Multimorbid life expectancy across race, socio-economic status, and sex in South Africa.

Multimorbidity is increasing globally as populations age. However, it is unclear how long individuals live with multimorbidity and how it varies by social and economic factors. We investigate this in South Africa, whose apartheid history further complicates race, socio-economic, and sex inequalities. We introduce the term 'multimorbid life expectancy' (MMLE) to describe the years lived with multimorbidity. Using data from the South African National Income Dynamics Study (2008-17) and incidence-based multistate Markov modelling, we find that females experience higher MMLE than males (17.3 vs 9.8 years), and this disparity is consistent across all race and education groups. MMLE is highest among Asian/Indian people and the post-secondary educated relative to other groups and lowest among African people. These findings suggest there are associations between structural inequalities and MMLE, highlighting the need for health-system and educational policies to be implemented in a way proportional to each group's level of need.

Inequalities in disability-free and disabling multimorbid life expectancy in Costa Rica, Mexico, and the United States.

OBJECTIVES: To better understand variations in multimorbidity severity over time, we estimate disability-free and disabling multimorbid life expectancy (MMLE), comparing Costa Rica, Mexico, and the United States. We also assess MMLE inequalities by sex and education. METHODS: Data come from the Costa Rican Study on Longevity and Healthy Aging (2005-2009), the Mexican Health and Aging Study (2012-2018), and the Health and Retirement Study (2004-2018). We apply an incidence-based multistate Markov approach to estimate disability-free and disabling MMLE and stratify models by sex and education to study within-country heterogeneity. Multimorbidity is defined as a count of two or more chronic diseases. Disability is defined using limitations in activities of daily living. RESULTS: Costa Ricans have the lowest MMLE, followed by Mexicans, then individuals from the US. Individuals from the US spend about twice as long with disability-free multimorbidity compared with individuals from Costa Rica or Mexico. Females generally have longer MMLE than males, with particularly stark differences in disabling MMLE. In the US, higher education was associated with longer disability-free MMLE and shorter disabling MMLE. We identified evidence for cumulative disadvantage in Mexico and the US, where sex differences in MMLE were larger among the lower educated. DISCUSSION: Substantial sex and educational inequalities in MMLE exist within and between these countries. Estimating disability-free and disabling MMLE reveals another layer of health inequality not captured when examining disability and multimorbidity separately. MMLE is a flexible population health measure that can be used to better understand the aging process across contexts.

Younger but sicker? Cohort trends in disease accumulation among middle-aged and older adults in Scotland using health-linked data from the Scottish Longitudinal Study.

BACKGROUND: In the United Kingdom, rising prevalence of multimorbidity-the co-occurrence of two or more chronic conditions- is coinciding with stagnation in life expectancy. We investigate patterns of disease accumulation and how they vary by birth cohort, social and environmental inequalities in Scotland, a country which has long suffered from excess mortality and poorer health outcomes relative to its neighbours. METHODS: Using a dataset which links census data from 1991, 2001 and 2011 to disease registers and hospitalization data, we follow cohorts of adults aged 30-69 years for 18 years. We model physical and mental disease accumulation using linear mixed-effects models. RESULTS: Recent cohorts experience higher levels of chronic disease accumulation compared to their predecessors at the same ages. Moreover, in more recently born cohorts we observe socioeconomic status disparities emerging earlier in the life course, which widen over time and with every successive cohort. Patterns of chronic conditions are also changing, and the most common diseases suffered by later born cohorts are cancer, hypertension, asthma, drug and alcohol problems and depression. CONCLUSION: We recommend policies which target prevention of chronic disease in working age adults, considering how and why certain conditions are becoming more prevalent across time and space.

Treatment seeking behaviours, antibiotic use and relationships to multi-drug resistance: A study of urinary tract infection patients in Kenya, Tanzania and Uganda.

Antibacterial resistance (ABR) is a major public health threat. An important accelerating factor is treatment-seeking behaviour, including inappropriate antibiotic (AB) use. In many low- and middle-income countries (LMICs) this includes taking ABs with and without prescription sourced from various providers, including health facilities and community drug sellers. However, investigations of complex treatment-seeking, AB use and drug resistance in LMICs are scarce. The Holistic Approach to Unravel Antibacterial Resistance in East Africa (HATUA) Consortium collected questionnaire and microbiological data from adult outpatients with urinary tract infection (UTI)-like symptoms presenting at healthcare facilities in Kenya, Tanzania and Uganda. Using data from 6,388 patients, we analysed patterns of self-reported treatment seeking behaviours ('patient pathways') using process mining and single-channel sequence analysis. Among those with microbiologically confirmed UTI (n = 1,946), we used logistic regression to assess the relationship between treatment seeking behaviour, AB use, and the likelihood of having a multi-drug resistant (MDR) UTI. The most common treatment pathway for UTI-like symptoms in this sample involved attending health facilities, rather than other providers like drug sellers. Patients from sites in Tanzania and Uganda, where over 50% of patients had an MDR UTI, were more likely to report treatment failures, and have repeat visits to providers than those from Kenyan sites, where MDR UTI proportions were lower (33%). There was no strong or consistent relationship between individual AB use and likelihood of MDR UTI, after accounting for country context. The results highlight the hurdles East African patients face in accessing effective UTI care. These challenges are exacerbated by high rates of MDR UTI, suggesting a vicious cycle of failed treatment attempts and sustained selection for drug resistance. Whilst individual AB use may contribute to the risk of MDR UTI, our data show that factors related to context are stronger drivers of variations in ABR.

Predominance of multidrug-resistant bacteria causing urinary tract infections among symptomatic patients in East Africa: a call for action.

Background: In low- and middle-income countries, antibiotics are often prescribed for patients with symptoms of urinary tract infections (UTIs) without microbiological confirmation. Inappropriate antibiotic use can contribute to antimicrobial resistance (AMR) and the selection of MDR bacteria. Data on antibiotic susceptibility of cultured bacteria are important in drafting empirical treatment guidelines and monitoring resistance trends, which can prevent the spread of AMR. In East Africa, antibiotic susceptibility data are sparse. To fill the gap, this study reports common microorganisms and their susceptibility patterns isolated from patients with UTI-like symptoms in Kenya, Tanzania and Uganda. Within each country, patients were recruited from three sites that were sociodemographically distinct and representative of different populations. Methods: UTI was defined by the presence of >104 cfu/mL of one or two uropathogens in mid-stream urine samples. Identification of microorganisms was done using biochemical methods. Antimicrobial susceptibility testing was performed by the Kirby-Bauer disc diffusion assay. MDR bacteria were defined as isolates resistant to at least one agent in three or more classes of antimicrobial agents. Results: Microbiologically confirmed UTI was observed in 2653 (35.0%) of the 7583 patients studied. The predominant bacteria were Escherichia coli (37.0%), Staphylococcus spp. (26.3%), Klebsiella spp. (5.8%) and Enterococcus spp. (5.5%). E. coli contributed 982 of the isolates, with an MDR proportion of 52.2%. Staphylococcus spp. contributed 697 of the isolates, with an MDR rate of 60.3%. The overall proportion of MDR bacteria (n = 1153) was 50.9%. Conclusions: MDR bacteria are common causes of UTI in patients attending healthcare centres in East African countries, which emphasizes the need for investment in laboratory culture capacity and diagnostic algorithms to improve accuracy of diagnosis that will lead to appropriate antibiotic use to prevent and control AMR.

Treatment seeking and antibiotic use for urinary tract infection symptoms in the time of COVID-19 in Tanzania and Uganda.

Background: There is still little empirical evidence on how the outbreak of coronavirus disease 2019 (COVID-19) and associated regulations may have disrupted care-seeking for non-COVID-19 conditions or affected antibiotic behaviours in low- and middle-income countries (LMICs). We aimed to investigate the differences in treatment-seeking behaviours and antibiotic use for urinary tract infection (UTI)-like symptoms before and during the pandemic at recruitment sites in two East African countries with different COVID-19 control policies: Mbarara, Uganda and Mwanza, Tanzania. Methods: In this repeated cross-sectional study, we used data from outpatients (pregnant adolescents aged >14 and adults aged >18) with UTI-like symptoms who visited health facilities in Mwanza, Tanzania and Mbarara, Uganda. We assessed the prevalence of self-reported behaviours (delays in care-seeking, providers visited, antibiotics taken) at three different time points, labelled as 'pre-COVID-19 phase' (February 2019 to February 2020), 'COVID-19 phase 1' (March 2020 to April 2020), and 'COVID-19 phase 2' (July 2021 to February 2022). Results: In both study sites, delays in care-seeking were less common during the pandemic than they were in the pre-COVID phase. Patients in Mwanza, Tanzania had shorter care-seeking pathways during the pandemic compared to before it, but this difference was not observed in Mbarara, Uganda. Health centres were the dominant sources of antibiotics in both settings. Over time, reported antibiotic use for UTI-like symptoms became more common in both settings. During the COVID-19 phases, there was a significant increase in self-reported use of antibiotics like metronidazole (<30% in the pre-COVID-19 phase to 40% in COVID phase 2) and doxycycline (30% in the pre-COVID-19 phase to 55% in COVID phase 2) that were not recommended for treating UTI-like symptoms in the National Treatment Guidelines in Mbarara, Uganda. Conclusions: There was no clear evidence that patients with UTI-like symptoms attending health care facilities had longer or more complex treatment pathways despite strict government-led interventions related to COVID-19. However, antibiotic use increased over time, including some antibiotics not recommended for treating UTI, which has implications for future antimicrobial resistance.

Spatial patterns of COVID-19 and non-COVID-19 mortality across waves of infection in England, Wales, and Scotland.

Recent studies have established the key individual-level risk factors of COVID-19 mortality such as age, gender, ethnicity, and socio-economic status. However, the spread of infectious diseases is a spatial and temporal process implying that COVID-19 mortality and its determinants may vary sub-nationally and over time. We investigate the spatial patterns of age-standardised death rates due to COVID-19 and their correlates across local authority districts in England, Wales, and Scotland across three waves of infection. Using a Spatial Durbin model, we explore within- and between-country variation and account for spatial dependency. Areas with a higher share of ethnic minorities and higher levels of deprivation had higher rates of COVID-19 mortality. However, the share of ethnic minorities and population density in an area were more important predictors of COVID-19 mortality in earlier waves of the pandemic than in later waves, whereas area-level deprivation has become a more important predictor over time. Second, during the first wave of the pandemic, population density had a significant spillover effect on COVID-19 mortality, indicating that the pandemic spread from big cities to neighbouring areas. Third, after accounting for differences in ethnic composition, deprivation, and population density, initial cross-country differences in COVID-19 mortality almost disappeared. COVID-19 mortality remained higher in Scotland than in England and Wales in the third wave when COVID-19 mortality was relatively low in all three countries. Interpreting these results in the context of higher overall (long-term) non-COVID-19 mortality in Scotland suggests that Scotland may have performed better than expected during the first two waves. Our study highlights that accounting for both spatial and temporal factors is essential for understanding social and demographic risk factors of mortality during pandemics.

SLCO5A1 and synaptic assembly genes contribute to impulsivity in juvenile myoclonic epilepsy.

Elevated impulsivity is a key component of attention-deficit hyperactivity disorder (ADHD), bipolar disorder and juvenile myoclonic epilepsy (JME). We performed a genome-wide association, colocalization, polygenic risk score, and pathway analysis of impulsivity in JME (n = 381). Results were followed up with functional characterisation using a drosophila model. We identified genome-wide associated SNPs at 8q13.3 (P = 7.5 × 10-9) and 10p11.21 (P = 3.6 × 10-8). The 8q13.3 locus colocalizes with SLCO5A1 expression quantitative trait loci in cerebral cortex (P = 9.5 × 10-3). SLCO5A1 codes for an organic anion transporter and upregulates synapse assembly/organisation genes. Pathway analysis demonstrates 12.7-fold enrichment for presynaptic membrane assembly genes (P = 0.0005) and 14.3-fold enrichment for presynaptic organisation genes (P = 0.0005) including NLGN1 and PTPRD. RNAi knockdown of Oatp30B, the Drosophila polypeptide with the highest homology to SLCO5A1, causes over-reactive startling behaviour (P = 8.7 × 10-3) and increased seizure-like events (P = 6.8 × 10-7). Polygenic risk score for ADHD genetically correlates with impulsivity scores in JME (P = 1.60 × 10-3). SLCO5A1 loss-of-function represents an impulsivity and seizure mechanism. Synaptic assembly genes may inform the aetiology of impulsivity in health and disease.

Practices and motives behind antibiotics provision in drug outlets in Tanzania: A qualitative study.

Dispensing antibiotics without prescription is among the major factors leading to antimicrobial resistance. Dispensing of antibiotics without prescription has negative impact at the individual and societal level leading to poor patient outcomes, and increased risks of resistant bacteria facilitated by inappropriate choice of antibiotics doses/courses. Antimicrobial resistance is a global public health threat which is projected to cause 10 million deaths by 2050 if no significant actions are taken to address this problem This study explored the practices and motives behind dispensing of antibiotics without prescription among community drug outlets in Tanzania. Finding of this study provides more strategies to antibiotics stewardship intervention. In-depth interviews with 28 drug dispensers were conducted for three months consecutively between November 2019 and January 2020 in 12 community pharmacies and 16 Accredited Drug Dispensing Outlets (ADDOs) in the Mwanza, Kilimanjaro and Mbeya regions of Tanzania. Transcripts were coded and analyzed thematically using NVivo12 software. Majority of dispensers admitted to providing antibiotics without prescriptions, selling incomplete courses of antibiotics and not giving detailed instructions to customers on how to use the drugs. These practices were motivated by several factors including customers' pressure/customers' demands, business orientation-financial gain of drug dispensers, and low purchasing power of patients/customers. It is important to address the motives behind the unauthorized dispensing antibiotics. On top of the existing regulation and enforcement, we recommend the government to empower customers with education and purchasing power of drugs which can enhance the dispensers adherence to the dispensing regulations. Furthermore, we recommend ethnographic research to inform antibiotic stewardship interventions going beyond awareness raising, education and advocacy campaigns. This will address structural drivers of AMR such as poverty and inadequate government health services, and the disconnect between public messaging and/or policy and the public itself.

Unravelling patient pathways in the context of antibacterial resistance in East Africa.

BACKGROUND: A key factor driving the development and maintenance of antibacterial resistance (ABR) is individuals' use of antibiotics (ABs) to treat illness. To better understand motivations and context for antibiotic use we use the concept of a patient treatment-seeking pathway: a treatment journey encompassing where patients go when they are unwell, what motivates their choices, and how they obtain antibiotics. This paper investigates patterns and determinants of patient treatment-seeking pathways, and how they intersect with AB use in East Africa, a region where ABR-attributable deaths are exceptionally high. METHODS: The Holistic Approach to Unravelling Antibacterial Resistance (HATUA) Consortium collected quantitative data from 6,827 adult outpatients presenting with urinary tract infection (UTI) symptoms in Kenya, Tanzania, and Uganda between February 2019- September 2020, and conducted qualitative in-depth patient interviews with a subset (n = 116). We described patterns of treatment-seeking visually using Sankey plots and explored explanations and motivations using mixed-methods. Using Bayesian hierarchical regression modelling, we investigated the associations between socio-demographic, economic, healthcare, and attitudinal factors and three factors related to ABR: self-treatment as a first step, having a multi-step treatment pathway, and consuming ABs. RESULTS: Although most patients (86%) sought help from medical facilities in the first instance, many (56%) described multi-step, repetitive treatment-seeking pathways, which further increased the likelihood of consuming ABs. Higher socio-economic status patients were more likely to consume ABs and have multi-step pathways. Reasons for choosing providers (e.g., cost, location, time) were conditioned by wider structural factors such as hybrid healthcare systems and AB availability. CONCLUSION: There is likely to be a reinforcing cycle between complex, repetitive treatment pathways, AB consumption and ABR. A focus on individual antibiotic use as the key intervention point in this cycle ignores the contextual challenges patients face when treatment seeking, which include inadequate access to diagnostics, perceived inefficient public healthcare and ease of purchasing antibiotics without prescription. Pluralistic healthcare landscapes may promote more complex treatment seeking and therefore inappropriate AB use. We recommend further attention to healthcare system factors, focussing on medical facilities (e.g., accessible diagnostics, patient-doctor interactions, information flows), and community AB access points (e.g., drug sellers).

Bacterial etiology of urinary tract infections in patients treated at Kenyan health facilities and their resistance towards commonly used antibiotics.

BACKGROUND: Evidence-based empirical antibiotic prescribing requires knowledge of local antimicrobial resistance patterns. The spectrum of pathogens and their susceptibility strongly influences guidelines for empirical therapies for urinary tract infections (UTI) management. OBJECTIVE: This study aimed to determine the prevalence of UTI causative bacteria and their corresponding antibiotic resistance profiles in three counties of Kenya. Such data could be used to determine the optimal empirical therapy. METHODS: In this cross-sectional study, urine samples were collected from patients who presented with symptoms suggestive of UTI in the following healthcare facilities; Kenyatta National Hospital, Kiambu Hospital, Mbagathi, Makueni, Nanyuki, Centre for Microbiology Research, and Mukuru Health Centres. Urine cultures were done on Cystine Lactose Electrolyte Deficient (CLED) to isolate UTI bacterial etiologies, while antibiotic sensitivity testing was done using the Kirby-Bauer disk diffusion using CLSI guidelines and interpretive criteria. RESULTS: A total of 1,027(54%) uropathogens were isolated from the urine samples of 1898 participants. Staphylococcus spp. and Escherichia coli were the main uropathogens at 37.6% and 30.9%, respectively. The percentage resistance to commonly used drugs for the treatment of UTI were as follows: trimethoprim (64%), sulfamethoxazole (57%), nalidixic acid(57%), ciprofloxacin (27%), amoxicillin-clavulanic acid (5%), and nitrofurantoin (9%) and cefixime (9%). Resistance rates to broad-spectrum antimicrobials, such as ceftazidime, gentamicin, and ceftriaxone, were 15%, 14%, and 11%, respectively. Additionally, the proportion of Multidrug-resistant (MDR) bacteria was 66%. CONCLUSION: High resistance rates toward fluoroquinolones, sulfamethoxazole, and trimethoprim were reported. These antibiotics are commonly used drugs as they are inexpensive and readily available. Based on these findings, more robust standardised surveillance is needed to confirm the patterns observed while recognising the potential impact of sampling biases on observed resistance rates.

Urogenital pathogens in urine samples of clinically diagnosed urinary tract infected patients in Tanzania: A laboratory based cross-sectional study.

Background: Urogenital pathogens such as Chlamydia trachomatis, Neisseria gonorrhoeae, Mycoplasma genitalium and Trichomonas vaginalis have been reported to cause pyuria, however they are not routinely cultured from urine samples of patients clinically diagnosed to have urinary tract infections (UTI). In this study, pathogen specific PCR was done to identify the urogenital pathogens in the urine samples among clinically diagnosed UTI patients with negative routine urine culture. Methods: A cross-sectional study was conducted involving 227 archived urine samples from clinically diagnosed UTI patients with positive leucocyte esterase but negative urine culture results. The urogenital pathogens were detected using pathogen specific singleplex PCR. Data were cleaned and analyzed using STATA version 15. Results: The median age of patients was 31[IQR 23 - 51] years and the majority (174, 76.7%) were females. Two thirds of patients had history of antibiotic use two weeks prior to recruitment (154, 67.8%). A total of 62(27.3%) urine samples were positive for at least one urogenital pathogen. Of 62 positive samples, 9 had two urogenital pathogens and 1 had three urogenital pathogens. The most predominant urogenital pathogen detected was Neisseria gonorrhoeae 25(34.2%) and Trichomonas vaginalis 24(32.9%). Being female (aOR 2.4; 95% CI: 1.04 - 5.49; p-value 0.039) and having history of using antibiotics in the past two weeks (aOR 1.9; 95%CI: 1.04 - 3.60; p-value 0.036) was independently associated with the presence of urogenital pathogens. Conclusion: More than a quarter of female patients with clinical symptoms of UTI and routine urine culture negative results were infected with urogenital pathogens mainly Neisseria gonorrhoeae and Trichomonas vaginalis. Further research with a larger sample set in a range of settings is required to understand the implications of these finding generally.

Treatment seeking behaviours, antibiotic use and relationships to multi-drug resistance: A study of urinary tract infection patients in Kenya, Tanzania and Uganda.

Antibacterial resistance (ABR) is a major public health threat. An important accelerating factor is treatment-seeking behaviours, including inappropriate antibiotic (AB) use. In many low- and middle-income countries (LMICs) this includes taking ABs with and without prescription sourced from various providers, including health facilities and community drug sellers. However, investigations of complex treatment-seeking, AB use and drug resistance in LMICs are scarce. The Holistic Approach to Unravel Antibacterial Resistance in East Africa (HATUA) Consortium collected questionnaire and microbiological data from 6,827 adult outpatients with urinary tract infection (UTI)-like symptoms presenting at healthcare facilities in Kenya, Tanzania and Uganda. Among 6,388 patients we analysed patterns of self-reported treatment seeking behaviours ('patient pathways') using process mining and single-channel sequence analysis. Of those with microbiologically confirmed UTI (n=1,946), we used logistic regression to assessed the relationship between treatment seeking behaviour, AB use, and likelihood of having a multi-drug resistant (MDR) UTI. The most common treatment pathways for UTI-like symptoms included attending health facilities, rather than other providers (e.g. drug sellers). Patients from the sites sampled in Tanzania and Uganda, where prevalence of MDR UTI was over 50%, were more likely to report treatment failures, and have repeated visits to clinics/other providers, than those from Kenyan sites, where MDR UTI rates were lower (33%). There was no strong or consistent relationship between individual AB use and risk of MDR UTI, after accounting for country context. The results highlight challenges East African patients face in accessing effective UTI treatment. These challenges increase where rates of MDR UTI are higher, suggesting a reinforcing circle of failed treatment attempts and sustained selection for drug resistance. Whilst individual behaviours may contribute to the risk of MDR UTI, our data show that factors related to context are stronger drivers of ABR.

Antibiotic dispensing practices during COVID-19 and implications for antimicrobial resistance (AMR): parallel mystery client studies in Uganda and Tanzania.

BACKGROUND: Over-the-counter antibiotic access is common in low-and-middle-income countries and this may accelerate antimicrobial resistance. Our study explores critical aspects of the drug seller-client interaction and antibiotic dispensing patterns for simulated COVID-19 symptoms during the pandemic in two study sites in Tanzania and Uganda, countries with different government responses to the pandemic. METHODS: Research assistants posing as clients approached different types of drug sellers such as pharmacies (Pharms), drug shops (DSs), and accredited drug dispensing outlets (ADDOs) in Mwanza, Tanzania (nPharms = 415, nADDOs = 116) and Mbarara, Uganda (nPharms = 440, nDSs = 67), from June 10 to July 30, 2021. The mystery clients held no prescription and sought advice for simulated COVID-19 symptoms from the drug sellers. They documented the quality of their interaction with sellers and the type of drugs dispensed. RESULTS: Adherence to COVID-19 preventive measures and vigilance to COVID-19 symptoms was low in both sites but significantly higher in Uganda than in Tanzania. A higher percentage of drug sellers in Mbarara (Pharms = 36%, DSs = 35%, P-value = 0.947) compared to Mwanza (Pharms = 9%, ADDOs = 4%, P-value = 0.112) identified the client's symptoms as possibly COVID-19. More than three-quarters of drug sellers that sold prescription-only medicines in both Mbarara (Pharms = 86%, DSs = 89%) and Mwanza (Pharms = 93%, ADDOs = 97%) did not ask the MCs for a prescription. A relatively high percentage of drug sellers that sold prescription-only medicines in Mwanza (Pharms = 51%, ADDOs = 67%) compared to Mbarara (Pharms = 31%, DSs = 42%) sold a partial course without any hesitation. Of those who sold antibiotics, a higher proportion of drug sellers in Mbarara (Pharms = 73%, DSs = 78%, P-value = 0.580) compared to Mwanza (Pharms = 40% ADDOs = 46%, P-value = 0.537) sold antibiotics relevant for treating secondary bacterial infections in COVID-19 patients. CONCLUSION: Our study highlights low vigilance towards COVID-19 symptoms, widespread propensity to dispense prescription-only antibiotics without a prescription, and to dispense partial doses of antibiotics. This implies that drug dispensing related to COVID-19 may further drive AMR. Our study also highlights the need for more efforts to improve antibiotic stewardship among drug sellers in response to COVID-19 and to prepare them for future health emergencies.

The role of multidimensional poverty in antibiotic misuse: a mixed-methods study of self-medication and non-adherence in Kenya, Tanzania, and Uganda.

BACKGROUND: Poverty is a proposed driver of antimicrobial resistance, influencing inappropriate antibiotic use in low-income and middle-income countries (LMICs). However, at subnational levels, studies investigating multidimensional poverty and antibiotic misuse are sparse, and the results are inconsistent. We aimed to investigate the relationship between multidimensional poverty and antibiotic use in patient populations in Kenya, Tanzania, and Uganda. METHODS: In this mixed-methods study, the Holistic Approach to Unravelling Antimicrobial Resistance (HATUA) Consortium collected data from 6827 outpatients (aged 18 years and older, or aged 14-18 years and pregnant) with urinary tract infection (UTI) symptoms in health-care facilities in Kenya, Tanzania, and Uganda. We used Bayesian hierarchical modelling to investigate the association between multidimensional poverty and self-reported antibiotic self-medication and non-adherence (ie, skipping a dose and not completing the course). We analysed linked qualitative in-depth patient interviews and unlinked focus-group discussions with community members. FINDINGS: Between Feb 10, 2019, and Sept 10, 2020, we collected data on 6827 outpatients, of whom 6345 patients had complete data; most individuals were female (5034 [79·2%]), younger than 35 years (3840 [60·5%]), worked in informal employment (2621 [41·3%]), and had primary-level education (2488 [39·2%]). Antibiotic misuse was more common among those least deprived, and lowest among those living in severe multidimensional poverty. Regardless of poverty status, difficulties in affording health care, and more familiarity with antibiotics, were related to more antibiotic misuse. Qualitative data from linked qualitative in-depth patient interviews (n=82) and unlinked focus-group discussions with community members (n=44 groups) suggested that self-medication and treatment non-adherence were driven by perceived inconvenience of the health-care system, financial barriers, and ease of unregulated antibiotic access. INTERPRETATION: We should not assume that higher deprivation drives antibiotic misuse. Structural barriers such as inefficiencies in public health care, combined with time and financial constraints, fuel alternative antibiotic access points and treatment non-adherence across all levels of deprivation. In designing interventions to reduce antibiotic misuse and address antimicrobial resistance, greater attention is required to these structural barriers that discourage optimal antibiotic use at all levels of the socioeconomic hierarchy in LMICs. FUNDING: UK National Institute for Health Research, UK Medical Research Council, and the Department of Health and Social Care.

A Longitudinal Analysis of the Association Between Long-Term Exposure to Air Pollution and Cognitive Function Among Adults Aged 45 and Older in China.

OBJECTIVES: Evidence suggests long-term exposure to fine particulate matter air pollution (PM2.5) is associated with a higher risk of cognitive impairment, especially among older adults. This study examines the relationship between PM2.5 exposure and cognitive function in China's aging population. METHODS: We used longitudinal data from the China Health and Retirement Longitudinal Study (2011-2015) linked with historical PM2.5 concentrations (2000-2015) from remotely sensed satellite data. Growth curve models were applied to estimate associations between PM2.5 exposure (measured in intensity, duration, and a joint variable of intensity with duration for cumulative exposure) and cognitive function. RESULTS: Relative to the lowest exposure group, exposure in the second group of PM2.5 intensity (35-50 µg/m3) is associated with poorer cognitive function, but higher levels of PM2.5 appear to be associated with better cognitive function, indicating a U-shaped association. Similar patterns are seen for fully adjusted models of PM2.5 duration: the second group (13-60 months) is associated with worse cognitive function than the first group (0-12 months), but coefficients are nonsignificant in longer duration groups. Joint analysis of PM2.5 intensity with duration suggests that duration may play a more detrimental role in cognitive function than intensity. However, we do not find a statistically significant association between PM2.5 exposure and the rate of cognitive decline. DISCUSSION: Our findings are mixed and suggest that some categories of higher and longer exposure to PM2.5 are associated with poorer cognitive function, while that exposures do not hasten cognitive decline. However, more work is necessary to disentangle PM2.5 exposure from individuals' background characteristics, particularly those jointly associated with cognitive function and urban living.

High-quality read-based phasing of cystic fibrosis cohort informs genetic understanding of disease modification.

Phasing of heterozygous alleles is critical for interpretation of cis-effects of disease-relevant variation. We sequenced 477 individuals with cystic fibrosis (CF) using linked-read sequencing, which display an average phase block N50 of 4.39 Mb. We use these samples to construct a graph representation of CFTR haplotypes, demonstrating its utility for understanding complex CF alleles. These are visualized in a Web app, CFTbaRcodes, that enables interactive exploration of CFTR haplotypes present in this cohort. We perform fine-mapping and phasing of the chr7q35 trypsinogen locus associated with CF meconium ileus, an intestinal obstruction at birth associated with more severe CF outcomes and pancreatic disease. A 20-kb deletion polymorphism and a PRSS2 missense variant p.Thr8Ile (rs62473563) are shown to independently contribute to meconium ileus risk (p = 0.0028, p = 0.011, respectively) and are PRSS2 pancreas eQTLs (p = 9.5 × 10-7 and p = 1.4 × 10-4, respectively), suggesting the mechanism by which these polymorphisms contribute to CF. The phase information from linked reads provides a putative causal explanation for variation at a CF-relevant locus, which also has implications for the genetic basis of non-CF pancreatitis, to which this locus has been reported to contribute.

Health outcomes of only children across the life course: An investigation using Swedish register data.

Only children (with no full biological siblings) are a growing subgroup in many high-income settings. Previous studies have largely focused on the short-term developmental outcomes of only children, but there is limited evidence on their health outcomes. Using Swedish population register data for cohorts born 1940-75, we compare the health of only children with that of children from multi-child sibling groups, taking into account birth order, family size, and presence of half-siblings. Only children showed lower height and fitness scores, were more likely to be overweight/obese in late adolescence, and experienced higher later-life mortality than those with one or two siblings. However, only children without half-siblings were consistently healthier than those with half-siblings, suggesting that parental disruption confers additional disadvantages. The health disadvantage was attenuated but not fully explained by adjustment for parental characteristics and after using within-family maternal cousin comparison designs.

Rapid chloride and bicarbonate determination by capillary electrophoresis for confirmatory testing of cystic fibrosis infants with volume-limited sweat specimens.

Objectives Cystic fibrosis (CF) is a debilitating genetic disorder that benefits from early detection. CF diagnosis relies on measuring elevated sweat chloride that is difficult in neonates with low sweat rates. We introduce a new method for sweat chloride determination from volume-limited specimens, and explore the potential utility of sweat bicarbonate in neonatal CF screening. Methods A rapid assay (< 5 min) was developed to analyze chloride and bicarbonate using capillary electrophoresis with indirect UV detection (CE-iUV). Pilocarpine-stimulated sweat samples from screen-positive CF infants were collected at two hospital sites, including confirmed CF (n = 12), CF screen-positive inconclusive diagnosis (n = 4), and unaffected non-CF cases (n = 37). All sweat chloride samples were analyzed by a coulometric titrator and CE-iUV, and the viability to measure acid-labile bicarbonate was also evaluated. Results Stability studies revealed that bicarbonate can be reliably assessed in sweat if acidification and heating were avoided. Method validation demonstrated that sweat chloride and bicarbonate were quantified with acceptable accuracy (recovery of 102%), precision (CV = 3.7%) and detection limits (∼ 0.1 mM). An inter-laboratory comparison confirmed a mean bias of 6.5% (n = 53) for sweat chloride determination by CE-iUV relative to a commercial chloridometer. However, sweat bicarbonate did not discriminate between CF and non-CF infants (AUC = 0.623, p = 0.215) unlike chloride (AUC = 1.00, p = 3.00 × 10-7). Conclusions CE-iUV offers a robust method for sweat chloride testing from presumptive CF infants that may reduce testing failure rates. However, sweat bicarbonate does not have clinical value in newborn CF diagnosis.

Treatment of missing data in Bayesian network structure learning: an application to linked biomedical and social survey data.

BACKGROUND: Availability of linked biomedical and social science data has risen dramatically in past decades, facilitating holistic and systems-based analyses. Among these, Bayesian networks have great potential to tackle complex interdisciplinary problems, because they can easily model inter-relations between variables. They work by encoding conditional independence relationships discovered via advanced inference algorithms. One challenge is dealing with missing data, ubiquitous in survey or biomedical datasets. Missing data is rarely addressed in an advanced way in Bayesian networks; the most common approach is to discard all samples containing missing measurements. This can lead to biased estimates. Here, we examine how Bayesian network structure learning can incorporate missing data. METHODS: We use a simulation approach to compare a commonly used method in frequentist statistics, multiple imputation by chained equations (MICE), with one specific for Bayesian network learning, structural expectation-maximization (SEM). We simulate multiple incomplete categorical (discrete) data sets with different missingness mechanisms, variable numbers, data amount, and missingness proportions. We evaluate performance of MICE and SEM in capturing network structure. We then apply SEM combined with community analysis to a real-world dataset of linked biomedical and social data to investigate associations between socio-demographic factors and multiple chronic conditions in the US elderly population. RESULTS: We find that applying either method (MICE or SEM) provides better structure recovery than doing nothing, and SEM in general outperforms MICE. This finding is robust across missingness mechanisms, variable numbers, data amount and missingness proportions. We also find that imputed data from SEM is more accurate than from MICE. Our real-world application recovers known inter-relationships among socio-demographic factors and common multimorbidities. This network analysis also highlights potential areas of investigation, such as links between cancer and cognitive impairment and disconnect between self-assessed memory decline and standard cognitive impairment measurement. CONCLUSION: Our simulation results suggest taking advantage of the additional information provided by network structure during SEM improves the performance of Bayesian networks; this might be especially useful for social science and other interdisciplinary analyses. Our case study show that comorbidities of different diseases interact with each other and are closely associated with socio-demographic factors.