Correlates of prior HIV testing and schistosomiasis treatment: Baseline survey findings from the "creating demand for fishermen's schistosomiasis HIV services" (FISH) cluster-randomized trial in Mangochi, Malawi.

BACKGROUND: Fishing exposes fishermen to schistosomiasis-infested fresh water and concurrently through precarious livelihoods to risky sexual behaviour, rendering these two infections occupational hazards for fishermen. This study aimed to characterize the knowledge of the two conditions to obtain necessary data for a subsequent cluster randomized trial designed to investigate demand creation strategies for joint HIV-schistosomiasis service provision in fishing villages on the shores of southern Lake Malawi. METHODS: Enumeration of all resident fishermen in 45 clusters (fishing communities) was carried out between November 2019 and February 2020. In a baseline survey, fishermen reported their knowledge, attitudes and practices in the uptake of HIV and schistosomiasis services. Knowledge of HIV status and previous receipt of praziquantel were modelled using random effects binomial regression, accounting for clustering. Prevalence of willingness to attend a beach clinic was computed. RESULTS: A total of 6,297 fishermen were surveyed from the 45 clusters with harmonic mean number of fishermen per cluster of 112 (95% CI: 97; 134). The mean age was 31.7y (SD: 11.9) and nearly 40% (2,474/6,297) could not read or write. Overall, 1,334/6,293 (21.2%) had never tested for HIV, with 64.4% (3,191/4,956) having tested in the last 12 months, and 5.9% (373/6290) taking antiretroviral therapy (ART). In adjusted analyses, being able to read and write (adjusted risk ratio [aRR: 1.91, 95% CI: 1.59-2.29, p<0.001); previous use of praziquantel (aRR: 2.00,95% CI: 1.73-2.30, p<0.001); knowing a relative or friend who died of HIV (aRR: 1.54,95% CI: 1.33-1.79, p<0.001); and being on ART (aRR: 12.93, 95% CI: 6.25-32.93, p<0.001) were associated with increased likelihood of ever testing for HIV. Only 40% (1,733/4,465) had received praziquantel in the last 12 months. Every additional year of age was associated with 1% decreased likelihood of having taken praziquantel in the last 12 months (aRR: 0.99, 95% CI: 0.98-0.99, p<0.001). However, recent HIV testing increased the likelihood of taking praziquantel by over 2-fold (aRR 2.24, 95% CI: 1.93-2.62, p<0.001). Willingness to attend a mobile beach clinic offering integrated HIV and schistosomiasis services was extremely high at 99.0% (6,224/6,284). CONCLUSION: In a setting with an underlying high prevalence of both HIV and schistosomiasis, we found low knowledge of HIV status and low utilization of free schistosomiasis treatment. Among fishermen who accessed HIV services, there was a very high likelihood of taking praziquantel suggesting that integrated service delivery may lead to good coverage. TRIAL REGISTRATION: This trial is registered in the ISRCTN registry: ISRCTN14354324; date of registration: 05 October 2020.

Impact of Community-Wide Tuberculosis Active Case Finding and Human Immunodeficiency Virus Testing on Tuberculosis Trends in Malawi.

BACKGROUND: Tuberculosis case-finding interventions are critical to meeting World Health Organization End TB strategy goals. We investigated the impact of community-wide tuberculosis active case finding (ACF) alongside scale-up of human immunodeficiency virus (HIV) testing and care on trends in adult tuberculosis case notification rates (CNRs) in Blantyre, Malawi. METHODS: Five rounds of ACF for tuberculosis (1-2 weeks of leafleting, door-to-door enquiry for cough and sputum microscopy) were delivered to neighborhoods ("ACF areas") in North-West Blantyre between April 2011 and August 2014. Many of these neighborhoods also had concurrent HIV testing interventions. The remaining neighborhoods in Blantyre City ("non-ACF areas") provided a non-randomized comparator. We analyzed TB CNRs from January 2009 until December 2018. We used interrupted time series analysis to compare tuberculosis CNRs before ACF and after ACF, and between ACF and non-ACF areas. RESULTS: Tuberculosis CNRs increased in Blantyre concurrently with start of ACF for tuberculosis in both ACF and non-ACF areas, with a larger magnitude in ACF areas. Compared to a counterfactual where pre-ACF CNR trends continued during ACF period, we estimated there were an additional 101 (95% confidence interval [CI] 42 to 160) microbiologically confirmed (Bac+) tuberculosis diagnoses per 100 000 person-years in the ACF areas in 3 and a half years of ACF. Compared to a counterfactual where trends in ACF area were the same as trends in non-ACF areas, we estimated an additional 63 (95% CI 38 to 90) Bac + diagnoses per 100 000 person-years in the same period. CONCLUSIONS: Tuberculosis ACF was associated with a rapid increase in people diagnosed with tuberculosis in Blantyre.

Needs assessment for enhancing pediatric clerkship readiness.

BACKGROUND: Many students report feeling inadequately prepared for their clinical experiences in pediatrics. There is striking variability on how pediatric clinical skills are taught in pre-clerkship curricula. METHODS: We asked students who completed their clerkships in pediatrics, family medicine, surgery, obstetrics-gynecology and internal medicine to rate their pre-clinical training in preparing them for each clerkship, specifically asking about medical knowledge, communication, and physical exam skills. Based on these results, we surveyed pediatric clerkship and clinical skills course directors at North American medical schools to describe the competence students should have in the pediatric physical exam prior to their pediatric clerkship. RESULTS: Close to 1/3 of students reported not feeling adequately prepared for their pediatrics, obstetrics-gynecology, or surgery clerkship. Students felt less prepared to perform pediatric physical exam skills compared to physical exam skills in all other clerkships. Pediatric clerkship directors and clinical skills course directors felt students should have knowledge of and some ability to perform a wide spectrum of physical exam skills on children. There were no differences between the two groups except that clinical skills educators identified a slightly higher expected competence for development assessment skills compared to pediatric clerkship directors. CONCLUSIONS: As medical schools undergo cycles of curricular reform, it may be beneficial to integrate more pre-clerkship exposure to pediatric topics and skills. Further exploration and collaboration establishing how and when to incorporate this learning could serve as a starting point for curricular improvements, with evaluation of effects on student experience and performance. A challenge is identifying infants and children for physical exam skills practice.

Neighbourhood prevalence-to-notification ratios for adult bacteriologically-confirmed tuberculosis reveals hotspots of underdiagnosis in Blantyre, Malawi.

Local information is needed to guide targeted interventions for respiratory infections such as tuberculosis (TB). Case notification rates (CNRs) are readily available, but systematically underestimate true disease burden in neighbourhoods with high diagnostic access barriers. We explored a novel approach, adjusting CNRs for under-notification (P:N ratio) using neighbourhood-level predictors of TB prevalence-to-notification ratios. We analysed data from 1) a citywide routine TB surveillance system including geolocation, confirmatory mycobacteriology, and clinical and demographic characteristics of all registering TB patients in Blantyre, Malawi during 2015-19, and 2) an adult TB prevalence survey done in 2019. In the prevalence survey, consenting adults from randomly selected households in 72 neighbourhoods had symptom-plus-chest X-ray screening, confirmed with sputum smear microscopy, Xpert MTB/Rif and culture. Bayesian multilevel models were used to estimate adjusted neighbourhood prevalence-to-notification ratios, based on summarised posterior draws from fitted adult bacteriologically-confirmed TB CNRs and prevalence. From 2015-19, adult bacteriologically-confirmed CNRs were 131 (479/371,834), 134 (539/415,226), 114 (519/463,707), 56 (283/517,860) and 46 (258/578,377) per 100,000 adults per annum, and 2019 bacteriologically-confirmed prevalence was 215 (29/13,490) per 100,000 adults. Lower educational achievement by household head and neighbourhood distance to TB clinic was negatively associated with CNRs. The mean neighbourhood P:N ratio was 4.49 (95% credible interval [CrI]: 0.98-11.91), consistent with underdiagnosis of TB, and was most pronounced in informal peri-urban neighbourhoods. Here we have demonstrated a method for the identification of neighbourhoods with high levels of under-diagnosis of TB without the requirement for a prevalence survey; this is important since prevalence surveys are expensive and logistically challenging. If confirmed, this approach may support more efficient and effective targeting of intensified TB and HIV case-finding interventions aiming to accelerate elimination of urban TB.

Same-day antiretroviral therapy initiation for people living with HIV who have tuberculosis symptoms: a systematic review.

OBJECTIVES: Tuberculosis symptoms are very common among people living with HIV (PLHIV) initiating antiretroviral therapy (ART), are not specific for tuberculosis disease and may result in delayed ART start. The risks and benefits of same-day ART initiation in PLHIV with tuberculosis symptoms are unknown. METHODS: We systematically reviewed nine databases on 12 March 2020 to identify studies that investigated same-day ART initiation among PLHIV with tuberculosis symptoms and reported both their approach to TB screening and clinical outcomes. We extracted and summarized data about TB screening, numbers of people starting same-day ART and outcomes. RESULTS: We included four studies. Two studies deferred ART for everyone with any tuberculosis symptoms (one or more of cough, fever, night sweats or weight loss) and substantial numbers of people had deferred ART start (28% and 39% did not start same-day ART). Two studies permitted some people with tuberculosis symptoms to start same-day ART, and fewer people deferred ART (2% and 16% did not start same-day). Two of the four studies were conducted sequentially; proven viral load suppression at 8 months was 31% when everyone with tuberculosis symptoms had ART deferred, and 44% when the algorithm was changed so that some people with tuberculosis symptoms could start same-day ART. CONCLUSIONS: Although tuberculosis symptoms are very common in people starting ART, there is insufficient evidence about whether presence of tuberculosis symptoms should lead to ART start being deferred or not. Research to inform clear guidelines would help to maximise the benefits of same-day ART.

Household Contact Tracing With Intensified Tuberculosis and Human Immunodeficiency Virus Screening in South Africa: A Cluster-Randomized Trial.

BACKGROUND: Household contact tracing for tuberculosis (TB) may facilitate diagnosis and access to TB preventive treatment (TPT). We investigated whether household contact tracing and intensive TB/human immunodeficiency virus (HIV) screening would improve TB-free survival. METHODS: Household contacts of index TB patients in 2 South African provinces were randomized to home tracing and intensive HIV/TB screening or standard of care (SOC; clinic referral letters). The primary outcome was incident TB or death at 15 months. Secondary outcomes included tuberculin skin test (TST) positivity in children ≤14 years and undiagnosed HIV. RESULTS: From December 2016 through March 2019, 1032 index patients (4459 contacts) and 1030 (4129 contacts) were randomized to the intervention and SOC arms. Of intervention arm contacts, 3.2% (69 of 2166) had prevalent microbiologically confirmed TB. At 15 months, the cumulative incidence of TB or death did not differ between the intensive screening (93 of 3230, 2.9%) and SOC (80 of 2600, 3.1%) arms (hazard ratio, 0.90; 95% confidence interval [CI], .66-1.24). TST positivity was higher in the intensive screening arm (38 of 845, 4.5%) compared with the SOC arm (15 of 800, 1.9%; odds ratio, 2.25; 95% CI, 1.07-4.72). Undiagnosed HIV was similar between arms (41 of 3185, 1.3% vs 32 of 2543, 1.3%; odds ratio, 1.02; 95% CI, .64-1.64). CONCLUSIONS: Household contact tracing with intensive screening and referral did not reduce incident TB or death. Providing referral letters to household contacts of index patients is an alternative strategy to home visits. CLINICAL TRIALS REGISTRATION: ISRCTN16006202.

Palliative care and catastrophic costs in Malawi after a diagnosis of advanced cancer: a prospective cohort study.

BACKGROUND: Inclusive universal health coverage requires access to quality health care without financial barriers. Receipt of palliative care after advanced cancer diagnosis might reduce household poverty, but evidence from low-income and middle-income settings is sparse. METHODS: In this prospective study, the primary objective was to investigate total household costs of cancer-related health care after a diagnosis of advanced cancer, with and without the receipt of palliative care. Households comprising patients and their unpaid family caregiver were recruited into a cohort study at Queen Elizabeth Central Hospital in Malawi, between Jan 16 and July 31, 2019. Costs of cancer-related health-care use (including palliative care) and health-related quality-of-life were recorded over 6 months. Regression analysis explored associations between receipt of palliative care and total household costs on health care as a proportion of household income. Catastrophic costs, defined as 20% or more of total household income, sale of assets and loans taken out (dissaving), and their association with palliative care were computed. FINDINGS: We recruited 150 households. At 6 months, data from 89 (59%) of 150 households were available, comprising 89 patients (median age 50 years, 79% female) and 64 caregivers (median age 40 years, 73% female). Patients in 55 (37%) of the 150 households died and six (4%) were lost to follow-up. 19 (21%) of 89 households received palliative care. Catastrophic costs were experienced by nine (47%) of 19 households who received palliative care versus 48 (69%) of 70 households who did not (relative risk 0·69, 95% CI 0·42 to 1·14, p=0·109). Palliative care was associated with substantially reduced dissaving (median US$11, IQR 0 to 30 vs $34, 14 to 75; p=0·005). The mean difference in total household costs on cancer-related health care with receipt of palliative care was -36% (95% CI -94 to 594; p=0·707). INTERPRETATION: Vulnerable households in low-income countries are subject to catastrophic health-related costs following a diagnosis of advanced cancer. Palliative care might result in reduced dissaving in these households. Further consideration of the economic benefits of palliative care is justified. FUNDING: Wellcome Trust; National Institute for Health Research; and EMMS International.

Community-based active case-finding interventions for tuberculosis: a systematic review.

BACKGROUND: Community-based active case-finding interventions might identify and treat more people with tuberculosis disease than standard case detection. We aimed to assess whether active case-finding interventions can affect tuberculosis epidemiology in the wider community. METHODS: We did a systematic review by searching PubMed, Embase, Scopus, and Cochrane Library for studies that compared tuberculosis case notification rates, tuberculosis disease prevalence, or tuberculosis infection prevalence or incidence in children, between populations exposed and unexposed to active case-finding interventions. We included studies published in English between Jan 1, 1980, and April 13, 2020. Studies of active case-finding in the general population, in populations perceived to be at high risk for tuberculosis, and in closed settings were included, whereas studies of tuberculosis screening at health-care facilities, among household contacts, or among children only, and studies that screened fewer than 1000 people were excluded. To estimate effectiveness, we extracted or calculated case notification rates, prevalence of tuberculosis disease, and incidence or prevalence of tuberculosis infection in children, and compared ratios of these outcomes between groups that were exposed or not exposed to active case-finding interventions. RESULTS: 27 883 abstracts were screened and 988 articles underwent full text review. 28 studies contributed data for analysis of tuberculosis case notifications, nine for prevalence of tuberculosis disease, and two for incidence or prevalence of tuberculosis infection in children. In one cluster-randomised trial in South Africa and Zambia, an active case-finding intervention based on community mobilisation and sputum drop-off did not affect tuberculosis prevalence, whereas, in a cluster-randomised trial in Vietnam, an active case-finding intervention based on sputum tuberculosis tests for everyone reduced tuberculosis prevalence in the community. We found inconsistent, low-quality evidence that active case-finding might increase the number of cases of tuberculosis notified in populations with structural risk factors for tuberculosis. INTERPRETATION: Community-based active case-finding for tuberculosis might be effective in changing tuberculosis epidemiology and thereby improving population health if delivered with high coverage and intensity. If possible, active case-finding projects should incorporate a well designed, robust evaluation to contribute to the evidence base and help elucidate which delivery methods and diagnostic strategies are most effective. FUNDING: WHO Global TB Programme.

Tuberculosis diagnosis cascade in Blantyre, Malawi: a prospective cohort study.

BACKGROUND: Tuberculosis (TB) control relies on early diagnosis and treatment. International guidelines recommend systematic TB screening at health facilities, but implementation is challenging. We investigated completion of recommended TB screening steps in Blantyre, Malawi. METHODS: A prospective cohort recruited adult outpatients attending Bangwe primary clinic. Entry interviews were linked to exit interviews. The proportion of participants progressing through each step of the diagnostic pathway were estimated. Factors associated with request for sputum were investigated using multivariable logistic regression. RESULTS: Of 5442 clinic attendances 2397 (44%) had exit interviews. In clinically indicated participants (n = 445) 256 (57.5%) were asked about cough, 36 (8.1%) were asked for sputum, 21 (4.7%) gave sputum and 1 (0.2%) received same-day results. Significant associations with request for sputum were: any TB symptom (aOR:3.20, 95%CI:2.02-5.06), increasing age (aOR:1.02, 95%CI:1.01-1.04 per year) and for HIV-negative participants only, a history of previous TB (aOR:3.37, 95%CI:1.45-7.81). Numbers requiring sputum tests (26/day) outnumbered diagnostic capacity (8-12/day). CONCLUSIONS: Patients were lost at every stage of the TB care cascade, with same day sputum submission following all steps of the diagnosis cascade achieved in only 4.7% if clinically indicated. Infection control strategies should be implemented, with reporting on early steps of the TB care cascade formalised. High-throughput screening interventions, such as digital CXR, that can achieve same-day TB diagnosis are urgently needed to meet WHO End TB goals.

'If not TB, what could it be?' Chest X-ray findings from the 2016 Kenya Tuberculosis Prevalence Survey.

BACKGROUND: The prevalence of diseases other than TB detected during chest X-ray (CXR) screening is unknown in sub-Saharan Africa. This represents a missed opportunity for identification and treatment of potentially significant disease. Our aim was to describe and quantify non-TB abnormalities identified by TB-focused CXR screening during the 2016 Kenya National TB Prevalence Survey. METHODS: We reviewed a random sample of 1140 adult (≥15 years) CXRs classified as 'abnormal, suggestive of TB' or 'abnormal other' during field interpretation from the TB prevalence survey. Each image was read (blinded to field classification and study radiologist read) by two expert radiologists, with images classified into one of four major anatomical categories and primary radiological findings. A third reader resolved discrepancies. Prevalence and 95% CIs of abnormalities diagnosis were estimated. FINDINGS: Cardiomegaly was the most common non-TB abnormality at 259 out of 1123 (23.1%, 95% CI 20.6% to 25.6%), while cardiomegaly with features of cardiac failure occurred in 17 out of 1123 (1.5%, 95% CI 0.9% to 2.4%). We also identified chronic pulmonary pathology including suspected COPD in 3.2% (95% CI 2.3% to 4.4%) and non-specific patterns in 4.6% (95% CI 3.5% to 6.0%). Prevalence of active-TB and severe post-TB lung changes was 3.6% (95% CI 2.6% to 4.8%) and 1.4% (95% CI 0.8% to 2.3%), respectively. INTERPRETATION: Based on radiological findings, we identified a wide variety of non-TB abnormalities during population-based TB screening. TB prevalence surveys and active case finding activities using mass CXR offer an opportunity to integrate disease screening efforts. FUNDING: National Institute for Health Research (IMPALA-grant reference 16/136/35).

Removal of p16 INK4 Expressing Cells in Late Life has Moderate Beneficial Effects on Skeletal Muscle Function in Male Mice.

Aging results in the progressive accumulation of senescent cells in tissues that display loss of proliferative capacity and acquire a senescence-associated secretory phenotype (SASP). The tumor suppressor, p16 INK4A , which slows the progression of the cell cycle, is highly expressed in most senescent cells and the removal of p16-expressing cells has been shown to be beneficial to tissue health. Although much work has been done to assess the effects of cellular senescence on a variety of different organs, little is known about the effects on skeletal muscle and whether reducing cellular senescent load would provide a therapeutic benefit against age-related muscle functional decline. We hypothesized that whole-body ablation of p16-expressing cells in the advanced stages of life in mice would provide a therapeutic benefit to skeletal muscle structure and function. Treatment of transgenic p16-3MR mice with ganciclovir (GCV) from 20 to 26 months of age resulted in reduced p16 mRNA levels in muscle. At 26 months of age, the masses of tibialis anterior, extensor digitorum longus, gastrocnemius and quadriceps muscles were significantly larger in GCV-treated compared with vehicle-treated mice, but this effect was limited to male mice. Maximum isometric force for gastrocnemius muscles was also greater in GCV-treated male mice compared to controls. Further examination of muscles of GCV- and vehicle-treated mice showed fewer CD68-positive macrophages present in the tissue following GCV treatment. Plasma cytokine levels were also measured with only one, granulocyte colony stimulating factor (G-CSF), out of 22 chemokines analyzed was reduced in GCV-treated mice. These findings show that genetic ablation of p16+ senescent cells provides moderate and sex specific therapeutic benefits to muscle mass and function.

Provider-initiated HIV testing and TB screening in the era of universal coverage: Are the right people being reached? A cohort study in Blantyre, Malawi.

INTRODUCTION: Patients with tuberculosis (TB) symptoms have high prevalence of HIV, and should be prioritised for HIV testing. METHODS: In a prospective cohort study in Bangwe primary care clinic, Blantyre, Malawi, all adults (18 years or older) presenting with an acute illness were screened for TB symptoms (cough, fever, night sweats, weight loss). Demographic characteristics were linked to exit interview by fingerprint bioidentification. Multivariable logistic regression models were constructed to estimate the proportion completing same-visit HIV testing, comparing between those with and without TB symptoms. RESULTS: There were 5427 adult attendees between 21/5/2018 and 6/9/2018. Exit interviews were performed for 2402 (44%). 276 patients were excluded from the analysis, being already on antiretroviral therapy (ART). Presentation with any TB symptom was common for men (54.6%) and women (57.4%). Overall 27.6% (585/ 2121) attenders reported being offered testing and 21.5% (455/2121) completed provider-initiated HIV testing and counselling (PITC) and received results. The proportions offered testing were similar among participants with and without TB symptoms (any TB symptom: 29.0% vs. 25.7%). This was consistent for each individual symptom; cough, weight loss, fever and night sweats. Multivariable regression models indicated men, younger adults and participants who had previously tested were more likely to complete PITC than women, older adults and those who had never previously tested. CONCLUSIONS: Same-visit completion of HIV testing was suboptimal, especially among groups known to have high prevalence of undiagnosed HIV. As countries approach universal coverage of ART, identifying and prioritising currently underserved groups for HIV testing will be essential.

Resolvin D1 supports skeletal myofiber regeneration via actions on myeloid and muscle stem cells.

Specialized proresolving mediators (SPMs) actively limit inflammation and expedite its resolution by modulating leukocyte recruitment and function. Here we profiled intramuscular lipid mediators via liquid chromatography-tandem mass spectrometry-based metabolipidomics following myofiber injury and investigated the potential role of SPMs in skeletal muscle inflammation and repair. Both proinflammatory eicosanoids and SPMs increased following myofiber damage induced by either intramuscular injection of barium chloride or synergist ablation-induced functional muscle overload. Daily systemic administration of the SPM resolvin D1 (RvD1) as an immunoresolvent limited the degree and duration of inflammation, enhanced regenerating myofiber growth, and improved recovery of muscle strength. RvD1 suppressed inflammatory cytokine expression, enhanced polymorphonuclear cell clearance, modulated the local muscle stem cell response, and polarized intramuscular macrophages to a more proregenerative subset. RvD1 had minimal direct impact on in vitro myogenesis but directly suppressed myokine production and stimulated macrophage phagocytosis, showing that SPMs can modulate both infiltrating myeloid and resident muscle cell populations. These data reveal the efficacy of immunoresolvents as a novel alternative to classical antiinflammatory interventions in the management of muscle injuries to modulate inflammation while stimulating tissue repair.

Use and awareness of and willingness to self-test for HIV: an analysis of cross-sectional population-based surveys in Malawi and Zimbabwe.

BACKGROUND: Many southern African countries are nearing the global goal of diagnosing 90% of people with HIV by 2020. In 2016, 84 and 86% of people with HIV knew their status in Malawi and Zimbabwe, respectively. However, gaps remain, particularly among men. We investigated awareness and use of, and willingness to self-test for HIV and explored sociodemographic associations before large-scale implementation. METHODS: We pooled responses from two of the first cross-sectional Demographic and Health Surveys to include HIV self-testing (HIVST) questions in Malawi and Zimbabwe in 2015-16. We investigated sociodemographic factors and sexual risk behaviours associated with previously testing for HIV, and past use, awareness of, and future willingness to self-test using univariable and multivariable logistic regression, adjusting for the sample design and limiting analysis to participants with a completed questionnaire and valid HIV test result. We restricted analysis of willingness to self-test to Zimbabwean men, as women and Malawians were not systematically asked this question. RESULTS: Of 31,385 individuals, 31.2% of men had never tested compared with 16.5% of women (p < 0.001). For men, the likelihood of having ever tested increased with age. Past use and awareness of HIVST was very low, 1.2 and 12.6%, respectively. Awareness was lower among women than men (9.1% vs 15.3%, adjusted odds ratio [aOR] = 1.55; 95% confidence interval [CI]: 1.37-1.75), and at younger ages, and lower education and literacy levels. Willingness to self-test among Zimbabwean men was high (84.5%), with greater willingness associated with having previously tested for HIV, being at high sexual risk (highest willingness [aOR = 3.74; 95%CI: 1.39-10.03, p < 0.009]), and being ≥25 years old. Wealthier men had greater awareness of HIVST than poorer men (p < 0.001). The highest willingness to self-test (aOR = 3.74; 95%CI: 1.39-10.03, p < 0.009) was among men at high HIV-related sexual risk. CONCLUSIONS: In 2015-16, many Malawian and Zimbabwean men had never tested for HIV. Despite low awareness and minimal HIVST experience, willingness to self-test was high among Zimbabwean men, especially older men with moderate-to-high HIV-related sexual risk. These data provide a valuable baseline against which to investigate population-level uptake of HIVST as programmes scale up. Programmes introducing, or planning to introduce, HIVST should consider including relevant questions in population-based surveys.

Study protocol for a single-centre observational study of household wellbeing and poverty status following a diagnosis of advanced cancer in Blantyre, Malawi - 'Safeguarding the Family' study.

Background: Many households in low-and-middle income countries face the additional burden of crippling out-of-pocket expenditure when faced with a diagnosis of life-limiting illness. Available evidence suggests that receipt of palliative care supports cost-savings for cancer-affected households. This study will explore the relationship between receipt of palliative care, total household out-of-pocket expenditure on health and wellbeing following a first-time diagnosis of advanced cancer at Queen Elizabeth Central Hospital in Blantyre, Malawi. Protocol: Patients and their primary family caregivers will be recruited at the time of cancer diagnosis.  Data on healthcare utilisation, related costs, coping strategies and wellbeing will be gathered using new and existing questionnaires (the Patient-and-Carer Cancer Cost Survey, EQ-5D-3L and the Integrated Palliative Care Outcome Score). Surveys will be repeated at one, three and six months after diagnosis. In the event of the patient's death, a brief five-item questionnaire on funeral costs will be administered to caregivers not less than two weeks following the date of death. Descriptive and Poisson regression analyses will assess the relationship between exposure to palliative care and total household expenditure from baseline to six months. A sample size of 138 households has been calculated in order to detect a medium effect (as determined by Cohen's f 2=0.15) of receipt of palliative care in a regression model for change in total household out-of-pocket expenditure as a proportion of annual household income. Ethics and dissemination: The study has received ethical approval. Results will be reported using STROBE guidelines and disseminated through scientific meetings, open access publications and a national stakeholder meeting.  Conclusions: This study will provide data on expenditure for healthcare by households affected by advanced cancer in Malawi. We also explore whether receipt of palliative care is associated with a reduction in out-of-pocket expenditure at household level.

Patient outcomes associated with post-tuberculosis lung damage in Malawi: a prospective cohort study.

BACKGROUND: Post-tuberculosis lung damage (PTLD) is a recognised consequence of pulmonary TB (pTB). However, little is known about its prevalence, patterns and associated outcomes, especially in sub-Saharan Africa and HIV-positive adults. METHODS: Adult (≥15 years) survivors of a first episode of pTB in Blantyre, Malawi, completed the St George's Respiratory Questionnaire, 6-minute walk test, spirometry and high-resolution CT (HRCT) chest imaging at TB treatment completion. Symptom, spirometry, health seeking, TB-retreatment and mortality data were collected prospectively to 1 year. Risk factors for persistent symptoms, pulmonary function decline and respiratory-related health-seeking were identified through multivariable regression modelling. RESULTS: Between February 2016 and April 2017, 405 participants were recruited. Median age was 35 years (IQR: 28 to 41), 77.3% (313/405) had had microbiologically proven pTB, and 60.3% (244/403) were HIV-positive. At pTB treatment completion, 60.7% (246/405) reported respiratory symptoms, 34.2% (125/365) had abnormal spirometry, 44.2% (170/385) had bronchiectasis ≥1 lobe and 9.4% (36/385) had ≥1 destroyed lobe on HRCT imaging. At 1 year, 30.7% (113/368) reported respiratory symptoms, 19.3% (59/305) and 14.1% (43/305) of patients had experienced declines in FEV1 or FVC of ≥100 mL, 16.3% (62/380) had reported ≥1 acute respiratory event and 12.2% (45/368) had symptoms affecting their ability to work. CONCLUSIONS: PTLD is a common and under-recognised consequence of pTB that is disabling for patients and associated with adverse outcomes beyond pTB treatment completion. Increased efforts to prevent PTLD and guidelines for management of established disease are urgently needed. Low-cost clinical interventions to improve patient outcomes must be evaluated.

Re-reading of OraQuick HIV-1/2 rapid antibody test results: quality assurance implications for HIV self-testing programmes.

INTRODUCTION: Scale-up of HIV self-testing (HIVST) will play a key role in meeting the United Nation's 90-90-90 targets. Delayed re-reading of used HIVST devices has been used by early implementation studies to validate the performance of self-test kits and to estimate HIV positivity among self-testers. We investigated the stability of results on used devices under controlled conditions to assess its potential as a quality assurance approach for HIVST scale-up. METHODS: 444 OraQuick® HIV-1/2 rapid antibody tests were conducted using commercial plasma from two HIV-positive donors and HIV-negative plasma (high-reactive n = 148, weak-reactive n = 148 and non-reactive n = 148) and incubated them for six months under four conditions (combinations of high and low temperatures and humidity). Devices were re-read daily for one week, weekly for one subsequent month and then once a month by independent readers unaware of the previous results. We used multistage transition models to investigate rates of change in device results, and between storage conditions. RESULTS AND DISCUSSION: There was a high incidence of device instability. Forty-three (29%) of 148 initially non-reactive results became false weak-reactive results. These changes were observed across all incubation conditions, the earliest on Day 4 (n = 9 kits). No initially HIV-reactive results changed to a non-reactive result. There were no significant associations between storage conditions and hazard of results transition. We observed substantial statistical agreement between independent re-readers over time (agreement range: 0.74 to 0.96). CONCLUSIONS: Delayed re-reading of used OraQuick® HIV-1/2 rapid antibody tests is not currently a valid methodological approach to quality assurance and monitoring as we observed a high incidence (29%) of true non-reactive tests changing to false weak-reactive and therefore its use may overestimate true HIV positivity.

Cost-Effectiveness of Community-based Human Immunodeficiency Virus Self-Testing in Blantyre, Malawi.

Background: Human immunodeficiency virus self-testing (HIVST) is effective, with scale-up underway in sub-Saharan Africa. We assessed cost-effectiveness of adding HIVST to existing facility-based HIV testing and counseling (HTC) services. Both 2010 (initiate at CD4 <350 cells/µL) and 2015 (initiate all) World Health Organization (WHO) guidelines for antiretroviral treatment (ART) were considered. Methods: A microsimulation model was developed to evaluate cost-effectiveness, from both health provider and societal perspectives, of an HIVST service implemented in a cluster-randomized trial (CRT; ISRCTN02004005) in Malawi. Costs and health outcomes were evaluated over a 20-year time horizon, using a discount rate of 3%. Probabilistic sensitivity analysis was conducted to account for parameter uncertainty. Results: From the health provider perspective and 20-year time horizon, facility HTC using 2010 WHO ART guidelines was the least costly ($294.71 per person; 95% credible interval [CrI], 270.79-318.45) and least effective (11.64 quality-adjusted life-years [QALYs] per person; 95% CrI, 11.43-11.86) strategy. Compared with this strategy, the incremental cost-effectiveness ratio (ICER) for facility HTC using 2015 WHO ART guidelines was $226.85 (95% CrI, 198.79-284.35) per QALY gained. The strategy of facility HTC plus HIVST, using 2010 WHO ART guidelines, was extendedly dominated. The ICER for facility HTC plus HIVST, using 2015 WHO ART guidelines, was $253.90 (95% CrI, 201.71-342.02) per QALY gained compared with facility HTC and using 2015 WHO ART guidelines. Conclusions: HIVST may be cost-effective in a Malawian population with high HIV prevalence. HIVST is suited to an early HIV diagnosis and treatment strategy. Clinical Trials registration: ISRCTN02004005.

Oxidative stress induced by UVA photoactivation of the tryptophan UVB photoproduct 6-formylindolo[3,2-b]carbazole (FICZ) inhibits nucleotide excision repair in human cells.

Potentially mutagenic DNA lesions induced by UVB (wavelengths 280-320 nm) are important risk factors for solar ultraviolet (UV) radiation-induced skin cancer. The carcinogenicity of the more abundant UVA (320-400 nm) is less well understood but is generally regarded to reflect its interaction with cellular chromophores that act as photosensitisers. The arylhydrocarbon receptor agonist 6-formylindolo[3,2-b] carbazole (FICZ), is a UVB photoproduct of tryptophan and a powerful UVA chromophore. Combined with UVA, FICZ generates reactive oxygen species (ROS) and induces oxidative DNA damage. Here we demonstrate that ROS generated by FICZ/UVA combinations also cause extensive protein damage in HaCaT human keratinocytes. We show that FICZ/UVA-induced oxidation significantly inhibits the removal of potentially mutagenic UVB-induced DNA photolesions by nucleotide excision repair (NER). DNA repair inhibition is due to FICZ/UVA-induced oxidation damage to the NER proteome and DNA excision repair is impaired in extracts prepared from FICZ/UVA-treated cells. NER protects against skin cancer. As a likely UVB photoproduct of intracellular tryptophan, FICZ represents a de facto endogenous UVA photosensitiser in sun-exposed skin. FICZ formation may increase the risk of solar UV-induced skin cancer by promoting photochemical damage to the NER proteome and thereby preventing the removal of UVB-induced DNA lesions.