with the cohort that had a principal diagnosis of COVID-19, those with a secondary diagnosis had a more than 2-fold higher in-hospital mortality rate (13.2% vs 28.0%, P<0.001). In the validation sample at Mayo Clinic, diagnosis codes more consistently identified SARS-CoV-2 infection (precision of 95%) but had lower recall (63.5%) with substantial variation across the 3 Mayo Clinic sites. Similar to Yale, diagnosis codes consistently identified COVID-19 hospitalizations at Mayo, with hospitalizations defined by secondary diagnosis code with 2-fold higher in-hospital mortality compared to those with a primary diagnosis of COVID-19.

Conclusions: COVID-19 diagnosis codes misclassified the SARS-CoV-2 infection status of many people, with implications for clinical research and epidemiological surveillance. Moreover, the codes had different performance across two academic health systems and identified groups with different risks of mortality. Real-world data from the EHR can be used to in conjunction with diagnosis codes to improve the identification of people infected with SARS-CoV-2.
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http://dx.doi.org/10.1101/2021.03.16.21253770DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132274PMC
May 2021

Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient.

Res Sq 2021 May 5. Epub 2021 May 5.

The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal-transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection 7 months after primary infection. To elucidate the immunological mechanisms responsible for reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses that was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we identified the development of neutralizing antibodies and humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation.
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http://dx.doi.org/10.21203/rs.3.rs-405958/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8132249PMC
May 2021

Diverse functional autoantibodies in patients with COVID-19.

Nature 2021 07 19;595(7866):283-288. Epub 2021 May 19.

Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, CT, USA.

COVID-19 manifests with a wide spectrum of clinical phenotypes that are characterized by exaggerated and misdirected host immune responses. Although pathological innate immune activation is well-documented in severe disease, the effect of autoantibodies on disease progression is less well-defined. Here we use a high-throughput autoantibody discovery technique known as rapid extracellular antigen profiling to screen a cohort of 194 individuals infected with SARS-CoV-2, comprising 172 patients with COVID-19 and 22 healthcare workers with mild disease or asymptomatic infection, for autoantibodies against 2,770 extracellular and secreted proteins (members of the exoproteome). We found that patients with COVID-19 exhibit marked increases in autoantibody reactivities as compared to uninfected individuals, and show a high prevalence of autoantibodies against immunomodulatory proteins (including cytokines, chemokines, complement components and cell-surface proteins). We established that these autoantibodies perturb immune function and impair virological control by inhibiting immunoreceptor signalling and by altering peripheral immune cell composition, and found that mouse surrogates of these autoantibodies increase disease severity in a mouse model of SARS-CoV-2 infection. Our analysis of autoantibodies against tissue-associated antigens revealed associations with specific clinical characteristics. Our findings suggest a pathological role for exoproteome-directed autoantibodies in COVID-19, with diverse effects on immune functionality and associations with clinical outcomes.
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http://dx.doi.org/10.1038/s41586-021-03631-yDOI Listing
July 2021

Maternal respiratory SARS-CoV-2 infection in pregnancy is associated with a robust inflammatory response at the maternal-fetal interface.

Med (N Y) 2021 May 30;2(5):591-610.e10. Epub 2021 Apr 30.

Department of Obstetrics, Gynecology, and Reproductive Sciences, Yale School of Medicine, New Haven, CT, USA.

Background: Pregnant women are at increased risk for severe outcomes from coronavirus disease 2019 (COVID-19), but the pathophysiology underlying this increased morbidity and its potential effect on the developing fetus is not well understood.

Methods: We assessed placental histology, ACE2 expression, and viral and immune dynamics at the term placenta in pregnant women with and without respiratory severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Findings: The majority (13 of 15) of placentas analyzed had no detectable viral RNA. ACE2 was detected by immunohistochemistry in syncytiotrophoblast cells of the normal placenta during early pregnancy but was rarely seen in healthy placentas at full term, suggesting that low ACE2 expression may protect the term placenta from viral infection. Using immortalized cell lines and primary isolated placental cells, we found that cytotrophoblasts, the trophoblast stem cells and precursors to syncytiotrophoblasts, rather than syncytiotrophoblasts or Hofbauer cells, are most vulnerable to SARS-CoV-2 infection . To better understand potential immune mechanisms shielding placental cells from infection , we performed bulk and single-cell transcriptomics analyses and found that the maternal-fetal interface of SARS-CoV-2-infected women exhibited robust immune responses, including increased activation of natural killer (NK) and T cells, increased expression of interferon-related genes, as well as markers associated with pregnancy complications such as preeclampsia.

Conclusions: SARS-CoV-2 infection in late pregnancy is associated with immune activation at the maternal-fetal interface even in the absence of detectable local viral invasion.

Funding: NIH (T32GM007205, F30HD093350, K23MH118999, R01AI157488, U01DA040588) and Fast Grant funding support from Emergent Ventures at the Mercatus Center.
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http://dx.doi.org/10.1016/j.medj.2021.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8084634PMC
May 2021

Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms.

Cell Rep Med 2021 May 3;2(5):100288. Epub 2021 May 3.

Department of Internal Medicine, Section of Infectious Diseases, Yale School of Medicine, New Haven, CT, USA.

Individuals with coronavirus disease 2019 (COVID-19) frequently develop neurological symptoms, but the biological underpinnings of these phenomena are unknown. Through single-cell RNA sequencing (scRNA-seq) and cytokine analyses of cerebrospinal fluid (CSF) and blood from individuals with COVID-19 with neurological symptoms, we find compartmentalized, CNS-specific T cell activation and B cell responses. All affected individuals had CSF anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies whose target epitopes diverged from serum antibodies. In an animal model, we find that intrathecal SARS-CoV-2 antibodies are present only during brain infection and not elicited by pulmonary infection. We produced CSF-derived monoclonal antibodies from an individual with COVID-19 and found that these monoclonal antibodies (mAbs) target antiviral and antineural antigens, including one mAb that reacted to spike protein and neural tissue. CSF immunoglobulin G (IgG) from 5 of 7 patients showed antineural reactivity. This immune survey reveals evidence of a compartmentalized immune response in the CNS of individuals with COVID-19 and suggests a role of autoimmunity in neurologic sequelae of COVID-19.
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http://dx.doi.org/10.1016/j.xcrm.2021.100288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8091032PMC
May 2021

Delayed production of neutralizing antibodies correlates with fatal COVID-19.

Nat Med 2021 07 5;27(7):1178-1186. Epub 2021 May 5.

Department of Medicine, Section of Infectious Diseases, Yale University School of Medicine, New Haven, CT, USA.

Recent studies have provided insights into innate and adaptive immune dynamics in coronavirus disease 2019 (COVID-19). However, the exact features of antibody responses that govern COVID-19 disease outcomes remain unclear. In this study, we analyzed humoral immune responses in 229 patients with asymptomatic, mild, moderate and severe COVID-19 over time to probe the nature of antibody responses in disease severity and mortality. We observed a correlation between anti-spike (S) immunoglobulin G (IgG) levels, length of hospitalization and clinical parameters associated with worse clinical progression. Although high anti-S IgG levels correlated with worse disease severity, such correlation was time dependent. Deceased patients did not have higher overall humoral response than discharged patients. However, they mounted a robust, yet delayed, response, measured by anti-S, anti-receptor-binding domain IgG and neutralizing antibody (NAb) levels compared to survivors. Delayed seroconversion kinetics correlated with impaired viral control in deceased patients. Finally, although sera from 85% of patients displayed some neutralization capacity during their disease course, NAb generation before 14 d of disease onset emerged as a key factor for recovery. These data indicate that COVID-19 mortality does not correlate with the cross-sectional antiviral antibody levels per se but, rather, with the delayed kinetics of NAb production.
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http://dx.doi.org/10.1038/s41591-021-01355-0DOI Listing
July 2021

Comparative analysis of DNA extraction protocols for ancient soft tissue museum samples.

Zool Res 2021 May;42(3):280-286

Key Laboratory of Vertebrate Evolution and Human Origins, Institute of Vertebrate Paleontology and Paleoanthropology, Chinese Academy of Sciences, Beijing 100044, China.

DNA studies of endangered or extinct species often rely on ancient or degraded remains. The majority of ancient DNA (aDNA) extraction protocols focus on skeletal elements, with skin and hair samples rarely explored. Similar to that found in bones and teeth, DNA extracted from historical or ancient skin and fur samples is also extremely fragmented with low endogenous content due to natural degradation processes. Thus, the development of effective DNA extraction methods is required for these materials. Here, we compared the performance of two DNA extraction protocols (commercial and custom laboratory aDNA methods) on hair and skin samples from decades-old museum specimens to Iron Age archaeological material. We found that apart from the impact sample-specific taphonomic and handling history has on the quantity and quality of DNA preservation, skin yielded more endogenous DNA than hair of the samples and protocols tested. While both methods recovered DNA from ancient soft tissue, the laboratory method performed better overall in terms of DNA yield and quality, which was primarily due to the poorer performance of the commercial binding buffer in recovering aDNA.
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http://dx.doi.org/10.24272/j.issn.2095-8137.2020.377DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8175948PMC
May 2021

Genomic insights into population history and biological adaptation in Oceania.

Nature 2021 Apr 14;592(7855):583-589. Epub 2021 Apr 14.

Human Evolutionary Genetics Unit, Institut Pasteur, UMR 2000, CNRS, Paris, France.

The Pacific region is of major importance for addressing questions regarding human dispersals, interactions with archaic hominins and natural selection processes. However, the demographic and adaptive history of Oceanian populations remains largely uncharacterized. Here we report high-coverage genomes of 317 individuals from 20 populations from the Pacific region. We find that the ancestors of Papuan-related ('Near Oceanian') groups underwent a strong bottleneck before the settlement of the region, and separated around 20,000-40,000 years ago. We infer that the East Asian ancestors of Pacific populations may have diverged from Taiwanese Indigenous peoples before the Neolithic expansion, which is thought to have started from Taiwan around 5,000 years ago. Additionally, this dispersal was not followed by an immediate, single admixture event with Near Oceanian populations, but involved recurrent episodes of genetic interactions. Our analyses reveal marked differences in the proportion and nature of Denisovan heritage among Pacific groups, suggesting that independent interbreeding with highly structured archaic populations occurred. Furthermore, whereas introgression of Neanderthal genetic information facilitated the adaptation of modern humans related to multiple phenotypes (for example, metabolism, pigmentation and neuronal development), Denisovan introgression was primarily beneficial for immune-related functions. Finally, we report evidence of selective sweeps and polygenic adaptation associated with pathogen exposure and lipid metabolism in the Pacific region, increasing our understanding of the mechanisms of biological adaptation to island environments.
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http://dx.doi.org/10.1038/s41586-021-03236-5DOI Listing
April 2021

in urban populations of terrestrial gastropods and rats in an impoverished region of Brazil.

Parasitology 2021 Apr 12:1-9. Epub 2021 Apr 12.

Universidade Federal da Bahia, UFBA, Salvador, Brazil.

The nematode Angiostrongylus cantonensis is the most common cause of neuroangiostrongyliasis (manifested as eosinophilic meningitis) in humans. Gastropod molluscs are used as intermediate hosts and rats of various species are definitive hosts of this parasite. In this study, we identified several environmental factors associated with the presence and abundance of terrestrial gastropods in an impoverished urban region in Brazil. We also found that body condition, age and presence of co-infection with other parasite species in urban Rattus norvegicus, as well as environmental factors were associated with the probability and intensity of A. cantonensis infection. The study area was also found to have a moderate prevalence of the nematode in rodents (33% of 168 individuals). Eight species of molluscs (577 individuals) were identified, four of which were positive for A. cantonensis. Our study indicates that the environmental conditions of poor urban areas (presence of running and standing water, sewage, humidity and accumulated rain and accumulation of construction materials) influenced both the distribution and abundance of terrestrial gastropods, as well as infected rats, contributing to the maintenance of the A. cantonensis transmission cycle in the area. Besides neuroangiostrongyliasis, the presence of these hosts may also contribute to susceptibility to other zoonoses.
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http://dx.doi.org/10.1017/S0031182021000597DOI Listing
April 2021

The escalating tuberculosis crisis in central and South American prisons.

Lancet 2021 Apr 8;397(10284):1591-1596. Epub 2021 Apr 8.

Division of Infectious Diseases & Geographic Medicine, School of Medicine, Stanford University, Stanford, CA, USA.

In the past decade, tuberculosis incidence has declined in much of the world, but has risen in central and South America. It is not yet clear what is driving this reversal of progress in tuberculosis control. Since 2000, the incarcerated population in central and South America has grown by 206%, the greatest increase in the world. Over the same period, notified tuberculosis cases among the incarcerated population (hereinafter termed persons deprived of their liberty [PDL], following the Inter-American Commission on Human Rights) have risen by 269%. In both central and South America, the rise of disease among PDL more than offsets tuberculosis control gains in the general population. Tuberculosis is increasingly concentrated among PDL; currently, 11% of all notified tuberculosis cases in central and South America occur among PDL who comprise less than 1% of the population. The extraordinarily high risk of acquiring tuberculosis within prisons creates a health and human rights crisis for PDL that also undermines wider tuberculosis control efforts. Controlling tuberculosis in this region will require countries to take urgent measures to prioritise the health of PDL.
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http://dx.doi.org/10.1016/S0140-6736(20)32578-2DOI Listing
April 2021

Case Study: Longitudinal immune profiling of a SARS-CoV-2 reinfection in a solid organ transplant recipient.

medRxiv 2021 Mar 26. Epub 2021 Mar 26.

Prior to the emergence of antigenically distinct SARS-CoV-2 variants, reinfections were reported infrequently - presumably due to the generation of durable and protective immune responses. However, case reports also suggested that rare, repeated infections may occur as soon as 48 days following initial disease onset. The underlying immunologic deficiencies enabling SARS-CoV-2 reinfections are currently unknown. Here we describe a renal transplant recipient who developed recurrent, symptomatic SARS-CoV-2 infection - confirmed by whole virus genome sequencing - 7 months after primary infection. To elucidate the immunological mechanisms responsible for SARS-CoV-2 reinfection, we performed longitudinal profiling of cellular and humoral responses during both primary and recurrent SARS-CoV-2 infection. We found that the patient responded to the primary infection with transient, poor-quality adaptive immune responses. The patient's immune system was further compromised by intervening treatment for acute rejection of the renal allograft prior to reinfection. Importantly, we also identified the development of neutralizing antibodies and the formation of humoral memory responses prior to SARS-CoV-2 reinfection. However, these neutralizing antibodies failed to confer protection against reinfection, suggesting that additional factors are required for efficient prevention of SARS-CoV-2 reinfection. Further, we found no evidence supporting viral evasion of primary adaptive immune responses, suggesting that susceptibility to reinfection may be determined by host factors rather than pathogen adaptation in this patient. In summary, our study suggests that a low neutralizing antibody presence alone is not sufficient to confer resistance against reinfection. Thus, patients with solid organ transplantation, or patients who are otherwise immunosuppressed, who recover from infection with SARS-CoV-2 may not develop sufficient protective immunity and are at risk of reinfection.
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http://dx.doi.org/10.1101/2021.03.24.21253992DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010761PMC
March 2021

Poverty, sanitation, and Leptospira transmission pathways in residents from four Brazilian slums.

PLoS Negl Trop Dis 2021 03 31;15(3):e0009256. Epub 2021 Mar 31.

Institute of Collective Health, Federal University of Bahia, Salvador, Brazil.

Residents of urban slums suffer from a high burden of zoonotic diseases due to individual, socioeconomic, and environmental factors. We conducted a cross-sectional sero-survey in four urban slums in Salvador, Brazil, to characterize how poverty and sanitation contribute to the transmission of rat-borne leptospirosis. Sero-prevalence in the 1,318 participants ranged between 10.0 and 13.3%. We found that contact with environmental sources of contamination, rather than presence of rat reservoirs, is what leads to higher risk for residents living in areas with inadequate sanitation. Further, poorer residents may be exposed away from the household, and ongoing governmental interventions were not associated with lower transmission risk. Residents at higher risk were aware of their vulnerability, and their efforts improved the physical environment near their household, but did not reduce their infection chances. This study highlights the importance of understanding the socioeconomic and environmental determinants of risk, which ought to guide intervention efforts.
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http://dx.doi.org/10.1371/journal.pntd.0009256DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8041187PMC
March 2021

Clinical characteristics and outcomes for 7,995 patients with SARS-CoV-2 infection.

PLoS One 2021 31;16(3):e0243291. Epub 2021 Mar 31.

Center for Outcomes Research and Evaluation, Yale-New Haven Hospital, New Haven, Connecticut, United States of America.

Objective: Severe acute respiratory syndrome virus (SARS-CoV-2) has infected millions of people worldwide. Our goal was to identify risk factors associated with admission and disease severity in patients with SARS-CoV-2.

Design: This was an observational, retrospective study based on real-world data for 7,995 patients with SARS-CoV-2 from a clinical data repository.

Setting: Yale New Haven Health (YNHH) is a five-hospital academic health system serving a diverse patient population with community and teaching facilities in both urban and suburban areas.

Populations: The study included adult patients who had SARS-CoV-2 testing at YNHH between March 1 and April 30, 2020.

Main Outcome And Performance Measures: Primary outcomes were admission and in-hospital mortality for patients with SARS-CoV-2 infection as determined by RT-PCR testing. We also assessed features associated with the need for respiratory support.

Results: Of the 28605 patients tested for SARS-CoV-2, 7995 patients (27.9%) had an infection (median age 52.3 years) and 2154 (26.9%) of these had an associated admission (median age 66.2 years). Of admitted patients, 2152 (99.9%) had a discharge disposition at the end of the study period. Of these, 329 (15.3%) required invasive mechanical ventilation and 305 (14.2%) expired. Increased age and male sex were positively associated with admission and in-hospital mortality (median age 80.7 years), while comorbidities had a much weaker association with the risk of admission or mortality. Black race (OR 1.43, 95%CI 1.14-1.78) and Hispanic ethnicity (OR 1.81, 95%CI 1.50-2.18) were identified as risk factors for admission, but, among discharged patients, age-adjusted in-hospital mortality was not significantly different among racial and ethnic groups.

Conclusions: This observational study identified, among people testing positive for SARS-CoV-2 infection, older age and male sex as the most strongly associated risks for admission and in-hospital mortality in patients with SARS-CoV-2 infection. While minority racial and ethnic groups had increased burden of disease and risk of admission, age-adjusted in-hospital mortality for discharged patients was not significantly different among racial and ethnic groups. Ongoing studies will be needed to continue to evaluate these risks, particularly in the setting of evolving treatment guidelines.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243291PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011821PMC
April 2021

Incidence and prevalence of tuberculosis in incarcerated populations: a systematic review and meta-analysis.

Lancet Public Health 2021 05 22;6(5):e300-e308. Epub 2021 Mar 22.

Division of Infectious Diseases and Geographic Medicine, Stanford, CA, USA.

Background: Prisons are recognised as high-risk environments for tuberculosis, but there has been little systematic investigation of the global and regional incidence and prevalence of tuberculosis, and its determinants, in prisons. We did a systematic review and meta-analysis to assess the incidence and prevalence of tuberculosis in incarcerated populations by geographical region.

Methods: In this systematic review and meta-analysis, we searched MEDLINE, Embase, Web of Knowledge, and the LILACS electronic database from Jan 1, 1980, to Nov 15, 2020, for cross-sectional and cohort studies reporting the incidence of Mycobacterium tuberculosis infection, incidence of tuberculosis, or prevalence of tuberculosis among incarcerated individuals in all geographical regions. We extracted data from individual studies, and calculated pooled estimates of incidence and prevalence through hierarchical Bayesian meta-regression modelling. We also did subgroup analyses by region. Incidence rate ratios between prisons and the general population were calculated by dividing the incidence of tuberculosis in prisons by WHO estimates of the national population-level incidence.

Findings: We identified 159 relevant studies; 11 investigated the incidence of M tuberculosis infection (n=16 318), 51 investigated the incidence of tuberculosis (n=1 858 323), and 106 investigated the prevalence of tuberculosis (n=6 727 513) in incarcerated populations. The overall pooled incidence of M tuberculosis infection among prisoners was 15·0 (95% credible interval [CrI] 3·8-41·6) per 100 person-years. The incidence of tuberculosis (per 100 000 person-years) among prisoners was highest in studies from the WHO African (2190 [95% CrI 810-4840] cases) and South-East Asia (1550 [240-5300] cases) regions and in South America (970 [460-1860] cases), and lowest in North America (30 [20-50] cases) and the WHO Eastern Mediterranean region (270 [50-880] cases). The prevalence of tuberculosis was greater than 1000 per 100 000 prisoners in all global regions except for North America and the Western Pacific, and highest in the WHO South-East Asia region (1810 [95% CrI 670-4000] cases per 100 000 prisoners). The incidence rate ratio between prisons and the general population was much higher in South America (26·9; 95% CrI 17·1-40·1) than in other regions, but was nevertheless higher than ten in the WHO African (12·6; 6·2-22·3), Eastern Mediterranean (15·6; 6·5-32·5), and South-East Asia (11·7; 4·1-27·1) regions.

Interpretation: Globally, people in prison are at high risk of contracting M tuberculosis infection and developing tuberculosis, with consistent disparities between prisons and the general population across regions. Tuberculosis control programmes should prioritise preventive interventions among incarcerated populations.

Funding: US National Institutes of Health.
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http://dx.doi.org/10.1016/S2468-2667(21)00025-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168455PMC
May 2021

Increased SARS-CoV-2 Testing Capacity with Pooled Saliva Samples.

Emerg Infect Dis 2021 04;27(4)

We analyzed feasibility of pooling saliva samples for severe acute respiratory syndrome coronavirus 2 testing and found that sensitivity decreased according to pool size: 5 samples/pool, 7.4% reduction; 10 samples/pool, 11.1%; and 20 samples/pool, 14.8%. When virus prevalence is >2.6%, pools of 5 require fewer tests; when <0.6%, pools of 20 support screening strategies.
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http://dx.doi.org/10.3201/eid2704.204200DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007323PMC
April 2021

Stability of SARS-CoV-2 RNA in Nonsupplemented Saliva.

Emerg Infect Dis 2021 04;27(4):1146-1150

The expense of saliva collection devices designed to stabilize severe acute respiratory syndrome coronavirus 2 RNA is prohibitive to mass testing. However, virus RNA in nonsupplemented saliva is stable for extended periods and at elevated temperatures. Simple plastic tubes for saliva collection will make large-scale testing and continued surveillance easier.
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http://dx.doi.org/10.3201/eid2704.204199DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007305PMC
April 2021
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