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Summary Background Mass drug administration of azithromycin to children in sub-Saharan Africa has been shown to improve survival in high-mortality settings. The period after hospital discharge is a time of elevated risk unaddressed by current interventions and might provide an opportunity for targeting empirical azithromycin administration. We aimed to assess the efficacy of azithromycin administered at hospital discharge on risk of death and rehospitalisation in Kenyan children younger than 5 years. Methods In this double-blind, placebo-controlled randomised trial, children were randomly assigned (1:1) to receive a 5-day course of azithromycin (oral suspension 10 mg/kg on day 1, followed by 5mg/kg per day on days 2–5) or identically appearing and tasting placebo at discharge from four hospitals in western Kenya. Children were eligible if they were aged 1–59 months at hospital discharge, weighed at least 2 kg, and had been admitted to hospital for any medical reason other than trauma, poisoning, or congenital anomaly. The primary outcome was death or rehospitalisation in the subsequent 6-month period in a modified intention-to-treat population, compared by randomisation group with Cox proportional hazards regression and Kaplan-Meier. Azithromycin resistance in Escherichia coli isolates from a random subset of children was compared by randomisation group with generalised estimating equations. This trial is registered with ClinicalTrials.gov , NCT02414399 . Findings Between June 28, 2016, and Nov 4, 2019, 1400 children were enrolled in the trial at discharge from hospital, with 703 (50·2%) randomly assigned to azithromycin and 697 (49·8%) to placebo. Among the 1398 children included in the modified intention-to-treat analysis (702 in the azithromycin group and 696 in the placebo group), the incidence of death or rehospitalisation was 20·4 per 100 child-years in the azithromycin group and 22·5 per 100 child-years in the placebo group (adjusted hazard ratio 0·91, 95·5% CI 0·64–1·29, p=0·58). Azithromycin resistance was common in commensal E coli isolates from enrolled children before randomisation (37·7% of 406 isolates) despite only 3·7% of children having received a macrolide antibiotic during the hospitalisation. Azithromycin resistance was slightly higher at 3 months after randomisation in the azithromycin group (26·9%) than in the placebo group (19·1%; adjusted prevalence ratio 1·41, 95% CI 0·95–2·09, p=0·088), with no difference observed at 6 months (1·17, 0·78–1·76, p=0·44). Interpretation We did not observe a significant benefit of a 5-day course of azithromycin delivered to children younger than 5 years at hospital discharge despite the overall high risk of mortality and rehospitalisation. These findings highlight the need for more research into mechanisms and interventions for prevention of morbidity and mortality in the post-discharge period. Funding Eunice Kennedy Shriver National Institute of Child Health & Human Development.

Objective The APHINITY trial assessed the effectiveness and the safety of adding pertuzumab to trastuzumab and chemotherapy (THP) compared to trastuzumab and chemotherapy (TH) in the adjuvant management of human epidermal growth factor 2-positive (HER2+) breast cancer. We performed a study to project the potential cost-effectiveness of THP vs. TH. Study Design Trial-based cost-utility modeling analysis. Methods We performed an economic evaluation from a payer perspective using a Markov model with six health states: invasive disease-free survival, non-metastatic recurrence, remission, first-line metastatic, subsequent line metastatic, and death. We parameterized the model using data from both arms in APHINITY extrapolated to a patient’s lifetime horizon. Estimates of health state utilities were based on EQ-5D trial data and the literature, and costs were estimated from government sources and the published literature. The primary outcomes of the model were life-years (LYs), quality-adjusted LYs (QALYs), costs, and incremental cost-effectiveness ratios (ICERs). Uncertainty was addressed via univariate and probabilistic sensitivity analyses. Results For the intention-to-treat population, the model projected improved outcomes (by 0.50 LYs and 0.45 QALYs) and increased costs (by $74 420) for ICERs of $147 774/LY gained and $167 185/QALY gained for PHT vs. HT patients. In the node-positive patient population, the model projected improved outcomes (by 0.86 LYs and 0.76 QALYs) and increased costs (by $66 647) for ICERs of $77 684/LY gained and $87 929/QALY gained. For the hormone-receptor-negative patient population, the model projected health gains, increased costs, and ICERs of $147 022/LY gained and $166 518/QALY gained. The results were sensitive to changes in the model time horizon. Conclusion The addition of pertuzumab to the available regimens for HER2+ early breast cancer is likely to be cost-effective for patients in the U.S. at high risk of recurrence.

Background The prevalence of pre-treatment drug resistance (PDR) to non-nucleoside reverse-transcriptase inhibitor (NNRTI) agents is increasing in sub-Saharan Africa, which may decrease the effectiveness of efavirenz-based antiretroviral therapy (ART) programs. However, due to recent safety concerns, there has been hesitancy to replace efavirenz-based ART with dolutegravir in women of reproductive potential. Our objective was to evaluate whether PDR testing for women not initiating dolutegravir-based ART would be a cost-effective strategy to address the challenges posed by PDR. Methods We developed an HIV drug resistance model that simulates the emergence and transmission of resistance mutations, calibrated to the Kenyan epidemic. We modeled three care strategies for PDR testing among women not initiating dolutegravir-based ART: no PDR testing, PDR testing with a low-cost point mutation assay, known as oligonucleotide ligation assay (OLA), and PDR testing with consensus sequencing. Using a health sector perspective, this model was used to evaluate the health outcomes, lifetime costs, and cost-effectiveness under each strategy over a 15-year time horizon starting in 2019. Findings OLA and CS PDR testing were projected to have incremental cost-effectiveness ratios (ICER) of $10,741/QALY gained and $134,396/QALY gained, respectively, which are not cost-effective by national income standards. Viral suppression rates among women at 12 months after ART initiation were 87·8%, 89·0%, and 89·3% with no testing, OLA testing, and CS testing, respectively. PDR testing with OLA and CS were associated with a 0.5% and 0.6% reduction in incidence rate compared to no PDR testing. Initial PDR prevalence among women was 13.1% in 2019. By 2034, this prevalence was 17·6%, 17·4%, and 17·3% with no testing, OLA testing, and CS testing, respectively. Interpretation PDR testing for women is unlikely to be cost-effective in Kenya whether one uses a low-cost assay, such as OLA, or consensus sequencing. Funding National Institutes of Health, Gilead Sciences.

Summary Background The way in which a government chooses to finance a health intervention can affect the uptake of health interventions and consequently the extent of health gains. In addition to health gains, some policies such as public finance can insure against catastrophic health expenditures. We aimed to evaluate the health and financial risk protection benefits of selected interventions that could be publicly financed by the government of Ethiopia. Methods We used extended cost-effectiveness analysis to assess the health gains (deaths averted) and financial risk protection afforded (cases of poverty averted) by a bundle of nine (among many other) interventions that the Government of Ethiopia aims to make universally available. These nine interventions were measles vaccination, rotavirus vaccination, pneumococcal conjugate vaccination, diarrhoea treatment, malaria treatment, pneumonia treatment, caesarean section surgery, hypertension treatment, and tuberculosis treatment. Findings Our analysis shows that, per dollar spent by the Ethiopian Government, the interventions that avert the most deaths are measles vaccination (367 deaths averted per $100 000 spent), pneumococcal conjugate vaccination (170 deaths averted per $100 000 spent), and caesarean section surgery (141 deaths averted per $100 000 spent). The interventions that avert the most cases of poverty are caesarean section surgery (98 cases averted per $100 000 spent), tuberculosis treatment (96 cases averted per $100 000 spent), and hypertension treatment (84 cases averted per $100 000 spent). Interpretation Our approach incorporates financial risk protection into the economic evaluation of health interventions and therefore provides information about the efficiency of attainment of both major objectives of a health system: improved health and financial risk protection. One intervention might rank higher on one or both metrics than another, which shows how intervention choice—the selection of a pathway to universal health coverage—might involve weighing up of sometimes competing objectives. This understanding can help policy makers to select interventions to target specific policy goals (ie, improved health or financial risk protection). It is especially relevant for the design and sequencing of universal health coverage to meet the needs of poor populations. Funding Bill & Melinda Gates Foundation.

Summary Background The six-dose regimen of artemether-lumefantrine is effective and is among combination therapies prioritised to replace antimalarials that no longer work in Africa. However, its effectiveness has not been assessed in the field, and could be compromised by poor adherence, incorrect timing of doses, and insufficient intake of fatty foods with every dose. Our aim, therefore, was to assess the effectiveness of artemether-lumefantrine prescribed under routine outpatient conditions, compared with its efficacy when given under supervision to inpatients with acute uncomplicated falciparum malaria. Methods We did a randomised trial to compare the efficacy, safety, and pharmacokinetics of artemether-lumefantrine when given in a supervised (all doses observed with fatty-food intake; n=313) or unsupervised (first dose supervised followed by outpatient treatment with nutritional advice; n=644) setting to patients of all ages (weight >10 kg) with acute, uncomplicated falciparum malaria in Mbarara, Uganda. Our primary endpoint was 28 day, PCR-adjusted, parasitological cure rate. Analysis was by intention to treat and evaluability analysis. Findings 38 patients were lost to follow-up and one withdrew consent. Day-28 cure rates were 97·7% (296 of 303) and 98·0% (603 of 615) in the supervised and unsupervised groups, respectively. We recorded 15 non-severe, drug-related adverse events, all of which resolved. Interpretation Artemether-lumefantrine has a high cure rate irrespective of whether given under supervision with food or under conditions of routine clinic practice. If used as first-line treatment, artemether-lumefantrine could make a substantial contribution to malaria control in Africa, though cost is an issue.

0.123 -0.179, -0.068

Average Quality Index 14.8 ± 2.9 • A comprehensive search of all prospective and retrospective cohort studies comparing MIS fusion to open fusion were searched using PubMed, EMBASE and the Cochrane libraries • The search is current as of June 7, 2012 • Figure 1 contains the PRISMA diagram of how studies were selected • Of the 15 selected for full-text review, 4 were excluded for wrong surgical technique, no use of MIS, and did not measure the proper outcomes. • All studies were coded for quality using the method by Downs and Black (1998)(8) where the higher the number the higher the quality of study • Where studies were missing standard deviation (SD) measurements, an average of studies that had SD was taken and the mean was imputed for those missing • Effects sizes (relative risks and standardized mean differences) were calculated using both fixedand randomeffects models with 95% confidence intervals • When measuring the ODI and VAS the postoperative score was taken at the last time point available for the study. For two studies it was estimated to be at 12 months and for 3 studies it was estimated at 24 months • Studies were analyzed using metan and metafunnel commands STATA MP 12.1 (College Station, TX) • Random-effects models was chosen due to the high heterogeneity across studies for each outcome (53.1% 93.5%) • Standardized mean difference (SMD) was converted by calculating the standard deviations of the mean scores for the open group and multiplied times the pooled SMD to give a meaningful value for reporting • The pooled results of these studies included 554 total patients, with 259 in the open TLIF group and 294 in the MIS TLIF group. Average follow-up across the studies ranged from 12 – 24 months. • The relative risk of complications was not statistically significant and was essentially equivalent in the two interventions. • There was a slight 1.5% decrease in the relative risk of complications when using MIS TLIF in the pooled results, but the confidence intervals crossed 1.0 (RRpooled = 0.99, 95% CI: 0.45 – 2.18 p=0.97).

Reductions in prices following the expiry of patents on second-generation antipsychotics means that they could be made available to patients with schizophrenia in low-income countries. In this study we examine the cost effectiveness of antipsychotics for schizophrenia in Uganda. We developed a decision-analytic 10-state Markov model to represent the clinical and treatment course of schizophrenia and the experience of the average patient within the Uganda healthcare system. The model was run for a base population of 25-years-old patients attending Butabika National Referral Mental Hospital, in annual cycles over a lifetime horizon. Parameters were derived from a primary chart abstraction study, a local community pharmacy survey, published literature, and expert opinion where necessary. We computed mean disability-adjusted life-years (DALYs) and costs (in US$ 2012) for each antipsychotic, incremental cost, and DALYs averted as well as incremental cost-effectiveness ratios (ICERs). In the base-case analysis, mean DALYs were highest with chlorpromazine (27.608), followed by haloperidol (27.563), while olanzapine (27.552) and risperidone had the lowest DALYs (27.557). Expected costs were highest with quetiapine (US$4943), and lowest with risperidone (US$4424). Compared to chlorpromazine, haloperidol was a dominant option (i.e. it was less costly and more effective); and risperidone was dominant over both haloperidol and quetiapine. The ICER comparing olanzapine to risperidone was US$5868 per DALY averted. When choosing between first-generation antipsychotics, clinicians should consider haloperidol as the first-line agent for schizophrenia. However, overall, risperidone is a cost-saving strategy; policymakers should consider its addition to essential medicines lists for treatment of schizophrenia in Uganda.