Single-test syphilis serology: A case of not seeing the forest for the trees.

INTRODUCTION: There have been few empirical studies for diagnostic test accuracy of syphilis using a sequence of rapid tests in populations with low prevalence of syphilis such as pregnant women. This analysis describes syphilis test positivity frequency among pregnant women at an antenatal clinic in Zambia using a reverse-sequence testing algorithm for antenatal syphilis screening. METHODS: Between August 2019 and May 2023, we recruited 1510 pregnant women from a peri-urban hospital in Lusaka, Zambia. HIV positive and HIV negative women were enrolled in a 1:1 ratio. Blood collected at recruitment from the pregnant mothers was tested on-site for syphilis using a rapid treponemal test. Samples that tested positive were further tested at a different laboratory, with rapid plasma reagin using archived plasma. RESULTS: Of the total 1,421 sera samples which were screened with a rapid treponemal test, 127 (8.9%) were positive and 1,294 (91.1%) were negative. Sufficient additional samples were available to perform RPR testing on 114 of the 127 (89.8%) RDT positive specimens. Thirty-one (27.2%) of these 114 were reactive by RPR and 83 (72.8%) were negative, resulting in a syphilis overtreatment rate of 3 fold (i.e, 84/114). Insufficient sample or test kit availability prevented any testing for the remaining 89 (5.9%) participants. CONCLUSION: Use of only treponemal tests in low prevalence populations, like pregnant women, subjects individuals with non-active syphilis to the costs and possible risks of overtreatment. The use of the dual treponemal and non-treponemal tests would minimize this risk at some additional cost.

The Utility of Sulfur Colloid Imaging to Differentiate Charcot's Neuroarthropathy from Osteomyelitis: A Case Study.

Charcot's neuroarthropathy and osteomyelitis can have similar initial presentations. The ability to differentiate between the two pathologic conditions is essential, as each requires different treatment. We present a case of a 53-year-old woman with pain, swelling, and warmth in her left first metatarsophalangeal joint and first tarsometatarsal joint. Radiographs showed comminuted fractures at the base of the first metatarsal. Osteomyelitis was suspected by the primary team based on physical findings and a history of previous first metatarsophalangeal joint arthrodesis. A triphasic bone scan and an indium white blood cell scan were positive for osteomyelitis. The podiatric medical team was suspicious for possible Charcot's neuroarthropathy based on physical findings and uncontrolled blood glucose levels at the time of her previous arthrodesis. A sulfur colloid scan was performed and compared with an indium scan, which showed no evidence of osteomyelitis. This case demonstrates the usefulness of sulfur colloid imaging compared with an indium white blood cell scan to differentiate osteomyelitis from Charcot's neuroarthropathy. This case also highlights the importance of using clinical judgment to make the correct diagnosis.

Curated and Annotated Dataset of Lung US Images in Zambian Children with Clinical Pneumonia.

See also the commentary by Sitek in this issue. Supplemental material is available for this article.

The role of stigma in cannabis use disclosure: an exploratory study.

BACKGROUND: Although cannabis use incidence, societal acceptance, and legislation all trend positively, cannabis remains federally illegal in the USA. Prior studies have revealed that patients are reluctant to disclose their cannabis use history in the healthcare system, which can negatively impact patient care. This study reports the frequency of cannabis use disclosure with special considerations for stigmatization. To better understand the limitations, providers face in providing collaborative, comprehensive, and informed care, this study evaluated four domains of stigma: perceived, anticipated, enacted, and internalized. METHODS: This study used a descriptive exploratory design. Data collection occurred using an anonymous, online national survey with a convenience sample in the USA. Recruitment relied on electronic media and occurred between July and December 2022. Participants were adults older than 21 years and self-identified as having used cannabis and accessed the healthcare system within the last five years. The survey measured demographic characteristics, cannabis use, and disclosure patterns. Stigma was measured using the Stigma Use Stigma Mechanism Scale (SU-SMS) and Substance Abuse Use Self-Stigma Scale (SASSS) with language modifications for cannabis. Ordinal logistic regression models were performed to evaluate associations between the frequency of cannabis use disclosure patterns and each stigma category. Associations were assessed using Chi-squared or Fisher's exact tests. RESULTS: Data were available for 249 respondents. Most participants (57.1%) reported initiating a conversation about cannabis with their healthcare provider; 27.8% of the time, cannabis is never discussed, and healthcare providers initiate only 15.1% of related discussions. Anticipated stigma [95% CI 1.045-1.164] and total stigma [95% CI 1.001-1.039] had statistically significant associations with nondisclosure. Annual household income (p = .04), chronicity of cannabis use (p = .03), frequency of cannabis use (p = .02), and a known amount of CBD in products consumed (p = .01) had statistically significant associations with the frequency of cannabis use disclosure. CONCLUSIONS: Patients who use cannabis experience stigmatization in the healthcare setting that may limit disclosure of cannabis use history. Future studies would be well served to explore anticipated stigma more deeply. Healthcare providers should be knowledgeable to lead such conversations relating to cannabis while maintaining an unbiased perspective.

Analysis of nasopharyngeal microbiome patterns in Zambian infants with fatal acute febrile illness.

Introduction: Associative connections have previously been identified between nasopharyngeal infections and infant mortality. The nasopharyngeal microbiome may potentially influence the severity of these infections. Methods: We conducted an analysis of a longitudinal prospective cohort study of 1,981 infants who underwent nasopharyngeal sampling from 1 week through 14 weeks of age at 2-3-week intervals. In all, 27 microbiome samples from 9 of the infants in the cohort who developed fatal acute febrile illness (fAFI) were analyzed in pooled comparisons with 69 samples from 10 healthy comparator infants. We completed 16S rRNA amplicon gene sequencing all infant NP samples and characterized the maturation of the infant NP microbiome among the fAFI(+) and fAFI(-) infant cohorts. Results: Beta diversity measures of fAFI(-) infants were markedly higher than those of fAFI(+) infants. The fAFI(+) infant NP microbiome was marked by higher abundances of Escherichia, Pseudomonas, Leuconostoc, and Weissella, with low relative presence of Alkalibacterium, Dolosigranulum, Moraxella, and Streptococcus. Conclusions: Our results suggest that nasopharyngeal microbiome dysbiosis precedes fAFI in young infants. Early dysbiosis, involving microbes such as Escherichia, may play a role in the causal pathway leading to fAFI or could be a marker of other pathogenic forces that directly lead to fAFI.

Using mortuary and burial data to place COVID-19 in Lusaka, Zambia within a global context.

Reported COVID-19 cases and associated mortality remain low in many sub-Saharan countries relative to global averages, but true impact is difficult to estimate given limitations around surveillance and mortality registration. In Lusaka, Zambia, burial registration and SARS-CoV-2 prevalence data during 2020 allow estimation of excess mortality and transmission. Relative to pre-pandemic patterns, we estimate age-dependent mortality increases, totalling 3212 excess deaths (95% CrI: 2104-4591), representing an 18.5% (95% CrI: 13.0-25.2%) increase relative to pre-pandemic levels. Using a dynamical model-based inferential framework, we find that these mortality patterns and SARS-CoV-2 prevalence data are in agreement with established COVID-19 severity estimates. Our results support hypotheses that COVID-19 impact in Lusaka during 2020 was consistent with COVID-19 epidemics elsewhere, without requiring exceptional explanations for low reported figures. For more equitable decision-making during future pandemics, barriers to ascertaining attributable mortality in low-income settings must be addressed and factored into discourse around reported impact differences.

Qualitative assessment of infant sleep practices and other risk factors of sudden infant death syndrome (SIDS) among mothers in Lusaka, Zambia.

BACKGROUND: There is very little information on the beliefs and perceptions of mothers about SIDS and its related risk factors in Africa. To better understand parental decisions about infant sleep practices and other risk factors for SIDS, we conducted focus group discussions (FGDs) with mothers of infants in Lusaka, Zambia. METHODS: FGDs involved 35 purposively sampled mothers aged 18-49 years. FGDs were conducted using a semi-structured interview guide in the local language, Nyanja. These were translated, transcribed verbatim into English, and then coded and analyzed using thematic analysis in NVivo 12. RESULTS: Six FGDs were conducted with 35 mothers in April-May 2021 across two study sites. FGD Participants were generally aware of sudden unexplained infant deaths, with several describing stories of apparent SIDS in the community. The side sleeping position was preferred and perceived to be safer for the infant with most believing the supine position posed an aspiration or choking risk to the infant. Bedsharing was also preferred and perceived to be convenient for breastfeeding and monitoring of the infant. Experienced family members such as grandmothers and mothers-in-law, and health care workers were frequently cited as sources of information on infant sleep position. A heightened awareness of the infant's sleeping environment was suggested as a mechanism to prevent SIDS and smothering. CONCLUSIONS: Decisions about bedsharing and infant sleep position were guided by maternal beliefs and perceptions about what is convenient for breastfeeding and safer for the infant. These concerns are vital to designing tailored interventions to address sleep-related sudden infant losses in Zambia. Public health campaigns with tailored messages that address these concerns are likely to be effective at ensuring optimal uptake of safe sleep recommendations.

Young Zambian infants with symptomatic RSV and pertussis infections are frequently prescribed inappropriate antibiotics: a retrospective analysis.

Pediatric community-acquired pneumonia (CAP) remains a pressing global health concern, particularly in low-resource settings where diagnosis and treatment rely on empiric, symptoms-based guidelines such as the WHO's Integrated Management of Childhood Illness (IMCI). This study details the delivery of IMCI-based health care to 1,320 young infants and their mothers in a low-resource urban community in Lusaka, Zambia during 2015. Our Southern Africa Mother Infant Pertussis Study (SAMIPS) prospectively monitored a cohort of mother/infant pairs across infants' first four months of life, recording symptoms of respiratory infection and antibiotics prescriptions (predominantly penicillins), and tested nasopharyngeal (NP) samples for respiratory syncytial virus (RSV) and Bordetella pertussis. Our retrospective analysis of the SAMIPS cohort found that symptoms and antibiotics use were more common in infants (43% and 15.7%) than in mothers (16.6% and 8%), while RSV and B. pertussis were observed at similar rates in infants (2.7% and 32.5%) and mothers (2% and 35.5%), albeit frequently at very low levels. In infants, we observed strong associations between symptoms, pathogen detection, and antibiotics use. Critically, we demonstrate that non-macrolide antibiotics were commonly prescribed for pertussis infections, some of which persisted across many weeks. We speculate that improved diagnostic specificity and/or clinician education paired with timely, appropriate treatment of pertussis could substantially reduce the burden of this disease while reducing the off-target use of penicillins.

Postmortem Nasopharyngeal Microbiome Analysis of Zambian Infants With and Without Respiratory Syncytial Virus Disease: A Nested Case Control Study.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and lower respiratory tract infections in children in their first year of life, disproportionately affecting infants in developing countries. Previous studies have found that the nasopharyngeal (NP) microbiome of infants with RSV infection has specific characteristics that correlate with disease severity, including lower biodiversity, perturbations of the microbiota and differences in relative abundance. These studies have focused on infants seen in clinical or hospital settings, predominantly in developed countries. METHODS: We conducted a nested case control study within a random sample of 50 deceased RSV+ infants with age at death ranging from 4 days to 6 months and 50 matched deceased RSV- infants who were all previously enrolled in the Zambia Pertussis and RSV Infant Mortality Estimation (ZPRIME) study. All infants died within the community or within 48 hours of facility admittance. As part of the ZPRIME study procedures, all decedents underwent one-time, postmortem NP sampling. The current analysis explored the differences between the NP microbiome profiles of RSV+ and RSV- decedents using the 16S ribosomal DNA sequencing. RESULTS: We found that Moraxella was more abundant in the NP microbiome of RSV+ decedents than in the RSV- decedents. Additionally, Gemella and Staphylococcus were less abundant in RSV+ decedents than in the RSV- decedents. CONCLUSIONS: These results support previously reported findings of the association between the NP microbiome and RSV and suggest that changes in the abundance of these microbes are likely specific to RSV and may correlate with mortality associated with the disease.

Social isolation and well-being in veterans with mental illness.

BACKGROUND: Veterans with mental illness are a growing population in the United States (US). For some veterans, their military service has a negative effect on well-being. Social isolation is problematic for veterans' mental health by increasing incidence of depression, suicidal ideation or attempts, and readmittance to psychiatric hospitals. Social support is a protective factor for individuals with mental illness and is key to a successful military-to-civilian transition. AIM: Thus, we examine the relationship of social isolation on well-being among veterans with any mental illness. METHODS: This cross-sectional correlational study consisted of a sample of 146 US veterans with any mental illness. A three-step hierarchical regression analysis was used to determine if social isolation is a predictor of well-being after controlling for demographics, functional limitations and depression. RESULTS: Findings revealed social isolation was positively correlated with functional limitations (r = 0.48, p < 0.001), depression (r = 0.66, p < 0.001) and negatively correlated with well-being (r = -.64, p < 0.001). Hierarchical regression analysis revealed social isolation was negatively correlated (ß = -.44, p < 0.001) with well-being. Overall, our three-step model accounted a total of 50% of variance in well-being, a large effect size. CONCLUSION: The findings underscore the importance of assessing the relationship of social isolation on well-being in veterans with mental illness. The findings also highlight promising targets to improve prevention and psychosocial interventions to improve well-being among veterans with mental illness.

Assessing infant sleep practices and other risk factors of SIDS in Zambia: a cross-sectional survey of mothers in Lusaka, Zambia.

BACKGROUND: Having infants sleep with their parents and sleeping face down or on their sides are the two most proximate and modifiable risk factors for sudden infant death syndrome (SIDS). Little is known about the burden of SIDS or the prevalence of these risk factors in Africa. Our primary objective was to determine the prevalence of modifiable risk factors of SIDS in Lusaka, Zambia. METHODS: We conducted cross-sectional surveys with recent mothers of infants aged < 1 year across two busy urban clinic sites in Lusaka, Zambia. We used log-binomial regression analysis to identify factors predictive of bedsharing and prone sleeping. RESULTS: Surveys were conducted with 478 mothers between April-May 2021. The sleep-related risk factors, bedsharing and side sleeping, were widely prevalent. 89.5% of respondents indicated that they share a bed with the infant during sleep, 73.0% preferred putting their baby on its side, and 19.9% preferred the prone position. Only 6.7% of respondents described using the safer, supine position. Age of infant was the only factor which was predictive of prone sleeping. Infants > 2 months old were twice as likely to be put to sleep in a prone position compared to infants aged less than 2 months old. Mothers reported that they rarely (24.1%) received advice from medical caregivers to use the supine position. Maternal use of alcohol (12.0%) and tobacco (0.8%) during pregnancy were uncommon. CONCLUSIONS: Bedsharing and placing the infant to sleep on the side were commonly reported among the mothers we interviewed. Whether this represents an opportunity to reduce SIDS in Zambia is unclear since accurate data on the burden of SIDS in Zambia is not available. There is a need for increased awareness of SIDS and more prospective data collection on its burden and related risk factors in these African populations.

Concomitant Achilles Tendon Lengthening with Transmetatarsal Amputation for the Prevention of Late Forefoot Ulceration.

BACKGROUND: Late development of forefoot ulcers is a common finding after transmetatarsal amputation (TMA). The primary aim of this study was to examine whether concomitant prophylactic Achilles tendon lengthening (ATL) was associated with a reduction in the incidence of forefoot ulcers postoperatively. METHODS: A retrospective chart review was performed by 2 authors to identify patients who underwent TMA over a period of 5.5 years from January 1, 2015, through July 31, 2020. They identified 110 feet in 107 patients; the 83 patients (85 feet) who had ≥120 days of follow-up were used for the study. Follow-up was performed with telephone calls (80 patients) or during the last office visit (3 patients). Those who were contacted by telephone were asked if they developed an ulcer after healing from the original surgery. Mean follow-up time was 672 ± 258 days for the 30 feet with concomitant Achilles lengthening and 663 ± 434 days for the 55 feet without Achilles lengthening. Demographic data were analyzed for association with late development of forefoot ulceration. RESULTS: Eighty-five feet were included in the analysis. Late forefoot ulcers developed in 35% of feet that had a TMA alone (n = 55) compared with 3% of feet who received a concomitant ATL (n = 30; p < 0.001); the 2 groups had similar mean follow-up times. Mean time to ulcer development was 587 ± 420 days in the 19 patients without Achilles lengthening. Of the patients who developed late forefoot ulcers, 47% also developed osteomyelitis, and 16% went on to proximal amputation. Patients who developed forefoot ulcers were younger (55 ± 12 versus 63 ± 11 years of age; p = 0.006) than those who did not. CONCLUSIONS: ATL at the time of TMA is associated with a reduction in the risk of later development of forefoot ulcers, especially in younger patients. LEVEL OF EVIDENCE: Therapeutic Level III . See Instructions for Authors for a complete description of levels of evidence.

Costs and Cost-Effectiveness of mCME Version 2.0: An SMS-Based Continuing Medical Education Program for HIV Clinicians in Vietnam.

BACKGROUND: The Mobile Continuing Medical Education (mCME) 2.0 project was a randomized controlled trial that found that a 6-month text message-based CME intervention improved both the use of online medical training resources and medical knowledge among a cadre of HIV clinicians in Vietnam. This companion study analyzed intervention costs and cost-effectiveness. METHODS: We conducted (1) a financial analysis based on costs incurred during the trial's planning and implementation; (2) an economic analysis to consider resource utilization; and (3) cost-effectiveness analyses to estimate cost inputs relative to impact: increase in self-study (measured by visits to online courses) and increase in knowledge (measured by exam score improvement) (in 2016 US$). Finally, we estimated the economic cost of a 9-month national program and a 10-year scaled-up model (in 2021 US$). RESULTS: The total financial cost of the intervention was US$49,552; the main cost drivers were personnel time (71.4%) and technology inputs (14.9%). The total economic cost was estimated at US$92,212, with the same key cost inputs (representing 77.7% and 8.0%, respectively, of total costs). The financial cost per 10% increase in accessing online courses was US$923, while the cost of improving knowledge, measured by a 10% improvement in mean exam score across the study population, was US$32,057 (US$605 per intervention clinician). The comparable total economic cost of each improvement, respectively, was US$1,770 and US$61,452 (US$1,159 per intervention clinician). A future 9-month national program was estimated to cost US$37,403, while the full 10-year scaled-up program was estimated at US$196,446. CONCLUSIONS: This analysis indicates that leveraging mobile technology could be a feasible way to provide distance learning to health professions across Vietnam at a relatively low cost. Given the need for practical ways to expand CME in resource-constrained regions of the world, this approach warrants further study and possible adoption.

Long-lasting, dissociable improvements in working memory and long-term memory in older adults with repetitive neuromodulation.

The development of technologies to protect or enhance memory in older people is an enduring goal of translational medicine. Here we describe repetitive (4-day) transcranial alternating current stimulation (tACS) protocols for the selective, sustainable enhancement of auditory-verbal working memory and long-term memory in 65-88-year-old people. Modulation of synchronous low-frequency, but not high-frequency, activity in parietal cortex preferentially improved working memory on day 3 and day 4 and 1 month after intervention, whereas modulation of synchronous high-frequency, but not low-frequency, activity in prefrontal cortex preferentially improved long-term memory on days 2-4 and 1 month after intervention. The rate of memory improvements over 4 days predicted the size of memory benefits 1 month later. Individuals with lower baseline cognitive function experienced larger, more enduring memory improvements. Our findings demonstrate that the plasticity of the aging brain can be selectively and sustainably exploited using repetitive and highly focalized neuromodulation grounded in spatiospectral parameters of memory-specific cortical circuitry.

Comparison of anterior nares CT values in asymptomatic and symptomatic individuals diagnosed with SARS-CoV-2 in a university screening program.

At our university based high throughput screening program, we test all members of our community weekly using RT-qPCR. RT-qPCR cycle threshold (CT) values are inversely proportional to the amount of viral RNA in a sample and are a proxy for viral load. We hypothesized that CT values would be higher, and thus the viral loads at the time of diagnosis would be lower, in individuals who were infected with the virus but remained asymptomatic throughout the course of the infection. We collected the N1 and N2 target gene CT values from 1633 SARS-CoV-2 positive RT-qPCR tests of individuals sampled between August 7, 2020, and March 18, 2021, at the BU Clinical Testing Laboratory. We matched this data with symptom reporting data from our clinical team. We found that asymptomatic patients had CT values significantly higher than symptomatic individuals on the day of diagnosis. Symptoms were followed by the clinical team for 10 days post the first positive test. Within the entire population, 78.1% experienced at least one symptom during surveillance by the clinical team (n = 1276/1633). Of those experiencing symptoms, the most common symptoms were nasal congestion (73%, n = 932/1276), cough (60.0%, n = 761/1276), fatigue (59.0%, n = 753/1276), and sore throat (53.1%, n = 678/1276). The least common symptoms were diarrhea (12.5%, n = 160/1276), dyspnea on exertion (DOE) (6.9%, n = 88/1276), foot or skin changes (including rash) (4.2%, n = 53/1276), and vomiting (2.1%, n = 27/1276). Presymptomatic individuals, those who were not symptomatic on the day of diagnosis but became symptomatic over the following 10 days, had CT values higher for both N1 (median = 27.1, IQR 20.2-32.9) and N2 (median = 26.6, IQR 20.1-32.8) than the symptomatic group N1 (median = 21.8, IQR 17.2-29.4) and N2 (median = 21.4, IQR 17.3-28.9) but lower than the asymptomatic group N1 (median = 29.9, IQR 23.6-35.5) and N2 (median = 30.0, IQR 23.1-35.7). This study supports the hypothesis that viral load in the anterior nares on the day of diagnosis is a measure of disease intensity at that time.

Gabapentinoids and Acetaminophen as Adjuvants for Managing Postoperative Pain.

With the current opiate epidemic in the United States, there is renewed interest in evaluating non-opiate adjuvant medications as effective alternatives for the prevention and treatment of postoperative pain. A systematic review of randomized, controlled trials on Pub Med, Medline, and Embase was conducted looking on postoperative pain management from 2008 to 2018. Studies were included if they used a gabapentenoid with or without acetaminophen and evaluated supplemental opiate use. All adult (18 years or older) surgical populations were considered for inclusion, and fourteen clinical trials met inclusion criteria. Gabapentenoid dosing varied among studies. In nine of fourteen studies, there was a finding of superiority as compared to placebo in managing postoperative pain and decreasing supplemental opiate use. Pregabalin was used in twelve of the fourteen studies and gabapentin was used in two of the fourteen studies. Of the nine studies that found a benefit from using a gabapentoid, all included pregabalin. While the rate of adverse effects was low in all studies, it was found to increase as dosages increased. Results support that pregabalin has a role in decreasing postoperative pain intensity and supplemental opiate use; however, the optimal dose or dosing regimen is not yet well understood.

Global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in children younger than 5 years in 2019: a systematic analysis.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

Measurement of Diacetyl and Related Compounds in Coffee Roasteries and Breweries.

α-Diketones such as diacetyl (2,3-butanedione) and 2,3-pentanedione are generated during the roasting and fermentation of foods and are also used as flavoring compounds. Exposure to these compounds has been associated with obliterative bronchiolitis in workers. We report indoor air concentrations of diacetyl and 2,3-pentanedione, as well as acetoin (3-hydroxy-2-butanone), in several small coffee roasteries and breweries using standard integrated air sampling sorbent tubes followed by gas chromatography tandem mass spectrometry as well as the first use of on-site continuous real-time proton-transfer reaction time-of-flight mass spectrometry (PTR-ToF-MS). Diacetyl and 2,3-pentanedione were detected in most of the sorbent samples at concentrations between 0.02 and 8 ppbv, and in general were higher in coffee roasteries compared with breweries. Three integrated air samples, all from the barista area at one facility, exceeded the NIOSH recommended exposure limit (REL) of 5 ppbv for diacetyl. 2,3-Pentanedione concentrations in these three samples were greater than 50% of its REL, but did not exceed it. Acetoin, a precursor to diacetyl, was also detected at concentrations between 0.03 and 5 ppbv in most sorbent tube samples, with concentrations generally higher in breweries. PTR-ToF-MS measurements exhibited similar trends and provided continuous real-time volatile organic compound data that showed episodic excursions with peak concentrations of diacetyl and 2,3-pentanedione between 15 and 20 ppbv. Examination of the time series data identified specific activities associated with peak diketone emissions, including transfer of freshly roasted coffee beans to the cooling tray, or the opening of a brew kettle. Additional indoor air quality parameters including CO2, NO2, and PM2.5 were also assessed on-site. Airway inflammation was assessed in 19 workers before and after each work shift using online measurements of fractional exhaled nitric oxide (FENO). The pre-shift mean FENO was 3.7 (95% confidence interval: -3.6, 11.0) ppbv higher and the post-shift FENO was 7.1 (-1.9, 16.1) ppbv higher for workers at coffee roasteries compared with breweries. The cross-shift change in FENO was 3.4 (-2.8, 9.6) ppbv higher for workers at coffee roasteries compared with breweries. However, none of these differences were statistically significant, and the cross-shift change in FENO was not statistically different from zero for either group of workers. The findings from this pilot study demonstrate that α-diketones and related compounds are present in the indoor air of both breweries and coffee roasteries and may exceed health protective guidelines in coffee roasteries. Additional studies are required to fully characterize worker exposures in these settings and to identify specific work activities and processes associated with high exposures. Engineering controls, including targeted exhaust ventilation and the use of low-cost sensors, are recommended as an approach to protect workers from exposure to hazardous levels of α-diketones.