Last data update: Apr 29, 2024. (Total: 46658 publications since 2009)
Records 1-30 (of 311 Records) |
Query Trace: Barr B [original query] |
---|
Inaccurately reported statin use affects the assessing of lipid profile measures and their association with coronary artery disease risk
Ivanova AA , Gardner MS , Kusovschi JD , Parks BA , Schieltz DM , Bareja A , McGarrah RW 3rd , Kraus WE , Kuklenyik Z , Pirkle JL , Barr JR . Clin Chem 2024 70 (3) 528-537 BACKGROUND: Lipid profiling is central for coronary artery disease (CAD) risk assessment. Nonadherence or unreported use of lipid-lowering drugs, particularly statins, can significantly complicate the association between lipid profile measures and CAD clinical outcomes. By combining medication history evaluation with statin analysis in plasma, we determined the effects of inaccurately reported statin use on lipid profile measures and their association with CAD risk. METHODS: We compared medication history of statin use with statin concentration measurements, by liquid chromatography-tandem mass spectrometry, in 690 participants undergoing coronary angiography (63 ± 11 years of age). Nominal logistic regression was employed to model CAD diagnosis with statin measurements, phenotypic, and lipid profile characteristics. RESULTS: Medication history of statin use was confirmed by statin assay for 81% of the patients. Surprisingly, statins were detected in 46% of patients without statin use records. Nonreported statin use was disproportionately higher among older participants. Stratifying samples by statin history resulted in underestimated LDL-lipid measures. Apolipoprotein B concentrations had a significant inverse CAD association, which became nonsignificant upon re-stratification using the statin assay data. CONCLUSIONS: Our study uncovered prominent discrepancies between medication records and actual statin use measured by mass spectrometry. We showed that inaccurate statin use assessments may lead to overestimation and underestimation of LDL levels in statin user and nonuser categories, exaggerating the reverse epidemiology association between LDL levels and CAD diagnosis. Combining medication history and quantitative statin assay data can significantly improve the design, analysis, and interpretation of clinical and epidemiological studies. |
Identifying delays in healthcare seeking and provision: The Three Delays-in-Healthcare and mortality among infants and children aged 1-59 months
Garcia Gomez E , Igunza KA , Madewell ZJ , Akelo V , Onyango D , El Arifeen S , Gurley ES , Hossain MZ , Chowdhury MAI , Islam KM , Assefa N , Scott JAG , Madrid L , Tilahun Y , Orlien S , Kotloff KL , Tapia MD , Keita AM , Mehta A , Magaço A , Torres-Fernandez D , Nhacolo A , Bassat Q , Mandomando I , Ogbuanu I , Cain CJ , Luke R , Kamara SIB , Legesse H , Madhi S , Dangor Z , Mahtab S , Wise A , Adam Y , Whitney CG , Mutevedzi PC , Blau DM , Breiman RF , Tippett Barr BA , Rees CA . PLOS Glob Public Health 2024 4 (2) e0002494 Delays in illness recognition, healthcare seeking, and in the provision of appropriate clinical care are common in resource-limited settings. Our objective was to determine the frequency of delays in the "Three Delays-in-Healthcare", and factors associated with delays, among deceased infants and children in seven countries with high childhood mortality. We conducted a retrospective, descriptive study using data from verbal autopsies and medical records for infants and children aged 1-59 months who died between December 2016 and February 2022 in six sites in sub-Saharan Africa and one in South Asia (Bangladesh) and were enrolled in Child Health and Mortality Prevention Surveillance (CHAMPS). Delays in 1) illness recognition in the home/decision to seek care, 2) transportation to healthcare facilities, and 3) the receipt of clinical care in healthcare facilities were categorized according to the "Three Delays-in-Healthcare". Comparisons in factors associated with delays were made using Chi-square testing. Information was available for 1,326 deaths among infants and under 5 children. The majority had at least one identified delay (n = 854, 64%). Waiting >72 hours after illness recognition to seek health care (n = 422, 32%) was the most common delay. Challenges in obtaining transportation occurred infrequently when seeking care (n = 51, 4%). In healthcare facilities, prescribed medications were sometimes unavailable (n = 102, 8%). Deceased children aged 12-59 months experienced more delay than infants aged 1-11 months (68% vs. 61%, P = 0.018). Delays in seeking clinical care were common among deceased infants and children. Additional study to assess the frequency of delays in seeking clinical care and its provision among children who survive is warranted. |
Burden of child mortality from malaria in high endemic areas: results from the CHAMPS Network using minimally invasive tissue sampling
Ogbuanu IU , Otieno K , Varo R , Sow SO , Ojulong J , Duduyemi B , Kowuor D , Cain CJ , Rogena EA , Onyango D , Akelo V , Tippett Barr BA , terKuile F , Kotloff KL , Tapia MD , Keita AM , Juma J , Assefa N , Assegid N , Acham Y , Madrid L , Scott JAG , Arifeen SE , Gurley ES , Mahtab S , Dangor Z , Wadula J , Dutoit J , Madhi SA , Mandomando I , Torres-Fernandez D , Kincardett M , Mabunda R , Mutevedzi P , Madewell ZJ , Blau DM , Whitney CG , Samuels AM , Bassat Q . J Infect 2024 BACKGROUND: Malaria is a leading cause of childhood mortality worldwide. However, accurate estimates of malaria prevalence and causality among patients who die at the country level are lacking due to the limited specificity of diagnostic tools used to attribute etiologies. Accurate estimates are crucial for prioritizing interventions and resources aimed at reducing malaria-related mortality. METHODS: Seven Child Health and Mortality Prevention Surveillance (CHAMPS) Network sites collected comprehensive data on stillbirths and children <5 years, using minimally invasive tissue sampling (MITS). A DeCoDe (Determination of Cause of Death) panel employed standardized protocols for assigning underlying, intermediate, and immediate causes of death, integrating sociodemographic, clinical, laboratory (including extensive microbiology, histopathology, and malaria testing), and verbal autopsy data. Analyses were conducted to ascertain the strength of evidence for cause of death (CoD), describe factors associated with malaria-related deaths, estimate malaria-specific mortality, and assess the proportion of preventable deaths. FINDINGS: Between December 3, 2016, and December 31, 2022, 2673 deaths underwent MITS and had a CoD attributed from four CHAMPS sites with at least 1 malaria-attributed death. No malaria-attributable deaths were documented among 891 stillbirths or 924 neonatal deaths, therefore this analysis concentrates on the remaining 858 deaths among children aged 1-59 months. Malaria was in the causal chain for 42.9% (126/294) of deaths from Sierra Leone, 31.4% (96/306) in Kenya, 18.2% (36/198) in Mozambique, 6.7% (4/60) in Mali, and 0.3% (1/292) in South Africa. Compared to non-malaria related deaths, malaria-related deaths skewed towards older infants and children (p<0.001), with 71.0% among ages 12-59 months. Malaria was the sole infecting pathogen in 184 (70.2%) of malaria-attributed deaths, whereas bacterial and viral co-infections were identified in the causal pathway in 24·0% and 12.2% of cases, respectively. Malnutrition was found at a similar level in the causal pathway of both malaria (26.7%) and non-malaria (30.7%, p=0.256) deaths. Less than two-thirds (164/262; 62.6%) of malaria deaths had received antimalarials prior to death. Nearly all (98·9%) malaria-related deaths were deemed preventable. INTERPRETATION: Malaria remains a significant cause of childhood mortality in the CHAMPS malaria-endemic sites. The high bacterial co-infection prevalence among malaria deaths underscores the potential benefits of antibiotics for severe malaria patients. Compared to non-malaria deaths, many of malaria-attributed deaths are preventable through accessible malaria control measures. FUNDING: This work was supported by the Bill & Melinda Gates Foundation [OPP1126780]. |
Inclusion of deuterated glycopeptides provides increased sequence coverage in hydrogen/deuterium exchange mass spectrometry analysis of SARS-CoV-2 spike glycoprotein
Haynes CA , Keppel TR , Mekonnen B , Osman SH , Zhou Y , Woolfitt AR , Baudys J , Barr JR , Wang D . Rapid Commun Mass Spectrom 2024 38 (5) Rationale: Hydrogen/deuterium exchange mass spectrometry (HDX-MS) can provide precise analysis of a protein's conformational dynamics across varied states, such as heat-denatured versus native protein structures, localizing regions that are specifically affected by such conditional changes. Maximizing protein sequence coverage provides high confidence that regions of interest were located by HDX-MS, but one challenge for complete sequence coverage is N-glycosylation sites. The deuteration of peptides post-translationally modified by asparagine-bound glycans (glycopeptides) has not always been identified in previous reports of HDX-MS analyses, causing significant sequence coverage gaps in heavily glycosylated proteins and uncertainty in structural dynamics in many regions throughout a glycoprotein. Methods: We detected deuterated glycopeptides with a Tribrid Orbitrap Eclipse mass spectrometer performing data-dependent acquisition. An MS scan was used to identify precursor ions; if high-energy collision-induced dissociation MS/MS of the precursor indicated oxonium ions diagnostic for complex glycans, then electron transfer low-energy collision-induced dissociation MS/MS scans of the precursor identified the modified asparagine residue and the glycan's mass. As in traditional HDX-MS, the identified glycopeptides were then analyzed at the MS level in samples labeled with D2O. Results: We report HDX-MS analysis of the SARS-CoV-2 spike protein ectodomain in its trimeric prefusion form, which has 22 predicted N-glycosylation sites per monomer, with and without heat treatment. We identified glycopeptides and calculated their average isotopic mass shifts from deuteration. Inclusion of the deuterated glycopeptides increased sequence coverage of spike ectodomain from 76% to 84%, demonstrated that glycopeptides had been deuterated, and improved confidence in results localizing structural rearrangements. Conclusion: Inclusion of deuterated glycopeptides improves the analysis of the conformational dynamics of glycoproteins such as viral surface antigens and cellular receptors. Published 2024. This article is a U.S. Government work and is in the public domain in the USA. |
Systematic review of microplastics and nanoplastics in indoor and outdoor air: identifying a framework and data needs for quantifying human inhalation exposures
Eberhard T , Casillas G , Zarus GM , Barr DB . J Expo Sci Environ Epidemiol 2024 BACKGROUND: Humans are likely exposed to microplastics (MPs) in a variety of places including indoor and outdoor air. Research to better understand how exposure to MPs correlates to health is growing. To fully understand the possible impacts of MPs on human health, it is necessary to quantify MP exposure and identify what critical data gaps exist. OBJECTIVES: The current paper provides a human exposure assessment of microplastics in the air using systematically reviewed literature that provided concentration of MPs in air as well as doses used in toxicology studies to calculate inhalation exposure dose. METHODS: All published peer-reviewed journal articles, non-published papers, and grey literature that focused on micro- or nano-plastics in indoor and outdoor air were systematically searched using PRISMA guidelines. Literature that defined specific concentrations and size of MPs in air or exposed to human lung cells, animals, or humans with measurable health impacts were included in data extraction. Inhalational exposures were calculated for different age groups using published MP concentrations from the included literature using exposure dose equations and values from U.S. ATSDR and EPA. RESULTS: Calculated mean indoor inhalational exposures from passive sampling methods were higher than those calculated from active sampling methods. When comparing indoor and outdoor sampling, calculated inhalation exposures from indoor samples were greater than those from outdoor samples. Inhalation exposures of MPs differed between age groups with infants having the highest calculated dose values for all locations followed by preschool age children, middle-school aged children, pregnant women, adolescents, and non-pregnant adults. MP doses used in toxicology studies produced higher calculated mean inhalational exposures than those from environmental samples. IMPACT: This study is the first known systematic review of inhalational MP exposure from indoor and outdoor air. It also provides inhalational exposures calculated from previously published environmental samples of MPs as well as from toxicology studies. |
An antibody-free evaluation of an mRNA COVID-19 vaccine
Branham PJ , Cooper HC , Williamson YM , Najjar FN , Sutton WJH , Pierce-Ruiz CL , Barr JR , Williams TL . Biologicals 2023 85 101738 This manuscript describes the use of an analytical assay that combines transfection of mammalian cells and isotope dilution mass spectrometry (IDMS) for accurate quantification of antigen expression. Expired mRNA COVID-19 vaccine material was stored at 4 °C, room temperature (∼25 °C), and 56 °C over a period of 5 weeks. The same vaccine was also exposed to 5 freeze-thaw cycles. Every week, the spike protein antigenic expression in mammalian (BHK-21) cells was evaluated. Housekeeping proteins, β-actin and GAPDH, were simultaneously quantified to account for the variation in cell counts that occurs during maintenance and growth of cell cultures. Data show that vaccine stored at elevated temperatures results in reduced spike protein expression. Also, maintaining the vaccine in ultracold conditions or exposing the vaccine to freeze-thaw cycles had less effect on the vaccine's ability to produce the antigen in mammalian cells. We describe the use of IDMS as an antibody-free means to accurately quantify expressed protein from mammalian cells transfected with mRNA vaccine. |
Epidemiologic and genomic evidence for zoonotic transmission of SARS-CoV-2 among people and animals on a Michigan mink farm, United States, 2020
Ghai RR , Straily A , Wineland N , Calogero J , Stobierski MG , Signs K , Blievernicht M , Torres-Mendoza Y , Waltenburg MA , Condrey JA , Blankenship HM , Riner D , Barr N , Schalow M , Goodrich J , Collins C , Ahmad A , Metz JM , Herzegh O , Straka K , Arsnoe DM , Duffiney AG , Shriner SA , Kainulainen MH , Carpenter A , Whitehill F , Wendling NM , Stoddard RA , Retchless AC , Uehara A , Tao Y , Li Y , Zhang J , Tong S , Barton Behravesh C . Viruses 2023 15 (12) Farmed mink are one of few animals in which infection with SARS-CoV-2 has resulted in sustained transmission among a population and spillback from mink to people. In September 2020, mink on a Michigan farm exhibited increased morbidity and mortality rates due to confirmed SARS-CoV-2 infection. We conducted an epidemiologic investigation to identify the source of initial mink exposure, assess the degree of spread within the facility's overall mink population, and evaluate the risk of further viral spread on the farm and in surrounding wildlife habitats. Three farm employees reported symptoms consistent with COVID-19 the same day that increased mortality rates were observed among the mink herd. One of these individuals, and another asymptomatic employee, tested positive for SARS-CoV-2 by real-time reverse transcription PCR (RT-qPCR) 9 days later. All but one mink sampled on the farm were positive for SARS-CoV-2 based on nucleic acid detection from at least one oral, nasal, or rectal swab tested by RT-qPCR (99%). Sequence analysis showed high degrees of similarity between sequences from mink and the two positive farm employees. Epidemiologic and genomic data, including the presence of F486L and N501T mutations believed to arise through mink adaptation, support the hypothesis that the two employees with SARS-CoV-2 nucleic acid detection contracted COVID-19 from mink. However, the specific source of virus introduction onto the farm was not identified. Three companion animals living with mink farm employees and 31 wild animals of six species sampled in the surrounding area were negative for SARS-CoV-2 by RT-qPCR. Results from this investigation support the necessity of a One Health approach to manage the zoonotic spread of SARS-CoV-2 and underscores the critical need for multifaceted public health approaches to prevent the introduction and spread of respiratory viruses on mink farms. |
Prevalence and missed cases of respiratory distress syndrome disease amongst neonatal deaths enrolled in the Kenya Child Health and Mortality Prevention Surveillance Network (CHAMPS) Program Between 2017 and 2021
Owuor HO , Akelo V , Murila F , Onyango D , Kuria M , Rogena E , Revathi G , Mitei P , Sava S , Were J , Igunza A , Khagayi S , Zielinski-Gutierrez E , Hawi S , Gethi D , Verani JR , Onyango C , Blau DM , Tippett Barr BA . Glob Pediatr Health 2023 10 2333794x231212819 Objectives. To describe RDS in neonatal deaths at the CHAMPS-Kenya site between 2017 and 2021. Methods. We included 165 neonatal deaths whose their Causes of death (COD) were determined by a panel of experts using data from post-mortem conducted through minimally invasive tissue specimen testing, clinical records, and verbal autopsy. Results. Twenty-six percent (43/165) of neonatal deaths were attributable to RDS. Most cases occurred in low birthweight and preterm neonates. From these cases, less than half of the hospitalizations were diagnosed with RDS before death, and essential diagnostic tests were not performed in most cases. Most cases received suboptimal levels of supplemental oxygen, and critical interventions like surfactant replacement therapy and mechanical ventilation were not adequately utilized when available. Conclusion. The study highlights the urgent need for improved diagnosis and management of RDS, emphasizing the importance of increasing clinical suspicion and enhancing training in its clinical management to reduce mortality rates. |
Performance of CHROMagar ESBL media for the surveillance of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) from rectal swabs in Botswana
Mannathoko N , Lautenbach E , Mosepele M , Otukile D , Sewawa K , Glaser L , Cressman L , Cowden L , Alby K , Jaskowiak-Barr A , Gross R , Mokomane M , Paganotti GM , Styczynski A , Smith RM , Snitkin E , Wan T , Bilker WB , Richard-Greenblatt M . J Med Microbiol 2023 72 (11) Introduction. Lack of laboratory capacity hampers consistent national antimicrobial resistance (AMR) surveillance. Chromogenic media may provide a practical screening tool for detection of individuals colonized by extended-spectrum beta-lactamase (ESBL)-producing organisms.Hypothesis. CHROMagar ESBL media represent an adequate screening method for the detection of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE), isolated from rectal swabs.Aim. To evaluate the performance of CHROMagar ESBL media to accurately identify ESCrE isolates from rectal swab samples attained from hospitalized and community participants.Methodology. All participants provided informed consent prior to enrolment. Rectal swabs from 2469 hospital and community participants were inoculated onto CHROMagar ESBL. The performance of CHROMagar ESBL to differentiate Escherichia coli and Klebsiella spp., Enterobacter spp. and Citrobacter spp. (KEC spp.) as well as select for extended-spectrum cephalosporin resistance were compared to matrix-assisted laser desorption/ionization-time-of-flight MS (MALDI-TOF-MS) and VITEK-2 automated susceptibility testing.Results. CHROMagar ESBL had a positive and negative agreement of 91.2 % (95 % CI, 88.4-93.3) and 86.8 % (95 % CI, 82.0-90.7) for E. coli and 88.1 % (95 % CI 83.2-92.1) and 87.6 % (95 % CI 84.7-90.2) for KEC spp. differentiation, respectively, when compared to species ID by MALDI-TOF-MS. When evaluated for phenotypic susceptibilities (VITEK-2), 88.1 % (714/810) of the isolates recovered on the selective agar exhibited resistance to third-generation cephalosporins.Conclusion. The performance characteristics of CHROMagar ESBL media suggest that they may be a viable screening tool for the identification of ESCrE from hospitalized and community participants and could be used to inform infection prevention and control practices in Botswana and potentially other low-and middle-income countries (LMICs). Further studies are required to analyse the costs and the impact on time-to-result of the media in comparison with available laboratory methods for ESCrE surveillance in the country. |
Standard-dose versus MF59-adjuvanted, high-dose or recombinant-hemagglutinin influenza vaccine immunogenicity in older adults: comparison of A(H3N2) antibody response by prior season's vaccine status
Zhong S , Ng TWY , Skowronski DM , Iuliano AD , Leung NHL , Perera Rapm , Ho F , Fang VJ , Tam YH , Ip DKM , Havers FG , Fry AM , Aziz-Baumgartner E , Barr IG , Peiris M , Thompson MG , Cowling BJ . J Infect Dis 2023 BACKGROUND: Annual influenza vaccination is recommended for older adults but repeated vaccination with standard-dose influenza vaccine has been linked to reduced immunogenicity and effectiveness, especially against A(H3N2) viruses. METHODS: Community-dwelling Hong Kong adults aged 65-82 years were randomly allocated to receive 2017/18 standard-dose quadrivalent, MF59-adjuvanted trivalent, high-dose trivalent, and recombinant-HA quadrivalent vaccination. Antibody response to unchanged A(H3N2) vaccine antigen was compared among participants with and without self-reported prior year (2016/17) standard-dose vaccination. RESULTS: Mean fold rise (MFR) in antibody titers from Day 0 to Day 30 by hemagglutination inhibition and virus microneutralization assays were lower among 2017/18 standard-dose and enhanced vaccine recipients with (range, 1.7-3.0) vs. without (range, 4.3-14.3) prior 2016/17 vaccination. MFR was significantly reduced by about one half to four fifths for previously vaccinated recipients of standard-dose and all three enhanced vaccines (β range, 0.21-0.48). Among prior-year vaccinated older adults, enhanced vaccines induced higher 1.43 to 2.39-fold geometric mean titers and 1.28 to 1.74-fold MFR vs. standard-dose vaccine by microneutralization assay. CONCLUSIONS: In the context of unchanged A(H3N2) vaccine strain, prior-year vaccination was associated with reduced antibody response among both standard-dose and enhanced influenza vaccine recipients. Enhanced vaccines improved antibody response among older adults with prior-year standard-dose vaccination. |
Acceptability of minimally invasive autopsy by community members and healthcare workers in Siaya and Kisumu counties, western Kenya, 2017-2018
Otieno P , Akelo V , Khagayi S , Omore R , Akoth K , Nyanjom M , Ngere S , Ochola K , Maixenchs M , Kone A , Blevins J , Zielinski-Gutierrez E , Barr BAT . PLOS Glob Public Health 2023 3 (9) e0001319 Worldwide, nearly six million children under the age of five (<5s) die annually, a substantial proportion of which are due to preventable and treatable diseases. Efforts to reduce child mortality indicators in the most affected regions are often undermined by a lack of accurate cause of death data. To generate timely and more accurate causes of death data for <5s, the Child Health and Mortality Prevention Surveillance (CHAMPS) Network established mortality surveillance in multiple countries using Minimally Invasive Tissue Sampling (MITS) in <5 deaths. Here we present acceptability of MITS by community members and healthcare workers in Siaya and Kisumu counties, western Kenya. From April 2017 to February 2018, we conducted 40 in-depth interviews and five focus group discussions with healthcare workers and community members, before and during CHAMPS implementation. Participants were purposively selected. Field observations to understand traditional death-related practices were also performed. Interviews were transcribed into Nvivo 11.0 for data organization and management. Analysis was guided by the grounded theory approach. Facilitators of acceptability were desire to understand why death occurred, timely performance of MITS procedures, potential for MITS results in improving clinical practice and specific assistance provided to families by the CHAMPS program. However, cultural and religious beliefs highlighted important challenges to acceptability, including CHAMPS teams recruiting after a child's death, rumours and myths, unmet expectations from families, and fear by healthcare workers that some families could use MITS results to sue for negligence. Increasing MITS uptake requires sustained strategies to strengthen the identified facilitators of acceptability and simultaneously address the barriers. MITS acceptance will contribute to better characterization of causes of death and support the development of improved interventions aimed at reducing <5 mortality. |
Provider adherence to clinical care recommendations for infants and children who died in seven low- and middle-income countries in the Child Health and Mortality Prevention Surveillance (CHAMPS) network
Rees CA , Igunza KA , Madewell ZJ , Akelo V , Onyango D , El Arifeen S , Gurley ES , Hossain MZ , Rahman A , Alam M , Scott JAG , Assefa N , Madrid L , Belachew A , Leulseged H , Kotloff KL , Sow SO , Tapia MD , Keita AM , Sidibe D , Sitoe A , Varo R , Ajanovic S , Bassat Q , Mandomando I , Tippett Barr BA , Ogbuanu I , Cain CJ , Bassey IA , Luke R , Gassama K , Madhi S , Dangor Z , Mahtab S , Velaphi S , du Toit J , Mutevedzi PC , Blau DM , Breiman RF , Whitney CG . EClinicalMedicine 2023 63 102198 BACKGROUND: Most childhood deaths globally are considered preventable through high-quality clinical care, which includes adherence to clinical care recommendations. Our objective was to describe adherence to World Health Organization recommendations for the management of leading causes of death among children. METHODS: We conducted a retrospective, descriptive study examining clinical data for children aged 1-59 months who were hospitalized and died in a Child Health and Mortality Prevention Surveillance (CHAMPS) catchment, December 2016-June 2021. Catchment areas included: Baliakandi and Faridpur, Bangladesh; Kersa, Haramaya, and Harar, Ethiopia; Kisumu and Siaya, Kenya; Bamako, Mali; Manhiça and Quelimane, Mozambique; Makeni, Sierra Leone; Soweto, South Africa. We reviewed medical records of those who died from lower respiratory tract infections, sepsis, malnutrition, malaria, and diarrheal diseases to determine the proportion who received recommended treatments and compared adherence by hospitalization duration. FINDINGS: CHAMPS enrolled 460 hospitalized children who died from the leading causes (median age 12 months, 53.0% male). Median hospital admission was 31 h. There were 51.0% (n = 127/249) of children who died from lower respiratory tract infections received supplemental oxygen. Administration of intravenous fluids for sepsis (15.9%, n = 36/226) and supplemental feeds for malnutrition (14.0%, n = 18/129) were uncommon. There were 51.4% (n = 55/107) of those who died from malaria received antimalarials. Of the 80 children who died from diarrheal diseases, 76.2% received intravenous fluids. Those admitted for ≥24 h more commonly received antibiotics for lower respiratory tract infections and sepsis, supplemental feeds for malnutrition, and intravenous fluids for sepsis than those admitted <24 h. INTERPRETATION: Provision of recommended clinical care for leading causes of death among young children was suboptimal. Further studies are needed to understand the reasons for deficits in clinical care recommendation adherence. FUNDING: Bill & Melinda Gates Foundation. |
Stillbirths and neonatal deaths caused by group B streptococcus in Africa and South Asia identified through Child Health and Mortality Prevention Surveillance (CHAMPS)
Mahtab S , Madewell ZJ , Madhi SA , Wise A , Swart PJ , Velaphi S , Mandomando I , Bramugy J , Mabunda R , Xerinda E , Scott AG , Assefa N , Madrid L , Bweihun M , Temesgen F , Onyango D , Akelo V , Oliech R , Otieno P , Verani JR , Arifeen SE , Gurley ES , Alam M , Rahman A , Hossain MZ , Sow S , Kotloff K , Tapia M , Keita AM , Sanogo D , Ogbuanu I , Ojulong J , Lako S , Ita O , Kaluma E , Wilson T , Mutevedzi P , Barr BAT , Whitney CG , Blau DM , Bassat Q . Open Forum Infect Dis 2023 10 (9) ofad356 BACKGROUND: Invasive Group B Streptococcus (GBS) is a common cause of early-onset neonatal sepsis and is also associated with stillbirth. This study aimed to determine the proportion of stillborn infants and infants who died between 0 and 90 days attributable to GBS using postmortem minimally invasive tissue sampling (MITS) in 7 low- and middle-income countries (LMICs) participating in Child Health and Mortality Prevention Surveillance (CHAMPS). METHODS: Deaths that occurred between December 2016 and December 2021 were investigated with MITS, including culture for bacteria of blood and cerebrospinal fluid (CSF), multipathogen polymerase chain reaction on blood, CSF, and lung tissue and histopathology of lung, liver, and brain. Data collection included clinical record review and verbal autopsy. Expert panels reviewed all information and assigned causes of death. RESULTS: We evaluated 2966 deaths, including stillborn infants (n = 1322), infants who died during first day of life (0 to <24 hours, n = 597), early neonatal deaths (END) (1 day to <7 days; END; n = 593), and deaths from 7 to 90 days (n = 454). Group B Streptococcus was determined to be in the causal pathway of death for 2.7% of infants (79 of 2, 966; range, 0.3% in Sierra Leone to 7.2% in South Africa), including 2.3% (31 of 1322) of stillbirths, 4.7% (28 of 597) 0 to <24 hours, 1.9% (11 of 593) END, and 2.0% (9 of 454) of deaths from 7 to 90 days of age. Among deaths attributed to GBS with birth weight data available, 61.9% (39 of 63) of decedents weighed <2500 grams at birth. Group B Streptococcus sepsis was the postmortem diagnosis for 100% (31 of 31) of stillbirths. For deaths <90 days, postmortem diagnoses included GBS sepsis (83.3%, 40 of 48), GBS meningitis (4.2%, 2 of 48), and GBS pneumonia (2.1%, 1 of 48). CONCLUSIONS: Our study reveals significant heterogeneity in the contribution of invasive GBS disease to infant mortality across different countries, emphasizing the need for tailored prevention strategies. Moreover, our findings highlight the substantial impact of GBS on stillbirths, shedding light on a previously underestimated aspect in LMICs. |
Prediction of postpartum hemorrhage (PPH) using machine learning algorithms in a Kenyan population
Shah SY , Saxena S , Rani SP , Nelaturi N , Gill S , Tippett Barr B , Were J , Khagayi S , Ouma G , Akelo V , Norwitz ER , Ramakrishnan R , Onyango D , Teltumbade M . Front Glob Womens Health 2023 4 1161157 INTRODUCTION: Postpartum hemorrhage (PPH) is a significant cause of maternal mortality worldwide, particularly in low- and middle-income countries. It is essential to develop effective prediction models to identify women at risk of PPH and implement appropriate interventions to reduce maternal morbidity and mortality. This study aims to predict the occurrence of postpartum hemorrhage using machine learning models based on antenatal, intrapartum, and postnatal visit data obtained from the Kenya Antenatal and Postnatal Care Research Collective cohort. METHOD: Four machine learning models - logistic regression, naïve Bayes, decision tree, and random forest - were constructed using 67% training data (1,056/1,576). The training data was further split into 67% for model building and 33% cross validation. Once the models are built, the remaining 33% (520/1,576) independent test data was used for external validation to confirm the models' performance. Models were fine-tuned using feature selection through extra tree classifier technique. Model performance was assessed using accuracy, sensitivity, and area under the curve (AUC) of the receiver operating characteristics (ROC) curve. RESULT: The naïve Bayes model performed best with 0.95 accuracy, 0.97 specificity, and 0.76 AUC. Seven factors (anemia, limited prenatal care, hemoglobin concentrations, signs of pallor at intrapartum, intrapartum systolic blood pressure, intrapartum diastolic blood pressure, and intrapartum respiratory rate) were associated with PPH prediction in Kenyan population. DISCUSSION: This study demonstrates the potential of machine learning models in predicting PPH in the Kenyan population. Future studies with larger datasets and more PPH cases should be conducted to improve prediction performance of machine learning model. Such prediction algorithms would immensely help to construct a personalized obstetric path for each pregnant patient, improve resource allocation, and reduce maternal mortality and morbidity. |
Vaccine safety surveillance in Kenya using GAIA standards: A feasibility assessment of existing national and subnational research and program systems
Izulla P , Wagai JN , Akelo V , Ombeva A , Okeri E , Onyango D , Omore R , Fuller S , Khagayi S , Were J , Anderson SA , Wong HL , Tippett Barr BA . Vaccine 2023 41 (39) 5722-5729 BACKGROUND: Active surveillance systems for monitoring vaccine safety among pregnant women address some of the limitations of a current passive surveillance approach utilized in low- and middle-income countries (LMIC). However, few active surveillance systems in LMIC exist. Our study assessed the feasibility of utilizing three existing data collection systems in Kenya for active surveillance of maternal immunization and to assess the applicability of Global Alignment of Immunization Safety Assessment in pregnancy (GAIA) case definitions that were initially developed for clinical trials within these systems. METHODS: We assessed applicability of GAIA case definition for maternal Tetanus Toxoid exposure, stillbirth, low birth weight, small for gestational age, Neonatal Invasive Blood Stream Infection (NIBSI), prematurity and neonatal death in two routine web-based health information systems (Kenya EMR and DHIS-2), and a web-based population-based pregnancy research platform (ANCOV(1)) in Kenya. RESULTS: All three HIS were capable of reporting selected outcomes to varying degrees of GAIA certainty. The ANCOV platform was the most robust in collecting and collating clinical data for effective maternal pharmacovigilance. The utilization of facility- and district-aggregated data limits the usefulness of DHIS-2 in pharmacovigilance as currently operationalized. While the Kenya EMR contained individual level data and meets the key considerations for effective pharmacovigilance, it was used primarily for HIV care and treatment records in a small proportion of health facilities and would require additional resources to expand to all antenatal care facilities and to link maternal and infant records. DISCUSSION: Population-based research studies may offer a responsive short-term option for implementing maternal vaccine pharmacovigilance in LMICs. However, the foundation exists for long-term capacity building within the national health electronic data systems to provide this critical service as well as ensure participation of the country in international studies on maternal vaccine safety. |
Robustness of the ferret model for influenza risk assessment studies: a cross-laboratory exercise (preprint)
Belser JA , Lau EHY , Barclay W , Barr IG , Chen H , Fouchier RAM , Hatta M , Herfst S , Kawaoka Y , Lakdawala SS , Lee LYY , Neumann G , Peiris M , Perez DR , Russell C , Subbarao K , Sutton TC , Webby RJ , Yang H , Yen HL . bioRxiv 2022 2022.04.02.486825 Ferrets represent the preferred animal model for assessing the transmission potential of newly emerged zoonotic influenza viruses. However, heterogeneity among established experimental protocols and facilities across different laboratories may lead to variable results, complicating interpretation of transmission experimental data. Between 2018-2020, a global exercise was conducted by 11 participating laboratories to assess the range of variation in ferret transmission experiments using two common stock H1N1 influenza viruses that possess different transmission characteristics in ferrets. Inoculation route, dose, and volume were standardized, and all participating laboratories followed the same experimental conditions for respiratory droplet transmission, including a strict 1:1 donor:contact ratio. Additional host and environmental parameters likely to affect influenza transmission kinetics were monitored throughout. Overall transmission outcomes for both viruses across 11 laboratories were concordant, suggesting the robustness of the ferret model for zoonotic influenza risk assessment. To attain high confidence in identifying zoonotic influenza viruses with moderate-to-high or low transmissibility, our analyses support that as few as three but as many as five laboratories, respectively, would need to independently perform viral transmission experiments with concordant results. This exercise facilitates the development of a more homogenous protocol for ferret transmission experiments that are employed for the purposes of risk assessment.Competing Interest StatementThe authors have declared no competing interest. |
Protocol for a sequential, prospective meta-analysis to describe coronavirus disease 2019 (COVID-19) in the pregnancy and postpartum periods (preprint)
Smith ER , Oakley E , He S , Zavala R , Ferguson K , Miller L , Grandner GW , Abejirinde IO , Afshar Y , Ahmadzia H , Aldrovandi G , Akelo V , Tippett Barr BA , Bevilacqua E , Brandt JS , Broutet N , Fernández Buhigas I , Carrillo J , Clifton R , Conry J , Cosmi E , Delgado-López C , Divakar H , Driscoll AJ , Favre G , Flaherman V , Gale C , Gil MM , Godwin C , Gottlieb S , Hernandez Bellolio O , Kara E , Khagayi S , Kim CR , Knight M , Kotloff K , Lanzone A , Le Doare K , Lees C , Litman E , Lokken EM , Laurita Longo V , Magee LA , Martinez-Portilla RJ , McClure E , Metz TD , Money D , Mullins E , Nachega JB , Panchaud A , Playle R , Poon LC , Raiten D , Regan L , Rukundo G , Sanin-Blair J , Temmerman M , Thorson A , Thwin S , Tolosa JE , Townson J , Valencia-Prado M , Visentin S , von Dadelszen P , Adams Waldorf K , Whitehead C , Yang H , Thorlund K , Tielsch JM . medRxiv 2022 2020.11.08.20228056 We urgently need answers to basic epidemiological questions regarding SARS-CoV-2 infection in pregnant and postpartum women and its effect on their newborns. While many national registries, health facilities, and research groups are collecting relevant data, we need a collaborative and methodologically rigorous approach to better combine these data and address knowledge gaps, especially those related to rare outcomes. We propose that using a sequential, prospective meta-analysis (PMA) is the best approach to generate data for policy- and practice-oriented guidelines. As the pandemic evolves, additional studies identified retrospectively by the steering committee or through living systematic reviews will be invited to participate in this PMA. Investigators can contribute to the PMA by either submitting individual patient data or running standardized code to generate aggregate data estimates. For the primary analysis, we will pool data using two-stage meta-analysis methods. The meta-analyses will be updated as additional data accrue in each contributing study and as additional studies meet study-specific time or data accrual thresholds for sharing. At the time of publication, investigators of 25 studies, including more than 76,000 pregnancies, in 41 countries had agreed to share data for this analysis. Among the included studies, 12 have a contemporaneous comparison group of pregnancies without COVID-19, and four studies include a comparison group of non-pregnant women of reproductive age with COVID-19. Protocols and updates will be maintained publicly. Results will be shared with key stakeholders, including the World Health Organization (WHO) Maternal, Newborn, Child, and Adolescent Health (MNCAH) Research Working Group. Data contributors will share results with local stakeholders. Scientific publications will be published in open-access journals on an ongoing basis.Competing Interest StatementClare Whitehead declares a a relationship with the following entities, Ferring Pharmaceuticals COVID19 Investigational, Grant, NHMRC Fellowship (salary support). Alice Panchaud declares the following research grants to institution: H2020-Grant (Consortium member of Innovative medicine initiative call 13 topic 9) (ConcePTION), Efficacy and safety studies on Medicines EMA/2017/09/PE/11, Lot 4, WP 2 lead (CONSIGN: Study on impact of COVID-19 infection and medicines in pregnancy), Safety monitoring of COVID-19 vaccines in the EU Reopening of competition no. 20 under a framework contract following procurement procedure EMA/2017/09/PE (Lot 3) 4. Federal Office of Public Health (207000 CHF). (The COVI-Preg registry). Edward Mullins declares a relationship with the following entities National Institute for Health Research (Project grant for PAN COVID study) Deborah Money declares a relationship with the following entities, Canadian Institutes of Health Research (payments to my institution only), Public Health Agency of Canada (payments to my institution only), BC Womens Foundation (payments to my institution only) and is a Member of the COVID-19 Immunity Task Force sponsored by the Canadian government. Torri D. Metz declares a relationship with the following entities, Pfizer (site Principal Investigator for SARS-CoV-2 vaccination in pregnancy study, money paid to institution and member of Medical Advisory Board for SARS-CoV-2 vaccination in pregnancy study, money paid to me), NICHD (subcommittee Chair for the NICHD Maternal-Fetal Medicine Units Network Gestational Research Assessments of COVID-19 (GRAVID) study), and Society for Maternal-Fetal Medicine (board member). Erica Lokken declares a relationship with the following entity, US NIH (paid institution). Karen L. Kotloff declares a relationship with the following entity, Bill and Melinda Gates Foundation. Siran He declares a relationship with the following entity, Bill and Melinda Gates Foundtion (payments made to my institution). Valerie Flaherman declares a relationship with the following entities, Bill and Melinda Gates Foundation (payments to my institution), Yellow Chair Foundati n (payments to my institution), Robert Woods Johnson Foundation (payments to my institution), CDC Foundation, California Health Care Foundation (payments to my institution), Tara Health Foundation (payments to my institution), UCSF Womens Health Center of Excellence (payments to my institution) and California Department of Health Care Services (payments made to my institution). Jose Sanin-Blair declares a relationship with the following entity, Ferring Pharmaceuticals which give a grant ($10,000) for the expenses of RECOGEST trial and is a part of the Columbian Federation of Perinatology Yalda Afshar declares a relationship with the following entities, Bill and Melinda Gates Foundation (payments made to my institution), CDC Foundation (payments made to my institution), Robert Woods Johnson Foundation (payments made to my institution), and UCLA Deans Office COVID-19 research (payments made to my institution). Rebecca Cliffton declares a relationship with the following entity, NIH HD36801 (MFMU Network DCC).Clinical TrialPROSPERO ID: 188955Funding StatementFunded by the Bill & Melinda Gates Foundation grant to Emily Smith (INV-022057) at George Washington University and a grant to Emily Smith via a grant from the Bill & Melinda Gates Foundation to Stephanie Gaw (INV-017035) at University of California San Francisco.Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:This is a protocol paper and thus exempt from ethical approval. Ultimately, the meta-analysis study is exempt from human research ethics approval as the study authors will be synthesizing de-identified or aggregate data.I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).YesI have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesThis is a protocol paper and there is no related data to share. |
N-glycosylation profiles of the SARS-CoV-2 spike D614G mutant and its ancestral protein characterized by advanced mass spectrometry (preprint)
Wang D , Zhou B , Keppel TR , Solano M , Baudys J , Goldstein J , Finn MG , Fan X , Chapman AP , Bundy JL , Woolfitt AR , Osman SH , Pirkle JL , Wentworth DE , Barr JR . bioRxiv 2021 2021.07.26.453787 N-glycosylation plays an important role in the structure and function of membrane and secreted proteins. The spike protein on the surface of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes COVID-19, is heavily glycosylated and the major target for developing vaccines, therapeutic drugs and diagnostic tests. The first major SARS-CoV-2 variant carries a D614G substitution in the spike (S-D614G) that has been associated with altered conformation, enhanced ACE2 binding, and increased infectivity and transmission. In this report, we used mass spectrometry techniques to characterize and compare the N-glycosylation of the wild type (S-614D) or variant (S-614G) SARS-CoV-2 spike glycoproteins prepared under identical conditions. The data showed that half of the N-glycosylation sequons changed their distribution of glycans in the S-614G variant. The S-614G variant showed a decrease in the relative abundance of complex-type glycans (up to 45%) and an increase in oligomannose glycans (up to 33%) on all altered sequons. These changes led to a reduction in the overall complexity of the total N-glycosylation profile. All the glycosylation sites with altered patterns were in the spike head while the glycosylation of three sites in the stalk remained unchanged between S-614G and S-614D proteins.Competing Interest StatementThe authors have declared no competing interest. |
Prevalence of Nonsuppressed Viral Load and Associated Factors Among Adults Receiving Antiretroviral Therapy in Eswatini, Lesotho, Malawi, Zambia, and Zimbabwe (2015-2017): Results from Population-Based Nationally-Representative Surveys (preprint)
Haas AD , Radin E , Hakim AJ , Jahn A , Philip NM , Jonnalagadda S , Saito S , Low A , Patel H , Schwitters AM , Rogers JH , Frederix K , Kim E , Bello G , Williams DB , Parekh B , Sachathep K , Barradas DT , Kalua T , Birhanu S , Musuka G , Mugurungi O , Tippett Barr BA , Sleeman K , Mulenga LB , Thin K , Ao TT , Brown K , Voetsch AC , Justman JE . medRxiv 2020 2020.07.13.20152553 Introduction The Joint United Nations Programme on HIV/AIDS (UNAIDS) has set a target of ≥90% of people living with HIV (PLHIV) receiving antiretroviral therapy (ART) to have viral load suppression (VLS). We examined factors associated with nonsuppressed viral Load (NVL).Methods We included PLHIV receiving ART aged 15–59 years from Eswatini, Lesotho, Malawi, Zambia, and Zimbabwe. Blood samples from PLHIV were analyzed for HIV RNA and recent exposure to antiretroviral drugs (ARVs). Outcomes were NVL (viral load ≥1000 copies/mL), virologic failure (VF; ARVs present and viral load ≥1000 copies/mL), interrupted ART (ARVs absent and viral load ≥1000 copies/mL), and receiving second-line ART. We calculated odds ratios and incidence rate ratios for factors associated with NVL, VF, interrupted ART, and switching to second-line ART.Results The prevalence of NVL was 11.2%: 8.2% experienced VF, and 3.0% interrupted ART. Younger age, male gender, less education, suboptimal adherence, receiving nevirapine, HIV non-disclosure, never having married, and residing in Zimbabwe, Lesotho, or Zambia were associated with higher odds of NVL. Among people with NVL, marriage, female gender, shorter ART duration, higher CD4 count, and alcohol use were associated with higher odds for interrupted ART and lower odds for VF. Many people with VF (44.8%) had CD4 counts <200 cells/µL, but few (0.31% per year) switched to second-line ART.Conclusions Countries are approaching UNAIDS VLS targets for adults. Treatment support for people initiating ART with asymptomatic HIV infection, scale-up of viral load monitoring, and optimized ART regimens may further reduce NVL prevalence.Competing Interest StatementThe authors have declared no competing interest.Funding StatementFunding: This research has been supported by the President's Emergency Plan for AIDS Relief (PEPFAR) through the Centers for Disease Control and Prevention (CDC) under the terms of grant number U2GGH001226. ADH was supported by a Swiss National Science Foundation (SNF) Early Postdoc Mobility Fellowship (grant number: P2BEP3_178602). Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding agencies. Author DeclarationsI confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.YesThe details of the IRB/oversight body that provided approval or exemption for the research described are given below:The Eswatini Scientific and Ethics Committee, the National Health Science Research Committee Malawi, the National Health Research Ethics Committee Lesotho, the National Health Research Ethics Committee Lesotho, the Tropical Diseases Research Centre Ethics Review Committee, Zambia, the Medical Research Council of Zimbabwe, and the Institutional Review Boards at the Centers for Disease Control and Prevention (CDC; Atlanta, GA) and Columbia University Medical Center (New York, NY) approved the PHIA surveys.All necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived.YesI understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable.YesPublic datasets for Eswatini, Malawi, and Zambia are available. Public datasets for Lesotho and Zimbabwe will be made available soon. For more information see: https://phia-data.icap.columbia.edu/ https://phia-data.icap.columbia.edu/ |
Integrating genotypes and phenotypes improves long-term forecasts of seasonal influenza A/H3N2 evolution (preprint)
Huddleston J , Barnes JR , Rowe T , Xu X , Kondor R , Wentworth DE , Whittaker L , Ermetal B , Daniels RS , McCauley JW , Fujisaki S , Nakamura K , Kishida N , Watanabe S , Hasegawa H , Barr I , Subbarao K , Neher RA , Bedford T . bioRxiv 2020 2020.06.12.145151 Seasonal influenza virus A/H3N2 is a major cause of death globally. Vaccination remains the most effective preventative. Rapid mutation of hemagglutinin allows viruses to escape adaptive immunity. This antigenic drift necessitates regular vaccine updates. Effective vaccine strains need to represent H3N2 populations circulating one year after strain selection. Experts select strains based on experimental measurements of antigenic drift and predictions made by models from hemagglutinin sequences. We developed a novel influenza forecasting framework that integrates phenotypic measures of antigenic drift and functional constraint with previously published sequence-only fitness estimates. Forecasts informed by phenotypic measures of antigenic drift consistently outperformed previous sequence-only estimates, while sequence-only estimates of functional constraint surpassed more comprehensive experimentally-informed estimates. Importantly, the best models integrated estimates of both functional constraint and either antigenic drift phenotypes or recent population growth.Competing Interest StatementThe authors have declared no competing interest. |
Transmission of SARS-CoV-2 in standardised first few X cases and household transmission investigations: A systematic review and meta-analysis
Lewis HC , Marcato AJ , Meagher N , Valenciano M , Villanueva-Cabezas JP , Spirkoska V , Fielding JE , Karahalios A , Subissi L , Nardone A , Cheng B , Rajatonirina S , Okeibunor J , Aly EA , Barakat A , Jorgensen P , Azim T , Wijesinghe PR , Le LV , Rodriguez A , Vicari A , Van Kerkhove M , McVernon J , Pebody R , Price DJ , Bergeri I , Alemu MA , Alvi Y , Bukusi EA , Chung PS , Dambadarjaa D , Das AK , Dub T , Dulacha D , Ebrahim F , Gonzalez-Duarte MA , Guruge D , Heredia-Melo DC , Herman-Roloff A , Herring BL , Islam F , Jeewandara KC , Kant S , Lako R , Leite J , Malavige GN , Mandakh U , Mariam W , Mend T , Mize VA , Musa S , Nohynek H , Olu OO , Osorio-Merchan MB , Pereyaslov D , Ransom J , Ariqi LA , Khan W , Saxena S , Sharma P , Sreedevi A , Satheesh M , Subhashini KJ , Tippet-Barr BA , Usha A , Wamala JF , Watare SH , Yadav K , Inbanathan FY . Influenza Other Respir Viruses 2022 16 (5) 803-819 Abstract We aimed to estimate the household secondary infection attack rate (hSAR) of SARS-CoV-2 in investigations aligned with the WHO Unity Studies Household Transmission Investigations (HHTI) protocol. We conducted a systematic review and meta-analysis according to PRISMA 2020 guidelines. We searched Medline, Embase, Web of Science, Scopus and medRxiv/bioRxiv for “Unity-aligned” First Few X cases (FFX) and HHTIs published 1 December 2019 to 26 July 2021. Standardised early results were shared by WHO Unity Studies collaborators (to 1 October 2021). We used a bespoke tool to assess investigation methodological quality. Values for hSAR and 95% confidence intervals (CIs) were extracted or calculated from crude data. Heterogeneity was assessed by visually inspecting overlap of CIs on forest plots and quantified in meta-analyses. Of 9988 records retrieved, 80 articles (64 from databases; 16 provided by Unity Studies collaborators) were retained in the systematic review; 62 were included in the primary meta-analysis. hSAR point estimates ranged from 2% to 90% (95% prediction interval: 3%–71%; I2 = 99.7%); I2 values remained >99% in subgroup analyses, indicating high, unexplained heterogeneity and leading to a decision not to report pooled hSAR estimates. FFX and HHTI remain critical epidemiological tools for early and ongoing characterisation of novel infectious pathogens. The large, unexplained variance in hSAR estimates emphasises the need to further support standardisation in planning, conduct and analysis, and for clear and comprehensive reporting of FFX and HHTIs in time and place, to guide evidence-based pandemic preparedness and response efforts for SARS-CoV-2, influenza and future novel respiratory viruses. |
Transmission of SARS-CoV-2 in standardised First Few X cases and household transmission investigations: a systematic review and meta-analysis (preprint)
Lewis HC , Marcato AJ , Meagher N , Valenciano M , Villanueva-Cabezas JP , Spirkoska V , Fielding JE , Karahalios A , Subissi L , Nardone A , Cheng B , Rajatonirina S , Okeibunor J , Aly EA , Barakat A , Jorgensen P , Azim T , Wijesinghe PR , Le LV , Rodriguez A , Vicari A , Van Kerkhove M , McVernon J , Pebody R , Price DJ , Bergeri I , Alemu MA , Alvi Y , Bukusi EA , Chung PS , Dambadarjaa D , Das AK , Dub T , Dulacha D , Ebrahim F , Gonzalez-Duarte MA , Guruge D , Heredia-Melo DC , Herman-Roloff A , Herring BL , Islam F , Jeewandara KC , Kant S , Lako R , Leite J , Malavige GN , Mandakh U , Mariam W , Mend T , Mize VA , Musa S , Nohynek H , Olu OO , Osorio-Merchan MB , Pereyaslov D , Ransom J , Ariqi LA , Khan W , Saxena S , Sharma P , Sreedevi A , Satheesh M , Subhashini KJ , Tippet-Barr BA , Usha A , Wamala JF , Watare SH , Yadav K , Inbanathan FY . medRxiv 2022 03 (5) 803-819 We aimed to estimate the household secondary infection attack rate (hSAR) of SARS-CoV-2 in investigations aligned with the WHO Unity Studies Household Transmission Investigations (HHTI) protocol. We conducted a systematic review and meta-analysis according to PRISMA 2020 guidelines. We searched Medline, Embase, Web of Science, Scopus and medRxiv/bioRxiv for 'Unity-aligned' First Few X cases (FFX) and HHTIs published between 1 December 2019 and 26 July 2021. Standardised early results were shared by WHO Unity Studies collaborators (to 1 October 2021). We used a bespoke tool to assess investigation methodological quality. Values for hSAR and 95% confidence intervals (CIs) were extracted or calculated from crude data. Heterogeneity was assessed by visually inspecting overlap of CIs on forest plots and quantified in meta-analyses. Of 9988 records retrieved, 80 articles (64 from databases; 16 provided by Unity Studies collaborators) were retained in the systematic review and 62 were included in the primary meta-analysis. hSAR point estimates ranged from 2%-90% (95% prediction interval: 3%-71%; I2=99.7%); I2 values remained >99% in subgroup analyses, indicating high, unexplained heterogeneity and leading to a decision not to report pooled hSAR estimates. FFX and HHTI remain critical epidemiological tools for early and ongoing characterisation of novel infectious pathogens. The large, unexplained variance in hSAR estimates emphasises the need to further support standardisation in planning, conduct and analysis, and for clear and comprehensive reporting of FFX and HHTIs in time and place, to guide evidence-based pandemic preparedness and response efforts for SARS-CoV-2, influenza and future novel respiratory viruses. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY 4.0 International license. |
Risk of Adverse Maternal and Fetal Outcomes Associated with COVID-19 Variants of Concern: A Sequential Prospective Meta-Analysis (preprint)
Farooq F , Oakley E , Kerchner D , Hee Kim JY , Akelo V , Tippett Barr BA , Bevilacqua E , Bracero N , del Mar Gil M , Delgado-Lopez C , Favre G , Buhigas IF , Hillary Leung HY , Longo VL , Panchaud A , Poon LC , Martinez-Portilla RJ , Valencia-Prado M , Tielsch JM , Smith ER , Omore R , Ouma G , Onyango C , Otieno K , Were ZA , Were J , Maisonneuve E , Poncelet C , de Tejada BM , Quibel T , Monod C , Yu FNY , Kong CW , Lo TK , So PL , Leung WC , Meli F , Bonanni G , Romanzi F , Torcia E , di Ilio C , Aquise A , Rayo MN , Santacruz B , Gonzalez-Gea L , Laiseca S , Ferrer LN , Huertas MM , Rosario GM , Ramos NA , Gonzalez SV . medRxiv 2023 04 Introduction The main objective of this study is to conduct an individual patient data meta-analysis with collaborators from various countries to identify SARS-CoV-2 variants of concern associated with adverse maternal and neonatal outcomes. Methods Eligible studies included registries and single- or multi-site cohort studies that recruited pregnant and recently postpartum women with confirmed COVID-19. Studies must have enrolled at least 25 women within a defined catchment area. Studies also had to have data that overlapped more than a single COVID-19 variant time period. We invited principal investigators already participating in an ongoing sequential, prospective meta-analysis of perinatal COVID-19. Investigators shared individual patient data (IPD) with the technical team for review and analysis. We examined 31 outcomes related to: i) COVID-19 severity (n=5); ii) maternal morbidities including adverse birth outcomes (n=14); iii) fetal and neonatal morbidity and mortality (n=5) and iv) adverse birth outcomes (n=8). SARS-CoV-2 strains that have been identified as variants of concern (VOC) by the WHO were analyzed using the publicly available strain frequency data by Nextstrain.org and strains were classified as dominant when they were more than half of sequences in a given geographic area. We applied a 2-stage IPD meta-analytic framework to generate pooled relative risks, with 95% CI for each dominant variant and outcome pair when there were one or more studies with available data. Results Our data show that the Delta wave, compared to Omicron, was associated with a higher risk of all adverse COVID-19 severity outcomes in pregnancy including risk of hospitalization [RR 4.02 (95% CI 1.10, 14.69), n=1 study], risk of ICU admissions [RR 2.59 (95% CI 1.26, 5.30, n=3 studies], risk of critical care admission [RR 2.52 (95% CI 1.25, 5.08, n=3 studies], risk of needing ventilation [RR 3.96 (95% CI 1.47, 10.71), n=3 studies] and risk of pneumonia [RR 6.73 (95% CI 2.17, 20.90), n=3 studies]. The majority of maternal morbidity and mortality indicators were not at increased risk during any of the COVID-19 variant waves except hemorrhage, any Cesarean section, intrapartum Cesarean section and maternal composite outcome, although data was limited. Risk of fetal and neonatal morbidity and mortality did not show significant increases in risks during any of the COVID-19 waves except stillbirth and perinatal death during the Delta wave ([RR 4.84 (95% CI 1.37, 17.05, n=3 studies], [RR 6.03 (95%CI 1.63, 22.34), n=3 studies], respectively) when compared to the Pre-alpha wave. Adverse birth outcomes including very low birthweight and very preterm birth also showed increased risks during the Delta wave compared to the Pre-alpha wave. Discussion During periods of Delta strain predominance, all COVID-19 severity outcomes were more severe among pregnant women, compared to periods when other COVID-19 strains predominated. In addition, there are limited data comparing the impact of different variants on pregnancy outcomes. This highlights the importance of ongoing genomic surveillance among special populations. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license. |
Causes of death among infants and children in the Child Health and Mortality Prevention Surveillance (CHAMPS) Network
Bassat Q , Blau DM , Ogbuanu IU , Samura S , Kaluma E , Bassey IA , Sow S , Keita AM , Tapia MD , Mehta A , Kotloff KL , Rahman A , Islam KM , Alam M , El Arifeen S , Gurley ES , Baillie V , Mutevedzi P , Mahtab S , Thwala BN , Tippett Barr BA , Onyango D , Akelo V , Rogena E , Onyango P , Omore R , Mandomando I , Ajanovic S , Varo R , Sitoe A , Duran-Frigola M , Assefa N , Scott JAG , Madrid L , Tesfaye T , Dessie Y , Madewell ZJ , Breiman RF , Whitney CG , Madhi SA . JAMA Netw Open 2023 6 (7) e2322494 IMPORTANCE: The number of deaths of children younger than 5 years has been steadily decreasing worldwide, from more than 17 million annual deaths in the 1970s to an estimated 5.3 million in 2019 (with 2.8 million deaths occurring in those aged 1-59 months [53% of all deaths in children aged <5 years]). More detailed characterization of childhood deaths could inform interventions to improve child survival. OBJECTIVE: To describe causes of postneonatal child deaths across 7 mortality surveillance sentinel sites in Africa and Asia. DESIGN, SETTING, AND PARTICIPANTS: The Child Health and Mortality Prevention Surveillance (CHAMPS) Network conducts childhood mortality surveillance in sub-Saharan Africa and South Asia using innovative postmortem minimally invasive tissue sampling (MITS). In this cross-sectional study, MITS was conducted in deceased children aged 1 to 59 months at 7 sites in sub-Saharan Africa and South Asia from December 3, 2016, to December 3, 2020. Data analysis was conducted between October and November 2021. MAIN OUTCOMES AND MEASURES: The expert panel attributed underlying, intermediate, and immediate conditions in the chain of events leading to death, based on histopathologic analysis, microbiological diagnostics, clinical data, and verbal autopsies. RESULTS: In this study, MITS was performed in 632 deceased children (mean [SD] age at death, 1.3 [0.3] years; 342 [54.1%] male). The 6 most common underlying causes of death were malnutrition (104 [16.5%]), HIV (75 [11.9%]), malaria (71 [11.2%]), congenital birth defects (64 [10.1%]), lower respiratory tract infections (LRTIs; 53 [8.4%]), and diarrheal diseases (46 [7.2%]). When considering immediate causes only, sepsis (191 [36.7%]) and LRTI (129 [24.8%]) were the 2 dominant causes. An infection was present in the causal chain in 549 of 632 deaths (86.9%); pathogens most frequently contributing to infectious deaths included Klebsiella pneumoniae (155 of 549 infectious deaths [28.2%]; 127 [81.9%] considered nosocomial), Plasmodium falciparum (122 of 549 [22.2%]), and Streptococcus pneumoniae (109 of 549 [19.9%]). Other organisms, such as cytomegalovirus (57 [10.4%]) and Acinetobacter baumannii (39 [7.1%]; 35 of 39 [89.7%] considered nosocomial), also played important roles. For the top underlying causes of death, the median number of conditions in the chain of events leading to death was 3 for malnutrition, 3 for HIV, 1 for malaria, 3 for congenital birth defects, and 1 for LRTI. Expert panels considered 494 of 632 deaths (78.2%) preventable and 26 of 632 deaths (4.1%) preventable under certain conditions. CONCLUSIONS AND RELEVANCE: In this cross-sectional study investigating causes of child mortality in the CHAMPS Network, results indicate that, in these high-mortality settings, infectious diseases continue to cause most deaths in infants and children, often in conjunction with malnutrition. These results also highlight opportunities for action to prevent deaths and reveal common interaction of various causes in the path toward death. |
Risk factors for community colonization with extended-spectrum cephalosporin-resistant enterobacterales (escre) in Botswana: An Antibiotic Resistance in Communities and Hospitals (ARCH) Study
Lautenbach E , Mosepele M , Smith RM , Styczynski A , Gross R , Cressman L , Jaskowiak-Barr A , Alby K , Glaser L , Richard-Greenblatt M , Cowden L , Sewawa K , Otukile D , Paganotti GM , Mokomane M , Bilker WB , Mannathoko N . Clin Infect Dis 2023 77 S89-s96 BACKGROUND: The epidemiology of extended-spectrum cephalosporin-resistant Enterobacterales (ESCrE) in low- and middle-income countries (LMICs) is poorly described. Identifying risk factors for ESCrE colonization is critical to inform antibiotic resistance reduction strategies because colonization is typically a precursor to infection. METHODS: From 15 January 2020 to 4 September 2020, we surveyed a random sample of clinic patients at 6 sites in Botswana. We also invited each enrolled participant to refer up to 3 adults and children. All participants had rectal swabs collected that were inoculated onto chromogenic media followed by confirmatory testing. Data were collected on demographics, comorbidities, antibiotic use, healthcare exposures, travel, and farm and animal contact. Participants with ESCrE colonization (cases) were compared with noncolonized participants (controls) to identify risk factors for ESCrE colonization using bivariable, stratified, and multivariable analyses. RESULTS: A total of 2000 participants were enrolled. There were 959 (48.0%) clinic participants, 477 (23.9%) adult community participants, and 564 (28.2%) child community participants. The median (interquartile range) age was 30 (12-41) and 1463 (73%) were women. There were 555 cases and 1445 controls (ie, 27.8% of participants were ESCrE colonized). Independent risk factors (adjusted odds ratio [95% confidence interval]) for ESCrE included healthcare exposure (1.37 [1.08-1.73]), foreign travel [1.98 (1.04-3.77]), tending livestock (1.34 [1.03-1.73]), and presence of an ESCrE-colonized household member (1.57 [1.08-2.27]). CONCLUSIONS: Our results suggest healthcare exposure may be important in driving ESCrE. The strong links to livestock exposure and household member ESCrE colonization highlight the potential role of common exposure or household transmission. These findings are critical to inform strategies to curb further emergence of ESCrE in LMICs. |
Analysis of the N-glycosylation profiles of the spike proteins from the Alpha, Beta, Gamma, and Delta variants of SARS-CoV-2
Wang D , Baudys J , Osman SH , Barr JR . Anal Bioanal Chem 2023 415 (19) 4779-4793 N-Glycosylation plays an important role in the structure and function of membrane and secreted proteins. Viral proteins used in cell entry are often extensively glycosylated to assist in protein folding, provide stability, and shield the virus from immune recognition by its host (described as a "glycan shield"). The SARS-CoV-2 spike protein (S) is a prime example, having 22 potential sites of N-glycosylation per protein protomer, as predicted from the primary sequence. In this report, we conducted mass spectrometric analysis of the N-glycosylation profiles of recombinant spike proteins derived from four common SARS-CoV-2 variants classified as Variant of Concern, including Alpha, Beta, Gamma, and Delta along with D614G variant spike as a control. Our data reveal that the amino acid substitutions and deletions between variants impact the abundance and type of glycans on glycosylation sites of the spike protein. Some of the N-glycosylation sequons in S show differences between SARS-CoV-2 variants in the distribution of glycan forms. In comparison with our previously reported site-specific glycan analysis on the S-D614G and its ancestral protein, glycan types on later variants showed high similarity on the site-specific glycan content to S-D614G. Additionally, we applied multiple digestion methods on each sample, and confirmed the results for individual glycosylation sites from different experiment conditions to improve the identification and quantification of glycopeptides. Detailed site-specific glycan analysis of a wide variety of SARS-CoV-2 variants provides useful information toward the understanding of the role of protein glycosylation on viral protein structure and function and development of effective vaccines and therapeutics. |
Neural tube defects as a cause of death among stillbirths, infants, and children younger than 5 years in sub-Saharan Africa and southeast Asia: an analysis of the CHAMPS network
Madrid L , Vyas KJ , Kancherla V , Leulseged H , Suchdev PS , Bassat Q , Sow SO , El Arifeen S , Madhi SA , Onyango D , Ogbuanu I , Scott JAG , Blau D , Mandomando I , Keita AM , Gurley ES , Mahtab S , Akelo V , Sannoh S , Tilahun Y , Varo R , Onwuchekwa U , Rahman A , Adam Y , Omore R , Lako S , Xerinda E , Islam KM , Wise A , Tippet-Barr BA , Kaluma E , Ajanovic S , Kotloff KL , Hossain MZ , Mutevedzi P , Tapia MD , Rogena E , Moses F , Whitney CG , Assefa N . Lancet Glob Health 2023 11 (7) e1041-e1052 BACKGROUND: Neural tube defects are common birth defects resulting in severe morbidity and mortality; they can largely be prevented with periconceptional maternal intake of folic acid. Understanding the occurrence of neural tube defects and their contribution to mortality in settings where their burden is highest could inform prevention and health-care policy. We aimed to estimate the mortality attributed to neural tube defects in seven countries in sub-Saharan Africa and southeast Asia. METHODS: This analysis used data from the Child Health and Mortality Prevention Surveillance (CHAMPS) network and health and demographic surveillance systems from South Africa, Mozambique, Bangladesh, Kenya, Mali, Ethiopia, and Sierra Leone. All stillbirths and infants and children younger than 5 years who died, who were enrolled in CHAMPS, whose families consented to post-mortem minimally invasive tissue sampling (MITS) between Jan 1, 2017, and Dec 31, 2021, and who were assigned a cause of death by a determination of cause of death panel as of May 24, 2022, were included in this analysis, regardless the cause of death. MITS and advanced diagnostic methods were used to describe the frequency and characteristics of neural tube defects among eligible deaths, identify risk factors, and estimate the mortality fraction and mortality rate (per 10 000 births) by CHAMPS site. FINDINGS: Causes of death were determined for 3232 stillbirths, infants, and children younger than 5 years, of whom 69 (2%) died with a neural tube defect. Most deaths with a neural tube defect were stillbirths (51 [74%]); 46 (67%) were neural tube defects incompatible with life (ie, anencephaly, craniorachischisis, or iniencephaly) and 22 (32%) were spina bifida. Deaths with a neural tube defect were more common in Ethiopia (adjusted odds ratio 8·09 [95% CI 2·84-23·02]), among female individuals (4·40 [2·44-7·93]), and among those whose mothers had no antenatal care (2·48 [1·12-5·51]). Ethiopia had the highest adjusted mortality fraction of deaths with neural tube defects (7·5% [6·7-8·4]) and the highest adjusted mortality rate attributed to neural tube defects (104·0 per 10 000 births [92·9-116·4]), 4-23 times greater than in any other site. INTERPRETATION: CHAMPS identified neural tube defects, a largely preventable condition, as a common cause of death among stillbirths and neonatal deaths, especially in Ethiopia. Implementing interventions such as mandatory folic acid fortification could reduce mortality due to neural tube defects. FUNDING: Bill & Melinda Gates Foundation. |
Quantification of SARS-CoV-2 spike protein expression from mRNA vaccines using isotope dilution mass spectrometry
Sutton WJH , Branham PJ , Williamson YM , Cooper HC , Najjar FN , Pierce-Ruiz CL , Barr JR , Williams TL . Vaccine 2023 The advent of mRNA vaccine technology has been vital in rapidly creating and manufacturing COVID-19 vaccines at an industrial scale. To continue to accelerate this leading vaccine technology, an accurate method is needed to quantify antigens produced by the transfection of cells with a mRNA vaccine product. This will allow monitoring of protein expression during mRNA vaccine development and provide information on how changes to vaccine components affects the expression of the desired antigen. Developing novel approaches that allow for high-throughput screening of vaccines to detect changes in antigen production in cell culture prior to in vivo studies could aid vaccine development. We have developed and optimized an isotope dilution mass spectrometry method to detect and quantify the spike protein expressed after transfection of baby hamster kidney cells with expired COVID-19 mRNA vaccines. Five peptides of the spike protein are simultaneously quantified and provide assurance that protein digestion in the region of the target peptides is complete since results between the five peptides had a relative standard deviation of less than 15 %. In addition, two housekeeping proteins, actin and GAPDH, are quantified in the same analytical run to account for any variation in cell growth within the experiment. IDMS allows a precise and accurate means to quantify protein expression by mammalian cells transfected with an mRNA vaccine. |
Confirmation of statin and fibrate use from small-volume archived plasma samples by high-throughput LC-MS/MS method
Kusovschi JD , Ivanova AA , Gardner MS , McGarrah RW 3rd , Kraus WE , Kuklenyik Z , Pirkle JL , Barr JR . Int J Mol Sci 2023 24 (9) Designing studies for lipid-metabolism-related biomarker discovery is challenging because of the high prevalence of various statin and fibrate usage for lipid-lowering therapies. When the statin and fibrate use is determined based on self-reports, patient adherence to the prescribed statin dose regimen remains unknown. A potentially more accurate way to verify a patient's medication adherence is by direct analytical measurements. Current analytical methods are prohibitive because of the limited panel of drugs per test and large sample volume requirement that is not available from archived samples. A 4-min-long method was developed for the detection of seven statins and three fibrates using 10 µL of plasma analyzed via reverse-phase liquid chromatography and tandem mass spectrometry. The method was applied to the analysis of 941 archived plasma samples collected from patients before cardiac catheterization. When statin use was self-reported, statins were detected in 78.6% of the samples. In the case of self-reported atorvastatin use, the agreement with detection was 90.2%. However, when no statin use was reported, 42.4% of the samples had detectable levels of statins, with a similar range of concentrations as the samples from the self-reported statin users. The method is highly applicable in population studies designed for biomarker discovery or diet and lifestyle intervention studies, where the accuracy of statin or fibrate use may strongly affect the statistical evaluation of the biomarker data. |
Stability of lipids in plasma and serum: Effects of temperature-related storage conditions on the human lipidome
Reis GB , Rees JC , Ivanova AA , Kuklenyik Z , Drew NM , Pirkle JL , Barr JR . J Mass Spectrom Adv Clin Lab 2021 22 34-42 Large epidemiological studies often require sample transportation and storage, presenting unique considerations when applying advanced lipidomics techniques. The goal of this study was to acquire lipidomics data on plasma and serum samples stored at potential preanalytical conditions (e.g., thawing, extracting, evaporating), systematically monitoring lipid species for a period of one month. Split aliquots of 10 plasma samples and 10 serum samples from healthy individuals were kept in three temperature-related environments: refrigerator, laboratory benchtop, or heated incubator. Samples were analyzed at six different time points over 28 days using a Bligh & Dyer lipid extraction protocol followed by direct infusion into a lipidomics platform using differential mobility with tandem mass spectrometry. The observed concentration changes over time were evaluated relative to method and inter-individual biological variability. In addition, to evaluate the effect of lipase enzyme levels on concentration changes during storage, we compared corresponding fasting and post-prandial plasma samples collected from 5 individuals. Based on our data, a series of low abundance free fatty acid (FFA), diacylglycerol (DAG), and cholesteryl ester (CE) species were identified as potential analytical markers for degradation. These FFA and DAG species are typically produced by endogenous lipases from numerous triacylglycerols (TAGs), and certain high abundance phosphatidylcholines (PCs). The low concentration CEs, which appeared to increase several fold, were likely mass-isobars from oxidation of other high concentration CEs. Although the concentration changes of the high abundant TAG, PC, and CE precursors remained within method variability, the concentration trends of FFA, DAG, and oxidized CE products should be systematically monitored over time to inform analysts about possible pre-analytical biases due to degradation in the study sample sets. |
- Page last reviewed:Feb 1, 2024
- Page last updated:Apr 29, 2024
- Content source:
- Powered by CDC PHGKB Infrastructure