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Cryptococcal meningitis is a major complication of HIV infection. In this phase 3, randomized, controlled trial in sub-Saharan Africa, a single dose of liposomal amphotericin B induction therapy combined with fluconazole and flucytosine for cryptococcal meningitis was shown to be noninferior to standard induction therapy with amphotericin B deoxycholate and was associated with fewer adverse events.

Hospitalized patients with alcohol use disorder (AUD) frequently pose diagnostic and therapeutic challenges due to the interplay of substance use, withdrawal, and coexisting medical conditions. This case presents a 49-year-old man with a history of chronic alcohol overuse and previous alcohol withdrawal seizures, admitted for a right middle lobe pneumonia. Initial management included empiric antibiotics, hydration, and nutritional supplementation. He was also placed on symptom-triggered benzodiazepine therapy, guided by the Clinical Institute Withdrawal Assessment for Alcohol-Revised (CIWA-Ar) protocol, to manage alcohol withdrawal. Despite the broad-spectrum antibiotic coverage, the patient continued to experience fever and tachycardia, raising concerns about an atypical infectious process versus the manifestation of severe alcohol withdrawal. Further consideration and evaluation ruled out antibiotic-resistant organisms, pneumonia-related complications, and alternative infections such as urinary tract infection, meningitis, and endocarditis. Blood cultures taken on admission remained persistently negative, and procalcitonin levels were significantly down-trending, indicating the resolution of a bacterial infectious etiology. By hospital day 3, the patient began exhibiting agitation, shakiness, and confusion, along with persistent spikes in temperature, heart rate, and blood pressure, raising strong suspicion for delirium tremens (DT). This necessitated escalating benzodiazepine dosage on the CIWA-Ar protocol. By hospital day 9, the patient's symptoms had largely resolved, and he was discharged with ongoing care for AUD and follow-up for a lung nodule incidentally identified on chest imaging. This case emphasizes the need for a systematic diagnostic approach to differentiate overlapping symptoms in AUD patients, particularly in the context of acute infections and withdrawal syndromes. Early recognition and aggressive management of DT are critical to prevent complications and improve outcomes in this high-risk population.

We present a case of a 73-year-old woman with a medical history significant for hyperlipidemia, on pravastatin, who developed Takotsubo cardiomyopathy following a diagnosis of osteoporosis. She presented to the Emergency Department with acute transient left arm pain that resolved spontaneously. Investigations revealed elevated troponin levels, non-specific electrocardiographic changes, no significant coronary artery disease on angiography, and left ventricular systolic dysfunction, findings consistent with Takotsubo cardiomyopathy. Further evaluation revealed that the patient's intense anxiety about her recent osteoporosis diagnosis served as the primary emotional stressor, ultimately triggering Takotsubo cardiomyopathy. Osteoporosis, though not immediately life-threatening, can evoke significant psychological distress due to fears about future fractures, physical limitations, and loss of independence. This highlights the broader impact of chronic disease diagnoses on emotional well-being, particularly in older adults. Management in this case included losartan, carvedilol, and supportive care. Beyond pharmacologic treatment, addressing the patient's emotional health was a priority. Specific psychosocial interventions included in-depth discussion with the patient to alleviate misconceptions about osteoporosis, referrals to counseling services to manage anxiety, and strategies to build coping mechanisms such as mindfulness and relaxation techniques. Providing education on the manageable nature of osteoporosis and available treatments helped reduce the patient's sense of helplessness. These interventions aimed to not only support the patient's immediate recovery but also to minimize the risk of recurrence of stress-induced adverse events such as Takotsubo cardiomyopathy. The case underscores the importance of integrating emotional well-being into routine clinical practice by offering tailored psychosocial support, including clear communication, access to mental health resources, and fostering a collaborative care environment. Holistic care that addresses both physical and psychological health can improve patient outcomes, reduce hospitalizations, and empower patients to manage their conditions more effectively.

To investigate whether partner bereavement is associated with adverse cardiovascular and kidney-related events in people with reduced kidney function. Two parallel matched cohort studies using linked routinely collected health data. England (general practices and hospitals using linked Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics) and Denmark (hospitals and community pharmacies using the Danish National Patient, Prescription and Education Registries and the Civil Registration System). Bereaved people with reduced kidney function (estimated glomerular filtration rate (eGFR) <60mL/min/1.73m2 (England) or hospital-coded chronic kidney disease (Denmark)) and non-bereaved people with reduced kidney function similarly defined, matched on age, sex, general practice (England), and county of residence (Denmark) and followed-up from the bereavement date of the exposed person. Cardiovascular disease (CVD) or acute kidney injury (AKI) hospitalization, or death. In people with reduced kidney function, we identified 19,820 (England) and 5,408 (Denmark) bereaved individuals and matched them with 134,828 (England) and 35,741 (Denmark) non-bereaved individuals. Among the bereaved, the rates of hospitalizations (per 1000 person-years) with CVD were 31.7 (95%-CI: 30.5-32.9) in England and 78.8 (95%-CI: 74.9-82.9) in Denmark; the rates of hospitalizations with AKI were 13.2 (95%-CI: 12.5-14.0) in England and 11.2 (95%-CI: 9.9-12.7) in Denmark; and the rates of death were 70.2 (95%-CI: 68.5-72.0) in England and 126.4 (95%-CI: 121.8-131.1) in Denmark. After adjusting for confounders, we found increased rates of CVD (England, HR 1.06 [95%-CI: 1.01-1.12]; Denmark, HR 1.10 [95%-CI: 1.04-1.17]), of AKI (England, HR 1.20 [95%-CI: 1.10-1.31]; Denmark HR 1.36 [95%-CI: 1.17-1.58]), and of death (England, HR 1.10 [95%-CI: 1.05-1.14]; Denmark HR 1.20 [95%-CI: 1.15-1.25]) in bereaved compared with non-bereaved people. Partner bereavement is associated with an increased rate of CVD and AKI hospitalization, and death in people with reduced kidney function. Additional supportive care for this at-risk population may help prevent serious adverse events.

Introduction HIV‐associated cryptococcal meningitis is the second leading cause of AIDS‐related mortality. Cryptococcal meningitis is a poverty‐related disease and the majority of cases occur in settings where resources are limited and access to quality care is often linked to an individual's ability to pay for services. We have previously demonstrated the efficacy, safety and cost‐effectiveness of a single, high‐dose liposomal amphotericin‐based treatment regimen within the AMBITION‐cm trial. Here, we present a five‐country, within‐trial analysis exploring the household economic impact of cryptococcal meningitis. Methods Eight hundred and ten participants were recruited into this sub‐study in Botswana, Malawi, South Africa, Uganda and Zimbabwe between January 2018 and February 2021. We collected data on annual household expenditure, direct costs and indirect costs incurred prior to enrolment and during the 10‐week trial period. Costs were inflated and converted to 2022 USD. We calculated out‐of‐pocket expenditure, lost income and catastrophic healthcare expenditure, defined as costs exceeding 20% of annual household expenditure. Results The average total out‐of‐pocket expenditure plus lost income prior to enrolment was$132 and 17.9% (145/810, 95% CI 15.3–20.5) of participant households had already experienced catastrophic healthcare expenditure. Among the 592 surviving participants, when combining out‐of‐pocket expenditure and lost income, the average cost was $ 516 and 29.1% of annual household expenditure across all countries, ranging from$230 (7.6%) in South Africa to $ 592 (64.2%) in Zimbabwe. More than half (296/581, 51.0%, 95% CI 46.9–55.0) of households experienced catastrophic healthcare expenditure by the end of the trial, ranging from 16.0% (13/81, 95% CI 7.9–24.2) in South Africa to 68.1% (156/229, 95% CI 62.0–74.2) in Uganda. Conclusions This is the first study exploring the household economic impact experienced by those diagnosed with cryptococcal meningitis. The household economic impact of cryptococcal meningitis is high and more than half of households of individuals who survive experience catastrophic healthcare expenditure. It is likely these figures are higher outside of the research setting. This highlights the profound financial impact of this devastating infection and provides a rationale to offer financial and social protection to those affected. Trial Registration Number ISRCTN72509687

Background Cryptococcal meningitis (CM) is a major cause of mortality in HIV programmes in Africa despite increasing access to antiretroviral therapy (ART). Mortality is driven in part by limited availability of amphotericin-based treatment, drug-induced toxicities of amphotericin B deoxycholate and prolonged hospital admissions. A single, high-dose of liposomal amphotericin (L-AmB, Ambisome) on a fluconazole backbone has been reported as non-inferior to 14 days of standard dose L-AmB in reducing fungal burden. This trial examines whether single, high-dose L-AmB given with high-dose fluconazole and flucytosine is non-inferior to a seven-day course of amphotericin B deoxycholate plus flucytosine (the current World Health Organization [WHO] recommended treatment regimen). Methods An open-label phase III randomised controlled non-inferiority trial conducted in five countries in sub-Saharan Africa: Botswana, Malawi, South Africa, Uganda and Zimbabwe. The trial will compare CM induction therapy with (1) a single dose (10 mg/kg) of L-AmB given with 14 days of fluconazole (1200 mg/day) and flucytosine (100 mg/kg/day) to (2) seven days amphotericin B deoxycholate (1 mg/kg/day) given alongside seven days of flucytosine (100 mg/kg/day) followed by seven days of fluconazole (1200 mg/day). The primary endpoint is all-cause mortality at ten weeks with a non-inferiority margin of 10% and 90% power. Secondary endpoints are early fungicidal activity, proportion of grade III/IV adverse events, pharmacokinetic parameters and pharmacokinetic/pharmacodynamic associations, health service costs, all-cause mortality within the first two and four weeks, all-cause mortality within the first ten weeks (superiority analysis) and rates of CM relapse, immune reconstitution inflammatory syndrome and disability at ten weeks. A total of 850 patients aged ≥ 18 years with a first episode of HIV-associated CM will be enrolled (425 randomised to each arm). All patients will be followed for 16 weeks. All patients will receive consolidation therapy with fluconazole 800 mg/day to complete ten weeks of treatment, followed by fluconazole maintenance and ART as per local guidance. Discussion A safe, sustainable and easy to administer regimen of L-AmB that is non-inferior to seven days of daily amphotericin B deoxycholate therapy may reduce the number of adverse events seen in patients treated with amphotericin B deoxycholate and shorten hospital admissions, providing a highly favourable and implementable alternative to the current WHO recommended first-line treatment. Trial registration ISRCTN, ISRCTN72509687 . Registered on 13 July 2017.

Following publication of the original article [1], we have been notified that one of the author names was listed incorrectly. Both incorrect and correct author names are presented below. The original publication has been corrected.

Abstract Background There are no host biomarkers of risk for HIV-associated cryptococcal meningitis (CM) except CD4+ T-cell deficiency. At present, serum cryptococcal antigen (CrAg) screening of those with CD4 <100 cells/µL is used to identify persons at risk for HIV-associated CM. We determined if plasma antibody profiles could discriminate CrAg+ from CrAg- patients. Methods We performed serological analyses of 237 HIV-infected asymptomatic Zimbabwean patients with CD4 <100 cells/µL; 125 CrAg- and CrAg+ but cerebrospinal fluid CrAg- by CrAg lateral flow assay. We measured plasma immunoglobulin M (IgM), immunoglobulin G (IgG) 1, and IgG2 concentrations by Luminex, and titers of Cryptococcus neoformans (Cn) glucuronoxylomannan (GXM) polysaccharide and naturally occurring Laminarin (natural Lam, a β-(1–3)-glucan linked polysaccharide)-binding IgM and IgG by enzyme-linked immunosorbent assay. Results GXM-IgG, -IgM, and -IgG2 levels were significantly higher in CrAg+ patients, whereas natural Lam-IgM and Lam-IgG were higher in CrAg- patients before and after adjustment for age, sex, and CD4 T-cell count, despite overlap of values. To address this variability and better discriminate the groups, we used Akaike Information Criteria to select variables that independently predicted CrAg+ status and included them in a receiver operating characteristic curve to predict CrAg status. By inclusion of CD4, GXM-IgG, GXM-IgM, and Lam-IgG, -IgG2, and -IgM, this model had an 80.4% probability (95% confidence interval, 0.75–0.86) of predicting CrAg+ status. Conclusions Statistical models that include multiple serological variables may improve the identification of patients at risk for CM and inform new directions in research on the complex role that antibodies may play in resistance and susceptibility to CM.

IntroductionCryptococcal 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 analysisCountry-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 disseminationThe 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 registrationISRCTN 7250 9687; Pre-results.