AMBIsome Therapy Induction OptimisatioN (AMBITION): High dose AmBisome for cryptococcal meningitis induction therapy in sub-Saharan Africa: economic evaluation protocol for a randomised controlled trial-based equivalence study.

INTRODUCTION: Cryptococcal meningitis is responsible for around 15% of all HIV-related deaths globally. Conventional treatment courses with amphotericin B require prolonged hospitalisation and are associated with multiple toxicities and poor outcomes. A phase II study has shown that a single high dose of liposomal amphotericin may be comparable to standard treatment. We propose a phase III clinical endpoint trial comparing single, high-dose liposomal amphotericin with the WHO recommended first-line treatment at six sites across five counties. An economic analysis is essential to support wide-scale implementation. METHODS AND ANALYSIS: Country-specific economic evaluation tools will be developed across the five country settings. Details of patient and household out-of-pocket expenses and any catastrophic healthcare expenditure incurred will be collected via interviews from trial patients. Health service patient costs and related household expenditure in both arms will be compared over the trial period in a probabilistic approach, using Monte Carlo bootstrapping methods. Costing information and number of life-years survived will be used as the input to a decision-analytic model to assess the cost-effectiveness of a single, high-dose liposomal amphotericin to the standard treatment. In addition, these results will be compared with a historical cohort from another clinical trial. ETHICS AND DISSEMINATION: The AMBIsome Therapy Induction OptimisatioN (AMBITION) trial has been evaluated and approved by the London School of Hygiene and Tropical Medicine, University of Botswana, Malawi National Health Sciences, University of Cape Town, Mulago Hospital and Zimbabwe Medical Research Council research ethics committees. All participants will provide written informed consent or if lacking capacity will have consent provided by a proxy. The findings of this economic analysis, part of the AMBITION trial, will be disseminated through peer-reviewed publications and at international and country-level policy meetings. TRIAL REGISTRATION: ISRCTN 7250 9687; Pre-results

Challenges and recent progress in drug discovery for tropical diseases

Infectious tropical diseases have a huge effect in terms of mortality and morbidity, and impose a heavy economic burden on affected countries. These diseases predominantly affect the world’s poorest people. Currently available drugs are inadequate for the majority of these diseases, and there is an urgent need for new treatments. This Review discusses some of the challenges involved in developing new drugs to treat these diseases and highlights recent progress. While there have been notable successes, there is still a long way to go.</p

Social Control in Transnational Families: Somali Women and Dignity in Johannesburg

Transnational mobility often separates families and distances individuals from the kinship and social structures by which they organized their lives prior to migration. Myriad forms of insecurity have been the impetus for Somali movement into the diaspora, with people fleeing the realities of conflict that have marked Somalia for decades while physically dividing families as individuals settle in different countries around the world. Mobility has altered the dynamics of households, families, and communities post-migration, reshaping social constructions as individuals move on without the familial support that sustained them in Somalia. While outcomes of these hardships are variable and often uneven in different settlement spaces, migration can offer new opportunities for people to pursue avenues from which they were previously excluded, such as by assuming roles and responsibilities their relatives once filled. These changes precipitate shifting identities and are challenging for women who find themselves self-reliant in the diaspora, particularly in the absence of (supportive) husbands and close kin.Drawing on ethnographic research in Johannesburg’s Somali community, this chapter explores the assumption that migration provides an opening for women to challenge subordinating gender norms. Settlement often grants women greater freedom to make choices in their lives, such as in employment and personal relationships, and yet they remain constrained by networks that limit their autonomy. Even with transnational migration and protracted separation, women are family representatives who must uphold cultural notions of respectability despite realities that position them as guardians and family providers. Women remain under the watchful eye of their extended families through expansive networks and the ease of modern communication, which facilitate a new form of social control as women’s behavior is carefully monitored and reported to relatives afar. These actualities raise questions about the degree to which transnational movement is a liberating force for women or rather a reconfiguration of social control. I argue that despite women’s changing position in their households and families, they remain limited by social control within their extended families and communities

Do lower antenatal blood pressure cut-offs in pregnant women with obesity identify those at greater risk of adverse maternal and perinatal outcomes? A secondary analysis of data from the UK Pregnancies Better Eating and Activity Trial (UPBEAT)

\ua9 The Author(s) 2025. Background: Obesity is a major risk-factor for adverse pregnancy outcomes. While the 2017 American College of Cardiology/American Heart Association (ACC/AHA) classification of normal and abnormal blood pressure (BP) outside pregnancy has been suggested for use in pregnancy, the impact on adverse outcomes has not been examined specifically in women with obesity. Methods: The UK Pregnancies Better Eating and Activity Trial (UPBEAT) enroled women with a body mass index (BMI) ≥ 30 kg/m2. In secondary analyses, maximal antenatal BP was categorised by 2017 ACC/AHA criteria: ‘Normal’ BP (systolic [sBP] &lt;120 mmHg and diastolic [dBP] &lt;80 mmHg), ‘Elevated’ BP (sBP 120–129 mmHg and dBP &lt;80 mmHg), ‘Stage 1 hypertension’ (sBP 130–139 mmHg and/or dBP 80-89 mmHg), and ‘Stage 2 hypertension’ (sBP ≥140 mmHg and/or dBP ≥90 mmHg, non-severe [sBP 140-159 mmHg and/or dBP 90–109 mmHg] and severe (sBP ≥160 mmHg and/or dBP ≥110 mmHg). Main outcomes were preterm birth, postpartum haemorrhage (PPH), birthweight &lt;10th centile (small-for-gestational age, SGA), and neonatal intensive care unit (NICU) admission. Associations with adverse outcomes were adjusted for UPBEAT intervention, maternal age, booking BMI, ethnicity, parity, smoking, alcohol, and previous pre-eclampsia or gestational diabetes. Diagnostic test properties (positive and negative likelihood ratios, -LR and +LR) were assessed as individual categories (vs. ‘Normal’ BP), and as threshold values. Results: Severe ‘Stage 2 hypertension’ (vs. BP &lt; 160/110 mmHg) was associated with PPH (RR 2.57 (1.35, 4.86)) and SGA (RR 2.52 (1.05, 6.07)) only in unadjusted analyses. No outcomes were associated with ‘Stage 1 hypertension’ or ‘Elevated BP’. All +LR were &lt;5.0 and -LR ≥ 0.20, indicating that no BP threshold was useful as a diagnostic test to detect preterm birth, PPH, SGA, or NICU admission. Conclusions: Among pregnant women with obesity, we found no evidence that lowering the antenatal BP considered to be abnormal (from 140/90 mmHg) would assist in identifying women and babies at risk

Establishing targets for advanced HIV disease: A call to action

The World Health Organization (WHO) has published a guideline for the management of individuals with advanced HIV disease (AHD) to reduce HIV-related deaths. The guideline consists of a package of recommendations including interventions to prevent, diagnose and treat common opportunistic infections, including tuberculosis (TB), cryptococcosis and severe bacterial infections, along with rapid initiation of antiretroviral treatment and enhanced adherence support. Currently no clear targets exist for these key interventions. Emerging programmatic data from Uganda, Tanzania and Nigeria suggest that an estimated 80% of eligible people continue to miss the recommended cryptococcal or TB testing, highlighting the remaining challenges to the effective implementation of WHO-recommended AHD packages of care in real-world resource-limited settings. The absence of mortality indicators for the leading causes of HIV-related deaths, because of the lack of mechanisms to ascertain cause of death, has had a negative impact on establishing interventions to reduce mortality. We suggest that setting 95-95-95 targets for CD4 testing, cryptococcal antigen and TB testing, and treatment that are aligned to the WHO AHD package of care would be a step in the right direction to achieving the greater goal of the WHO End TB strategy and the proposed new strategy to end cryptococcal meningitis deaths. However, these targets will only be achieved if there is healthcare worker training, expanded access to bedside point-of-care diagnostics for hospitalised patients and those in outpatient care who meet the criteria for AHD, and health systems strengthening to minimise delays in initiating the WHO-recommended therapies for TB and cryptococcal disease

Cost-effectiveness of single, high-dose, liposomal amphotericin regimen for HIV-associated cryptococcal meningitis in five countries in sub-Saharan Africa: an economic analysis of the AMBITION-cm trial

BACKGROUND: HIV-associated cryptococcal meningitis is a leading cause of AIDS-related mortality. The AMBITION-cm trial showed that a regimen based on a single high dose of liposomal amphotericin B deoxycholate (AmBisome group) was non-inferior to the WHO-recommended treatment of seven daily doses of amphotericin B deoxycholate (control group) and was associated with fewer adverse events. We present a five-country cost-effectiveness analysis. METHODS: The AMBITION-cm trial enrolled patients with HIV-associated cryptococcal meningitis from eight hospitals in Botswana, Malawi, South Africa, Uganda, and Zimbabwe. Taking a health service perspective, we collected country-specific unit costs and individual resource-use data per participant over the 10-week trial period, calculating mean cost per participant by group, mean cost-difference between groups, and incremental cost-effectiveness ratio per life-year saved. Non-parametric bootstrapping and scenarios analyses were performed including hypothetical real-world resource use. The trial registration number is ISRCTN72509687, and the trial has been completed. FINDINGS: The AMBITION-cm trial enrolled 844 participants, and 814 were included in the intention-to-treat analysis (327 from Uganda, 225 from Malawi, 107 from South Africa, 84 from Botswana, and 71 from Zimbabwe) with 407 in each group, between Jan 31, 2018, and Feb 17, 2021. Using Malawi as a representative example, mean total costs per participant were US$1369 (95$1237 (1181–1293) in the control group. The incremental cost-effectiveness ratio was $128 (59–257) per life-year saved. Excluding study protocol-driven cost, using a real-world toxicity monitoring schedule, the cost per life-year saved reduced to$80 (15–275). Changes in the duration of the hospital stay and antifungal medication cost showed the greatest effect in sensitivity analyses. Results were similar across countries, with the cost per life-year saved in the real-world scenario ranging from $71 in Botswana to$121 in Uganda. INTERPRETATION: The AmBisome regimen was cost-effective at a low incremental cost-effectiveness ratio. The regimen might be even less costly and potentially cost-saving in real-world implementation given the lower drug-related toxicity and the potential for shorter hospital stays. FUNDING: European Developing Countries Clinical Trials Partnership, Swedish International Development Cooperation Agency, Wellcome Trust and Medical Research Council, UKAID Joint Global Health Trials, and the National Institute for Health Research

The ethical ambivalence of resistant violence: notes from postcolonial south Asia

In the face of mounting militarism in south Asia, this essay turns to anti-state, ‘liberatory’ movements in the region that employ violence to achieve their political aims. It explores some of the ethical quandaries that arise from the embrace of such violence, particularly for feminists for whom political violence and militarism is today a moot point. Feminist responses towards resistant political violence have, however, been less straightforward than towards the violence of the state, suggesting a more ambivalent ethical position towards the former than the latter. The nature of this ambivalence can be located in a postcolonial feminist ethics that is conceptually committed to the use of political violence in certain, albeit exceptional circumstances on the basis of the ethical ends that this violence (as opposed to other oppressive violence) serves. In opening up this ethical ambivalence – or the ethics of ambiguity, as Simone de Beauvoir says – to interrogation and reflection, I underscore the difficulties involved in ethically discriminating between forms of violence, especially when we consider the manner in which such distinctions rely on and reproduce gendered modes of power. This raises particular problems for current feminist appraisals of resistant political violence as an expression of women's empowerment and ‘agency’