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A multicenter, prospective, randomized, open-label, blinded endpoint trial of intravenous thrombolysis with tenecteplase for acute non-large vessel occlusion in extended time window (OPTION): Rationale and design
Get PDFBackground and Objectives: Recombinant human tenecteplase (TNK) tissue-type plasminogen activator (rhTNK-tPA, also named tenecteplase) is non-inferior to alteplase when given up to 4.5 hours after acute ischemic stroke (AIS) within 4.5 hours. Whether intravenous tenecteplase compared with supportive care improves the outcome of patients with AIS due to non-large vessel occlusion (non-LVO) between 4.5-24 hours is uncertain. The Tenecteplase for Acute Non-large vessel occlusion in the Extended Time Window (OPTION) trial aims to test the efficacy and safety of intravenous tenecteplase in patients presenting between 4.5-24 hours after symptom onset who have a non-LVO and evidence of salvageable tissue on perfusion imaging. Methods: OPTION is a multicenter, prospective, randomized, open-label, blinded endpoint (PROBE) study. Patients with AIS due to non-LVO and evidence of salvageable brain tissue within 4.5-24 hour time window meeting eligibility criteria will be allocated in a 1∶1 ratio to tenecteplase or standard medical treatment. A target mismatch profile is defined as ischemic core volume <50 mL, a mismatch ratio ≥1.2, and a mismatch volume ≥10 mL. A total of 568 patients will provide >80% power to detect a 12% absolute difference in the proportion of patients achieving an excellent functional outcome (modified Rankin scale [mRS] 0-1 at 90 days) at the two-sided 0.05 significance level. The primary efficacy outcome is excellent functional outcome (mRS 0-1) at 90 days. Secondary efficacy outcomes include disability level (ordinal distribution of mRS) at 90 days, functional independence (mRS 0-2) at 90 days, reperfusion at 24 hours, infarct volume at 24 hours, early clinical response at 24 hours, the National Institutes of Health Stroke Scale (NIHSS) change from baseline at 7 days/discharge, health status and quality of life at 90 days. Safety outcomes include symptomatic intracranial hemorrhage within 36 hours, systemic bleeding within 90 days, and mortality within 90 days. Discussion: The OPTION trial (NCT05752916) will provide evidence regarding the efficacy and safety of tenecteplase 4.5 to 24 hours in patients with AIS due to non-LVO.</p
A Prospective Cohort Study Investigating the Prognostic Performance and Utility of 3 Severity of Illness Scores
Get PDFBackground: Mortality prediction is difficult in resource-constrained settings. Severity of illness scores have not been tested in hypoxemic adults in Africa. Research Question: How well do 3 severity of illness scores (Modified Early Warning Score [MEWS], quick Sequential Organ Failure Assessment [qSOFA], and Universal Vital Assessment [UVA]) and the ability to walk predict mortality in hypoxemic hospitalized adults in Africa? Study Design and Methods: All adults with hypoxemia on admission in 5 hospitals in Kenya, Malawi, and Rwanda between November 2022 and April 2023 were prospectively enrolled in the study. The capability of MEWS, qSOFA, UVA, and the ability to walk was evaluated to predict hospital mortality. In exploratory analyses, differences in disease severity and mortality were compared between sites. Results: A total of 24,724 admissions were screened; 1,732 of these were hypoxemic and had complete outcomes data. Median age was 52 years (interquartile range, 36-70 years), and hospital mortality was 35% (n = 615). Sites varied in the completeness of score variables (44%-99%). Increased odds of mortality were found using predefined thresholds for each score; UVA predicted best, with an OR of 3.40 (95% CI, 2.54-4.56). The area under the receiver-operating curves for MEWS, qSOFA, and UVA were 0.66 (95% CI, 0.62-0.69), 0.66 (95% CI, 0.63-0.69), and 0.69 (95% CI, 0.65-0.72), respectively, using complete case analysis; they were 0.61 (95% CI, 0.58-0.64), 0.65 (95% CI, 0.62-0.67), and 0.66 (95% CI, 0.64-0.69) with missing data imputed as normal. Inability to walk independently was also predictive of mortality (OR, 2.26; 95% CI, 1.62-3.15). UVA pairwise comparisons showed different mortality between 4 of 6 sites; these differences remained significant in 2 comparisons when adjusting for illness severity. Interpretation: In the largest prospective cohort of hypoxemic adults in Africa to date, MEWS, qSOFA, UVA, and ability to walk on admission had modest capability to predict hospital death. Missing data were common. Imputation of missing variables only slightly altered performance, and thus it is possible that scores could be simplified. UVA had the best predictive performance and may be cautiously used to aid clinical decision-making, quality improvement, research comparisons, and risk adjustment.</p
Olfactory gene dynamics in invasive Indian and non-invasive African malaria vectors at the crossroads of development, infection and resistance
Get PDFOlfaction plays a pivotal role in a mosquito’s lifecycle, influencing vital functions such as finding food, mates, identifying hosts, and locating sites for laying eggs. However, a detailed catalog of the olfactory genes in mosquitoes has remained elusive—until now. In this study, we compiled the olfactory genes catalog for four key malaria vectors: two major Indian species, Anopheles stephensi and Anopheles culicifacies, along with two African species, Anopheles gambiae and Anopheles funestus. Using an extensive genome-wide approach, we uncovered crucial carrier proteins like odorant binding proteins (OBPs), chemosensory proteins (CSPs), and several receptors, including odorant receptors (ORs), ionotropic receptors (IRs), and gustatory receptors (GusRs). A particularly striking discovery was the significantly higher number of OBP, OR, and IR genes in African malaria vectors compared to their Indian counterparts, hinting at the gene gain and functional diversification in these species. The invasive A. stephensi—which has spread from Asia to Africa—showed closer genetic ties to A. minimus and A. gambiae than to A. culicifacies. Furthermore, when examining the expression of CSPs and SAPs in the larval stage of A. stephensi, we found that pyrethroid-resistant mosquito larvae exhibited elevated expression of SAP2 and SAP3, providing new evidence of their potential role in insecticide resistance. This study not only sheds light on the genetic basis of mosquito olfaction but also offers crucial insights into how these genes are linked to different physiological functions, paving the way for improved malaria control strategies.</p
Protocol for the economic evaluation of individualised (early) patient-directed rehabilitation versus standard rehabilitation after surgical repair of the rotator cuff of the shoulder (RaCeR 2)
Get PDFIntroduction RaCeR 2 is a pragmatic multicentre, open-label, randomised controlled trial, with full economic evaluation. The primary aim is to assess whether individualised (early) patient-directed rehabilitation (EPDR) results in less shoulder pain and disability at 12 weeks postrandomisation following surgical repair of full-thickness tears of the rotator cuff of the shoulder compared with the current standard (delayed) rehabilitation. This paper provides the protocol for the RaCeR 2 health economic evaluation. Methods and analysis. The health economic analysis of RaCeR 2 is made up of three phases: (1) development of an initial state-transition model structure, (2) within-trial cost consequence analysis and (3) long-term model-based cost-effectiveness analysis (CEA) from the National Health Service and Personal Social Service perspective in England. Descriptive statistics (eg, mean, standard deviation, 95% confidence intervals and minimum and maximum values) will be reported for within-trial resource use, costs and health-related quality of life (HRQoL). Health state-specific costs and HRQoL will be estimated using regression model approaches and used to inform a state-transition simulation model designed to quantify the long-term costs and quality-adjusted life years (QALYs) experienced by patients over the model’s time horizon. Where appropriate, final CEA model results will be reported as cost per QALY gained for individualised EPDR versus standard (delayed) rehabilitation. Model assumptions and overall parameter uncertainty will be tested using probabilistic sensitivity analysis and scenario analyses. All regression analyses will be adjusted for baseline participant demographic and symptomatic characteristics. Ethics and dissemination A favourable ethical review was granted by London-Stanmore Research Ethics Committee (23/LO/0195) on 13 April 2023. Findings will be disseminated in peer-reviewed journals, at scientific conferences, and via the study website.</p
Adolescent menstrual health must go beyond pads
No full textMenstruation and the menstrual cycle are important aspects of female health and wellbeing across the lifespan from menarche, the first menstrual period, to menopause (1–3). Adolescent girls and women worldwide consistently report negative experiences with menstruation, including missed or delayed diagnosis of menstrual disorders. These issues have far-reaching consequences for their wellbeing, education, livelihood opportunities, empowerment, and overall health (4–6). In response, investment in menstrual health (see Box 1) during adolescence is increasingly recognised as a pathway to mitigate these consequences and address gender inequality. This was emphasized in 2022 when the World Health Organization declared menstrual health as a health and human rights issue and not solely a hygiene issue (7). The emerging concept of menstrual justice highlights how harmful power structures and social norms result in menstrual related discrimination in many spheres of life that impede menstrual health (8). Despite increased attention, data on adolescent girls’ menstrual health is insufficient across countries. The absence of data on girls’ multidimensional requirements for menstrual health renders these challenges invisible. For this and likely other reasons, the media, donors, governments, and implementers have concentrated on menstrual pads as a ‘quick fix’, tangible, and easily measurable solution. Competing health and human rights priorities with stronger and more well-established links to female morbidity and mortality also limit the funding available to expand the evidence base on menstrual health. Better data from well-resourced rigorous research would serve to inform the development of more comprehensive, impactful, and cost-effective interventions (9). Current gaps must be addressed by increasing the visibility of menstrual health in monitoring efforts, research, and the development and implementation of contextually grounded interventions (10). This in turn would enable a move away from a narrow focus on the provision of pads to address the complexity of adolescent girls’ menstrual health needs. In this analysis, we focus on adolescent girls due to the unique needs and critical importance of investing in this age group, with an emphasis on low resource settings, though the insights have global relevance. Although not discussed here, women and others who menstruate are important to consider in a broader menstrual health agenda. We also focus on menstrual pads rather than other products (e.g., cups, panties) because single-use pads are the most commonly provided menstrual material in government, donor, and programmatic initiatives targeting girls.</p
Intra-Arterial Urokinase After Endovascular Reperfusion for Acute Ischemic Stroke: The POST-UK Randomized Clinical Trial
Get PDFImportance. Persisting or new thrombi in the distal arteries and the microcirculation have been reported to limit the benefits of successful endovascular thrombectomy for patients with acute ischemic stroke. It remains uncertain whether intra-arterial thrombolysis by urokinase following near-complete to complete reperfusion by thrombectomy improves outcomes among patients with ischemic stroke due to large vessel occlusion.Objective. To assess the efficacy and adverse events of intra-arterial urokinase after near-complete to complete reperfusion by thrombectomy for acute ischemic stroke due to large vessel occlusion.Design, Setting, and Participants. This investigator-initiated, randomized, open-label, blinded–end point trial was implemented at 35 hospitals in China, enrolling 535 patients with proximal intracranial large vessel occlusion presenting within 24 hours of time last known well, who achieved near-complete or complete reperfusion by endovascular thrombectomy and did not receive intravenous thrombolysis prior to the procedure. Recruitment took place between November 15, 2022, and March 29, 2024, with final follow-up on July 4, 2024.Interventions. Eligible patients were randomly assigned to the intra-arterial urokinase group (a single dose of intra-arterial 100 000 IU urokinase injected in the initial target territory; n = 267) or control group (without intra-arterial thrombolysis; n = 267).Main Outcomes and Measures. The primary efficacy outcome was the percentage of patients achieving survival without disability (modified Rankin Scale score of 0 or 1) at 90 days. The primary safety outcomes were mortality at 90 days and incidence of symptomatic intracranial hemorrhage within 48 hours.Results. A total of 535 patients were enrolled (median age, 69 years; 223 [41.8%] female) and 532 (99.6%) completed the trial. The percentage of patients with survival without disability at 90 days was 45.1% (120/266) in the intra-arterial urokinase group and 40.2% (107/266) in the control group (adjusted risk ratio, 1.13 [95% CI, 0.94-1.36]; P = .19). Mortality at 90 days (18.4% vs 17.3%, respectively; adjusted hazard ratio, 1.06 [95% CI, 0.71-1.59]; P = .77) and incidence of symptomatic intracranial hemorrhage (4.1% vs 4.1%, respectively; adjusted risk ratio, 1.05 [95% CI, 0.45-2.44]; P = .91) were not significantly different between groups.Conclusions and Relevance. Among patients with acute ischemic stroke due to large vessel occlusion, adjunct intra-arterial urokinase after near-complete to complete reperfusion by endovascular thrombectomy did not significantly increase the likelihood of survival without disability at 90 days.</p
Developing and applying a training needs analysis tool for healthcare workers managing snakebite envenoming: A cross-sectional study in Eswatini
Get PDFA considerable number of patients present to hospitals in Eswatini each year following bites by venomous snakes. Effectively diagnosing and treating patients with snakebite envenoming requires healthcare workers to have a variety of generic and snakebite-specific medical skills. In several countries, however, healthcare workers have been found to have limited skills in managing snakebite patients. We used the Delphi method to adapt the Hennessy-Hicks training needs analysis questionnaire to the context of snakebite envenoming and subsequently used the adapted questionnaire to assess the self-perceived training needs of 90 healthcare workers from ten hospitals in Eswatini. Two-thirds (63%) of participants were nursing staff and one third (34%) medical doctors. Overall, 74% of healthcare workers had previously received training on snakebite. Although a training need was reported for all skills included in the survey, the extent of the training need varied between different skills and groups of healthcare workers. The highest average training need was registered in the domains ‘research and audit’ and ‘clinical tasks’ with the latter accounting for nine of the ten skills with the highest training need. Nurses reported a higher training need than doctors, especially for clinical tasks. Receiving snakebite training before as well as after obtaining the primary qualification was associated with the lowest average training need, particularly in clinical skills. Ninety-three percent of interviewed healthcare workers would welcome more frequent training opportunities on the clinical management of snakebite patients. This newly developed snakebite training needs analysis tool can aid in adapting training initiatives to a dynamic and evolving healthcare workforce and it is designed to be transferrable to snakebite endemic settings worldwide.</p
Insecticide resistant Anopheles from Ethiopia but not Burkina Faso show a microbiota composition shift upon insecticide exposure
Get PDFBackgroundMalaria remains a key contributor to mortality and morbidity across Africa, with the highest burden in children under 5. Insecticide-based vector control tools, which target the adult Anopheles mosquitoes, are the most efficacious tool in disease prevention. Due to the widespread use of these interventions, insecticide resistance to the most used classes of insecticides is now pervasive across Africa. Understanding the underlying mechanisms contributing to this phenotype is necessary to both track the spread of resistance and to design new tools to overcome it.MethodsHere, we compare the microbiota composition of insecticide-resistant populations of Anopheles gambiae, An. coluzzii and An. arabiensis from Burkina Faso, and in the latter case additionally from Ethiopia, to insecticide-susceptible populations.ResultsWe show that the microbiota composition between insecticide-resistant and -susceptible populations does not differ in Burkina Faso. This result is supported by data from laboratory colonies originating in Burkina Faso across two countries. In contrast, An. arabiensis from Ethiopia demonstrates clear differences in microbiota composition in those dying from and those surviving insecticide exposure. To further understand resistance in this An. arabiensis population, we performed RNAseq and saw differential expression of detoxification genes associated with insecticide resistance and changes in respiration, metabolism and synapse-related ion channels.ConclusionsOur results indicate that, in addition to changes in the transcriptome, microbiota can contribute to insecticide resistance in certain settings.</p
Longitudinal observational (single cohort) study on the causes of trypanocide failure in cases of African animal trypanosomosis in cattle near wildlife protected areas of Northern Tanzania
Get PDFAfrican animal trypanosomosis (AAT) in cattle is primarily managed through trypanocide administration and insecticide application. Trypanocides can be used for both treatment and prophylaxis, but failure is often reported; this may occur due to resistance, substandard drugs, or inappropriate administration. This study in Tanzania aims to quantify reasons for trypanocide failure. An observational year-long longitudinal study was conducted in high-risk AAT areas in Serengeti District between June 2021-October 2022. Purposive sampling targeted herds with high utilization of the prophylactic trypanocide isometamidium chloride (ISM). When a farmer administered a trypanocide (ISM, diminazine aceturate, homidium), the project veterinarian assessed administration and treatment outcomes were determined based on PCR results from blood samples. A multivariable mixed model was utilized to evaluate risk factors for prophylaxis failure. Quality analysis was performed on trypanocide samples using High Performance Liquid Chromatography. A total of 630 cattle from 21 farms were monitored for a year-long period. A total of 295 trypanocide administrations were reported, predominantly being ISM (56%) used for prophylaxis (87%). One-third of trypanocide administrations were not given adequately, and many trypanocides were given to animals that tested negative for trypanosome infections by PCR. Failures occurred in 7% (95% CI 3.0–14%) of curative treatments, and 44% (95% CI 35–42%) of prophylactic administrations. The brand of ISM was significantly associated with odds of prophylaxis failure (p = 0.011). On quality analysis, two ISM samples had no detectable ISM isomers, but the remainder of ISM and DA samples (n = 46) fell within the range of acceptable levels. Drug counterfeiting, inadequate use of trypanocides, and resistance are all contributing to trypanocide failure, limiting effective AAT control and with implications for human disease risk. In order to curb trypanocide failure a multi-modal approach to managing the use of trypanocides is required to address all contributing factors.</p
Causes of HIV-related CNS infection in Cameroon, Malawi, and Tanzania: epidemiological findings from the DREAMM HIV-related CNS implementation study.
Get PDFBackgroundCNS infections cause approximately a third of HIV-related deaths. The Driving Reduced AIDS-Associated Meningo-encephalitis Mortality DREAMM study aimed to prospectively diagnose the aetiology of HIV-related CNS infection in five public hospitals in Cameroon, Malawi, and Tanzania.MethodsDREAMM was a multicentre, hybrid type-2 implementation science project. Adults (aged ≥18 years) presenting with a first episode of suspected CNS infection, who were HIV seropositive or willing to have an HIV test, were eligible for recruitment. Following implementation of the DREAMM model of care, we measured the prevalence of cryptococcal meningitis, tuberculous meningitis, bacterial meningitis, and cerebral toxoplasmosis and did a χ2 test to assess whether prevalence differed between countries. We also reported disease-specific mortality and Toxoplasma gondii seroprevalence.FindingsOf 356 participants with suspected CNS infection analysed at baseline, 269 (76%) were diagnosed as having a CNS infection. Of these, 202 (75%) had a confirmed diagnosis. Between Cameroon, Malawi, and Tanzania, the prevalence of the four main types of CNS infection differed (cryptococcal meningitis p=0·0014, bacterial meningitis p=0·0043, CNS tuberculosis p<0·0001, and toxoplasmosis p<0·0001). Cryptococcal meningitis (148 [55%] of 269) was the leading cause overall. The next most common causes were CNS tuberculosis in Tanzania (29 [29%] of 99) and bacterial meningitis in Malawi (15 [19%] of 80). In Cameroon, cerebral toxoplasmosis (39 [43%] of 90) was the leading cause followed by cryptococcal meningitis (36 [40%] of 90). For cryptococcal meningitis, all-cause 2-week mortality was 23% (34 of 147) and all-cause 10-week mortality was 45% (66 of 146).InterpretationWithin the study population, the aetiology of HIV-related CNS infection varied substantially between Malawi, Cameroon, and Tanzania. Additional prospective epidemiological data are needed to inform HIV programmes. 2-week cryptococcal meningitis mortality outcomes were similar to those of clinical trials. However, new interventions are urgently needed to sustain mortality reductions following hospital discharge.</p