Hendramoorthy Maheswaran

Aim: The aim of this analysis was to assess the cost–effectiveness of the EmboTrap ^® Revascularization Device compared with the Solitaire™ Revascularization Device and Trevo ^® Retriever for the treatment of acute ischemic stroke (AIS) from the perspective of the Chinese healthcare system. Methods: According to MASTRO I, a recent living systematic literature review and meta-analysis, mechanical thrombectomy (MT) with EmboTrap in the treatment of AIS resulted in better functional outcomes compared with the use of Solitaire or Trevo. Based on the proportion of patients that achieved 90-day modified Rankin Scale (mRS) scores of 0–2, 3–5 and 6 reported in MASTRO I, a combined 90-day short-term decision tree and Markov model with a 10-year time horizon was used to compare the cost–effectiveness of the three devices. The primary outcome was the incremental cost–effectiveness ratio (ICER), representing the incremental cost (in 2022 Chinese Yuan [CNY]) per incremental quality-adjusted life-year (QALY). The ICERs were compared against willingness-to-pay (WTP) thresholds of 1, 1.5 and 3-times the 2022 national gross domestic product (GDP) per capita in China. Results: Treatment with EmboTrap resulted in total QALYs of 3.28 and total costs of 110,058 CNY per patient. Treatment with Trevo resulted in total QALYs of 3.05 and total costs of 116,941 CNY per patient. Treatment with Solitaire resulted in total QALYs of 2.81 and total costs of 99,090 CNY per patient. Trevo was dominated by EmboTrap as it was a more costly and less effective intervention. As such, Trevo was not cost-effective at any WTP threshold. Compared with Solitaire, EmboTrap was more effective and more costly, with an ICER of 23,615 CNY per QALY. This result suggests that EmboTrap is cost-effective when compared with Solitaire since the ICER was lower than all WTP thresholds assessed. Conclusion: EmboTrap dominated Trevo and is cost-effective for the treatment of patients with AIS compared with Solitaire when assessed from the perspective of the Chinese healthcare system and based on the device-level meta-analysis MASTRO I. Selecting a stent retriever (SR) that optimizes 90-day mRS score is an important consideration from both a clinical and healthcare payer perspective in China as it is associated with reduced long-term costs and increased quality of life.

Background: Suboptimal tuberculosis (TB) diagnostics and HIV contribute to the high global burden of TB. We investigated costs and yield from systematic HIV-TB screening, including computer-aided digital chest X-ray (DCXR-CAD). Methods and findings: In this open, three-arm randomised trial, adults (≥18 years) with cough attending acute primary services in Malawi were randomised (1:1:1) to standard of care (SOC); oral HIV testing (HIV screening) and linkage to care; or HIV testing and linkage to care plus DCXR-CAD with sputum Xpert for high CAD4TBv5 scores (HIV-TB screening). Participants and study staff were not blinded to intervention allocation, but investigator blinding was maintained until final analysis. The primary outcome was time to TB treatment. Secondary outcomes included proportion with same-day TB treatment; prevalence of undiagnosed/untreated bacteriologically confirmed TB on day 56; and undiagnosed/untreated HIV. Analysis was done on an intention-to-treat basis. Cost-effectiveness analysis used a health-provider perspective. Between 15 November 2018 and 27 November 2019, 8,236 were screened for eligibility, with 473, 492, and 497 randomly allocated to SOC, HIV, and HIV-TB screening arms; 53 (11%), 52 (9%), and 47 (9%) were lost to follow-up, respectively. At 56 days, TB treatment had been started in 5 (1.1%) SOC, 8 (1.6%) HIV screening, and 15 (3.0%) HIV-TB screening participants. Median (IQR) time to TB treatment was 11 (6.5 to 38), 6 (1 to 22), and 1 (0 to 3) days (hazard ratio for HIV-TB versus SOC: 2.86, 1.04 to 7.87), with same-day treatment of 0/5 (0%) SOC, 1/8 (12.5%) HIV, and 6/15 (40.0%) HIV-TB screening arm TB patients (p = 0.03). At day 56, 2 SOC (0.5%), 4 HIV (1.0%), and 2 HIV-TB (0.5%) participants had undiagnosed microbiologically confirmed TB. HIV screening reduced the proportion with undiagnosed or untreated HIV from 10 (2.7%) in the SOC arm to 2 (0.5%) in the HIV screening arm (risk ratio [RR]: 0.18, 0.04 to 0.83), and 1 (0.2%) in the HIV-TB screening arm (RR: 0.09, 0.01 to 0.71). Incremental costs were US$3.58 and US$19.92 per participant screened for HIV and HIV-TB; the probability of cost-effectiveness at a US$1,200/quality-adjusted life year (QALY) threshold was 83.9% and 0%. Main limitations were the lower than anticipated prevalence of TB and short participant follow-up period; cost and quality of life benefits of this screening approach may accrue over a longer time horizon. Conclusions: DCXR-CAD with universal HIV screening significantly increased the timeliness and completeness of HIV and TB diagnosis. If implemented at scale, this has potential to rapidly and efficiently improve TB and HIV diagnosis and treatment. Trial registration: clinicaltrials.gov NCT03519425.

Objective: To examine the general public’s views around willingness to receive COVID-19 vaccines and concerns regarding their safety. Design: Repeat cross-sectional surveys. Setting: Online surveys in Australia, Canada, Denmark, Finland, France, Germany, Italy, Japan, Netherlands, Norway, Singapore, South Korea, Spain, Sweden and the United Kingdom Participants: National samples of adults aged >=18 years in November 2020 and January 2021. Main outcomes measures: The proportion of adults reporting: willingness to receive a COVID-19 vaccination; concern regarding side-effects from vaccinations; concerns over contraction COVID-19, and beliefs around vaccine provision in their country. Changes between the November and January surveys are also reported. Results: Across the 15 countries, the proportion of respondents reporting they would have the COVID-19 vaccine increased from 40.7% (range: 25.0-55.1) to 55.2% (range: 34.8-77.5), proportion reporting worried about the side-effects of vaccine decreased from 53.3% (range: 42.1-66.7) to 47.9% (range: 28.0-66.1). On the second survey, willingness to receive vaccine remained low in females (49.4%, range: 30.2-79.1), aged 18-39 years (42.1%, range: 25.9-71.7), those not working or unemployed (48.9, range: 18.8-67.0), students (45.9%, range: 22.8-70.0), and those with children at home (46.5%, range: 32.4-68.9). Concerns regarding safety of vaccine remained high in females (53.7%, range: 31.8-70.4), aged 18-39 years (50.8%, range: 28.2-60.7), aged 40-64 years (51.3%, range: 30.7-68.5), those working (50.5%, range: 26.7-65.0), those not working or unemployed (53.3, range: 35.4-73.8) and those with children at home (55.8%, range: 36.5-64.7). Conclusion: COVID-19 vaccine hesitancy decreased considerably over a relatively short time coinciding with the discovery of effective vaccines. The public remain concerned about their safety, and public health messaging will need to emphasis their safety especially amongst females, parents and younger adults.

Background: The relationship between ambient temperature and mental health outcomes has not been sufficiently synthesised and communicated. Methods: A systematic search included all original studies on humans until 20/03/2020 examining a relationship between ambient temperatures and mental health outcomes (suicide, hospital attendance for mental disorders, community mental health and emotional wellbeing). Databases WebOfScience, Embase, PsychINFO, and PubMed were searched, alongside a limited search of Google Scholar. The risk of bias for individual studies was assessed using the Newcastle-Ottawa Scale (NOS), while the quality of evidence across studies was assessed using the GRADE approach. Findings: 123 studies were included in the review, with 19 studies suitable for meta-analysis. Pooled data on suicide rates (7 articles, N=1,805,734) indicate a risk ratio of 1.01 per 1ºC increase in mean temperature (95%CI: 1.00, 1.01), a 1.7% increase (95%CI: 1.1%, 2.3%) in suicide incidence per 1ºC temperature rise (5 articles, N=219,096), and a 6.2% (95%CI: 5.2%, 7.2%) increase for each 2-5ºC temperature rise (3 articles, N=416,976). Hospital attendance for mental disorders was 9.7% higher (95%CI: 7.6%, 11.9%) during heatwaves than non-heatwave periods (3 articles, N=362,086), with a risk ratio of 1.02 (95%CI: 1.01, 1.03) at the 99th temperature percentile compared with the 50^th (3 articles, N=532,296). In qualitative synthesis of the literature, higher ambient temperature (including average temperatures, heatwaves and temperature variation) across multiple time windows were positively associated with increases in attempted and completed suicides (78 studies in this category, >3,976,577 suicide events), increased hospital attendance for mental disorders (33 studies, >6,222,993 hospital attendances), and worse outcomes for community mental health and wellbeing (15 studies, >4,875,006 individuals). Interpretation: Climate change brings increasing ambient temperatures, heatwaves and temperature variation, which are all risk factors for worse mental health outcomes. Health system leaders and policy makers must be adequately prepared. Building resilience to the impacts of increasing temperatures on mental health outcomes in public health and health systems will require equitable and proactive support for those most vulnerable, including individuals with a diagnosable mental disorder, rural populations and those in 'urban heat islands'. Although many LMIC are particularly vulnerable to climate change, only 25 studies were conducted in these regions. More good quality standardised research is required to improve our understanding of the nature, severity, context and modulating factors of these effects. Funding Statement: RT receives a studentship from the National Institute for Health Research (NIHR) School for Public Health Research (PD-SPH-2015). MBT is partially supported by a donation from Marit Mohn to the Mohn Centre for Children’s Health and Wellbeing. No other external funding contributed to the study or researcher's time. Declaration of Interests: None to declare.

Objectives: SARS-CoV-2 has challenged health service provision worldwide. This work evaluates safe surgical pathways and standard operating procedures implemented in the high volume, global city of London during the first wave of SARS-CoV-2 infection. We also assess the safety of minimally invasive surgery(MIS) for anatomical lung resection. Methods: This multicentre cohort study was conducted across all London thoracic surgical units, covering a catchment area of approximately 14.8 Million. A Pan-London Collaborative was created for data sharing and dissemination of protocols. All patients undergoing anatomical lung resection 1st March-1st June 2020 were included. Primary outcomes were SARS-CoV-2 infection, access to minimally invasive surgery, post-operative complication, length of intensive care and hospital stay (LOS), and death during follow up. Results: 352 patients underwent anatomical lung resection with an median age of 69 (IQR: 35-86) years. Self-isolation and pre-operative screening were implemented following the UK national lockdown. Pre-operative SARS-CoV-2 swabs were performed in 63.1% and CT imaging in 54.8%. 61.7% of cases were performed minimally invasively. Median LOS was 6 days. Significant complications developed in 7.3% of patients (Clavien-Dindo Grade 3-4). There were 6 deaths(1.7%) and 12 re-admissions(3.4%). Seven patients(2.0%) were diagnosed with SARS-CoV-2 infection, two of whom died (28.5%). Conclusions: Major elective surgery can be safely undertaken via open and MIS approaches at the peak of a viral pandemic if precautionary measures are implemented. High volume surgery should continue during further viral peaks to minimise health service burden and potential harm to cancer patients. Funding Statement: Nil. Declaration of Interests: None of the authors have conflict of interests to declare. Ethics Approval Statement: Institutional approval was obtained from all Trusts contributing to the collaborative. Approval was granted by each hospital trust for data sharing, collaborative work and retrospective review. Formal individual informed consent was not required due to the retrospective nature of the study.

Background Tuberculosis (TB) control relies on early diagnosis and treatment. International guidelines recommend systematic TB screening at health facilities in high-burden settings, but implementation is challenging. To construct a TB diagnosis care cascade, we investigated screening guideline adherence and completion of TB testing steps in Blantyre, Malawi. Methods A prospective cohort recruited adult (≥18) outpatients attending Bangwe acute-care primary clinic between 21/5/2018 and 6/9/2018. Entry interviews recording TB symptoms and demographic characteristics were linked to exit interviews by biometrics. Care cascades were constructed to estimate the proportion of patients progressing through each step of the diagnostic pathway. Multivariable logistic regression was used to investigate factors associated with being asked to submit sputum. Results Of 5,442 clinic attendances 2,397 (44%) had exit interviews. In clinically indicated participants (n=330) 203 (61.5%) were asked about cough, 39 (11.8%) were asked for sputum, 27 (8.2%) gave sputum and 1 (0.3%) 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 survey (20/day) outnumbered diagnostic capacity (8-12/day). Conclusion Patients were lost at every stage of the TB care cascade, with same day sputum submission achieved in only 8.2% if clinically indicated. Infection control strategies should be implemented, with reporting on early steps of the TB care cascade formalised. High-throughput interventions, such as digital CXR, that can optimise same-day TB screening are urgently needed to meet WHO End TB goals. What is already known? WHO guidelines recommend systematic screening for Tuberculosis at health facilities in high-burden settings, but implementation is challenging. Care cascades have been widely used by HIV programmes to evaluate care delivery but have only recently been applied to TB care. Care cascades help to define the steps of the cascade most in need of intervention What are the new findings? In this study, only 8.2% of those clinically indicated to test for TB (as per national guidelines in Malawi) did so, with patients lost at every step of the diagnosis care cascade. Failure to request sputum by clinicians despite elicited symptoms led to the biggest single gap in the diagnosis care cascade, followed by not asking about symptoms. If all patients attending the clinic were screened for TB as per the guidelines, the current testing facilities would only be able to process up to two thirds of the required samples. What do the new findings imply? Interventions focusing on health worker behaviour may have the greatest potential for retaining presumptive TB patients within the diagnosis cascade We must formalise and strengthen reporting on the early steps in the TB care cascade: a requirement to report numbers of screened presumptive TB cases would allow greater focus on these critical steps. If identification of presumptive TB patients is subsequently improved a novel high-throughput approach to triage testing using new diagnostics will be required for LMICs to increase capacity.

Introduction: Antimicrobial resistance (AMR) is a global public health concern, but the problems are context specific, with each county or setting facing differing challenges. In sub-Saharan Africa, third-generation cephalosporin resistant Enterobacterales (3GCR-E) are of particular concern, given the widespread reliance on ceftriaxone for treatment of severe infection in this setting. In Malawi, despite rising prevalence of 3GCR-E, the health-impact of these infections has not been described. This study is designed to estimate attributable mortality, morbidity and economic cost of 3GCR-E bloodstream infection (BSI) in a large, urban hospital. Methods: This study will investigate the burden of AMR by recruiting a a prospective longitudinal cohort of patients who have bloodstream infection with 3GCR-E, at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients whose blood culture is positive for either third-generation cephalosporin susceptible (3GC-S) or third-generation resistant (3GC-R) Enterobacterales will be enrolled and provide clinical and healthcare economic data. Patients will be followed throughout their hospital stay and to 6-months post discharge. The primary outcomes for the study are mortality and morbidity from 3GCR-E. Healthcare economic outcomes will be assessed by comparing healthcare provider costs, indirect patient costs and health-related quality of life outcomes in patients with 3GC-S and 3GC-R BSI. Based on our observation that some patients with clinical suspicion of sepsis and 3GC-R BSI are surviving without an effective antibiotic, we review each patient prospectively and classify what role the isolated bacteria is playing in the patient’s clinical presentation. Each BSI episode will be classified into the following categories: definite Gram-negative sepsis, probable Gram-negative sepsis, transient or occult bacteraemia, or contaminated blood culture. These classifications will be incorporated into our analysis. Ethics and dissemination: The study protocol has been approved by the Malawi College of Medicine Research Ethics Committee and by the Liverpool School of Tropical Medicine Research Ethics committee.

Introduction: Antimicrobial resistance is a global public health concern, but the problems are context specific, with each county or setting facing differing challenges. In Africa, third-generation cephalosporin resistant Enterobacterales (3GCR-E) are of particular concern, given the widespread reliance on ceftriaxone for treatment of severe infection in this setting. In Malawi, despite the rising prevalence of 3GCR-E, the health impact of these infections has not been described. This study is designed to estimate attributable mortality, morbidity and economic cost of 3GC-R bloodstream infection (BSI) in a large, urban hospital. Methods: This study will investigate the burden of antimicrobial resistance by recruiting a a prospective longitudinal cohort of patients who have bloodstream infection with 3GCR-E, at Queen Elizabeth Central Hospital, Blantyre, Malawi. Patients whose blood culture is positive for either 3GC-S or 3GC-R Enterobacterales will be enrolled and provide clinical and healthcare economic data. Patients will be followed throughout their hospital stay and to 6-months post discharge. Mortality, direct and indirect costs and other health outcomes will be compared between patients with 3GC-R and comparable 3GC-sensitive BSI. Based on our observation that some patients with clinical suspicion of sepsis and 3GC-R BSI are surviving without an effective antibiotic, we review each patient prospectively and classify what role the isolated bacteria is playing in the patient’s clinical presentation. These classifications will then be incorporated into our analysis. Ethics and dissemination: The study protocol has been approved by the Malawi College of Medicine Research Ethics Committee and by the Liverpool School of Tropical Medicine Research Ethics committee. Written informed consent will be obtained from study participants or their parents/guardians. Results will be submitted to international peer-reviewed journals, presented at international conferences and shared with participating communities and collaborators.

Conventional HIV testing services have been less comprehensive in reaching men than in reaching women globally, but HIV self-testing (HIVST) appears to be an acceptable alternative. Measurement of linkage to post-test services following HIVST remains the biggest challenge, yet is the biggest driver of cost-effectiveness. We investigated the impact of HIVST alone or with additional interventions on the uptake of testing and linkage to care or prevention among male partners of antenatal care clinic attendees in a novel adaptive trial. An adaptive multi-arm, 2-stage cluster randomised trial was conducted between 8 August 2016 and 30 June 2017, with antenatal care clinic (ANC) days (i.e., clusters of women attending on a single day) as the unit of randomisation. Recruitment was from Ndirande, Bangwe, and Zingwangwa primary health clinics in urban Blantyre, Malawi. Women attending an ANC for the first time for their current pregnancy (regardless of trimester), 18 years and older, with a primary male partner not known to be on ART were enrolled in the trial after giving consent. Randomisation was to either the standard of care (SOC; with a clinic invitation letter to the male partner) or 1 of 5 intervention arms: the first arm provided women with 2 HIVST kits for their partners; the second and third arms provided 2 HIVST kits along with a conditional fixed financial incentive of $3 or $10; the fourth arm provided 2 HIVST kits and a 10% chance of receiving $30 in a lottery; and the fifth arm provided 2 HIVST kits and a phone call reminder for the women’s partners. The primary outcome was the proportion of male partners who were reported to have tested for HIV and linked into care or prevention within 28 days, with referral for antiretroviral therapy (ART) or circumcision accordingly. Women were interviewed at 28 days about partner testing and adverse events. Cluster-level summaries compared each intervention versus SOC using eligible women as the denominator (intention-to-treat). Risk ratios were adjusted for male partner testing history and recruitment clinic. A total of 2,349/3,137 (74.9%) women participated (71 ANC days), with a mean age of 24.8 years (SD: 5.4). The majority (2,201/2,233; 98.6%) of women were married, 254/2,107 (12.3%) were unable to read and write, and 1,505/2,247 (67.0%) were not employed. The mean age for male partners was 29.6 years (SD: 7.5), only 88/2,200 (4.0%) were unemployed, and 966/2,210 (43.7%) had never tested for HIV before. Women in the SOC arm reported that 17.4% (71/408) of their partners tested for HIV, whereas a much higher proportion of partners were reported to have tested for HIV in all intervention arms (87.0%–95.4%, p < 0.001 in all 5 intervention arms). As compared with those who tested in the SOC arm (geometric mean 13.0%), higher proportions of partners met the primary endpoint in the HIVST + $3 (geometric mean 40.9%, adjusted risk ratio [aRR] 3.01 [95% CI 1.63–5.57], p < 0.001), HIVST + $10 (51.7%, aRR 3.72 [95% CI 1.85–7.48], p < 0.001), and phone reminder (22.3%, aRR 1.58 [95% CI 1.07–2.33], p = 0.021) arms. In contrast, there was no significant increase in partners meeting the primary endpoint in the HIVST alone (geometric mean 17.5%, aRR 1.45 [95% CI 0.99–2.13], p = 0.130) or lottery (18.6%, aRR 1.43 [95% CI 0.96–2.13], p = 0.211) arms. The lottery arm was dropped at interim analysis. Overall, 46 male partners were confirmed to be HIV positive, 42 (91.3%) of whom initiated ART within 28 days; 222 tested HIV negative and were not already circumcised, of whom 135 (60.8%) were circumcised as part of the trial. No serious adverse events were reported. Costs per male partner who attended the clinic with a confirmed HIV test result were $23.73 and $28.08 for the HIVST + $3 and HIVST + $10 arms, respectively. Notable limitations of the trial included the relatively small number of clusters randomised to each arm, proxy reporting of the male partner testing outcome, and being unable to evaluate retention in care. In this study, the odds of men’s linkage to care or prevention increased substantially using conditional fixed financial incentives plus partner-delivered HIVST; combinations were potentially affordable. ISRCTN 18421340.

Background: Adults seeking diagnosis and treatment for tuberculosis (TB) and HIV in low-resource settings face considerable barriers and have high pre-treatment mortality. Efforts to improve access to prompt TB treatment have been hampered by limitations in TB diagnostics, with considerable uncertainty about how available and new tests can best be implemented. Design and methods: The PROSPECT Study is an open, three-arm pragmatic randomised study that will investigate the effectiveness and cost-effectiveness of optimised HIV and TB diagnosis and linkage to care interventions in reducing time to TB diagnosis and prevalence of undiagnosed TB and HIV in primary care in Blantyre, Malawi. Participants (≥ 18 years) attending a primary care clinic with TB symptoms (cough of any duration) will be randomly allocated to one of three groups: (i) standard of care; (ii) optimised HIV diagnosis and linkage; or (iii) optimised HIV and TB diagnosis and linkage. We will test two hypotheses: firstly, whether prompt linkage to HIV care should be prioritised for adults with TB symptoms; and secondly, whether an optimised TB triage testing algorithm comprised of digital chest x-ray evaluated by computer-aided diagnosis software and sputum GeneXpert MTB/Rif can outperform clinician-directed TB screening. The primary trial outcome will be time to TB treatment initiation by day 56, and secondary outcomes will include prevalence of undiagnosed TB and HIV, mortality, quality of life, and cost-effectiveness. Conclusions: The PROSPECT Study will provide urgently-needed evidence under “real-life” conditions to inform clinicians and policy makers on how best to improve TB/HIV diagnosis and treatment in Africa. Clinical trial registration: NCT03519425 (08/05/2018)