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In a trial in patients with pelvic or acetabular fractures or extremity fractures that were treated operatively, aspirin thromboprophylaxis was noninferior to low-molecular-weight heparin in preventing death at 90 days.

Background. Mass drug administration (MDA) using dihydroartemisinin plus piperaquine (DHAp) represents a potential strategy to clear Plasmodium falciparum infections and reduce the human parasite reservoir. Methods. A cluster-randomized controlled trial in Southern Province, Zambia, was used to assess the short-term impact of 2 rounds of community-wide MDA and household-level (focal) MDA with DHAp compared with no mass treatment. Study end points included parasite prevalence in children, infection incidence, and confirmed malaria case incidence. Results. All end points significantly decreased after intervention, irrespective of treatment group. Parasite prevalence from 7.71% at baseline to 0.54% after MDA in lower-transmission areas, resulting in an 87% reduction compared with control (adjusted odds ratio, 0.13; 95% confidence interval, .02–.92; P = .04). No difference between treatment groups was observed in areas of high transmission. The 5-month cumulative infection incidence was 70% lower (crude incidence rate ratio, 0.30; 95% confidence interval, .06– 1.49; P = .14) and 58% lower (0.42; .18–.98; P = .046) after MDA compared with control in lower- and higher-transmission areas, respectively. No significant impact of focal MDA was observed for any end point. Conclusions. Two rounds of MDA with DHAp rapidly reduced infection prevalence, infection incidence, and confirmed case incidence rates, especially in low-transmission areas. Clinical Trials Registration. NCT02329301.

Seasonal malaria chemoprevention (SMC) is recommended in the Sahel region of Africa for children under 5 years of age, for up to 4 months of the year. It may be appropriate to include older children, and to provide protection for more than 4 months. We evaluated the effectiveness of SMC using sulfadoxine-pyrimethamine plus amodiaquine given over 5 months to children under 10 years of age in Saraya district in south-east Senegal in 2011. Twenty-four villages, including 2,301 children aged 3-59 months and 2,245 aged 5-9 years, were randomised to receive SMC with community case management (CCM) (SMC villages) or CCM alone (control villages). In all villages, community health workers (CHWs) were trained to treat malaria cases with artemisinin combination therapy after testing with a rapid diagnostic test (RDT). In SMC villages, CHWs administered SMC to children aged 3 months to 9 years once a month for 5 months. The study was conducted from 27 July to 31 December 2011. The primary outcome was malaria (fever or history of fever with a positive RDT). The prevalence of anaemia and parasitaemia was measured in a survey at the end of the transmission season. Molecular markers associated with resistance to SMC drugs were analysed in samples from incident malaria cases and from children with parasitaemia in the survey. SMC was well tolerated with no serious adverse reactions. There were 1,472 RDT-confirmed malaria cases in the control villages and 270 in the SMC villages. Among children under 5 years of age, the rate difference was 110.8/1,000/month (95% CI 64.7, 156.8; p < 0.001) and among children 5-9 years of age, 101.3/1,000/month (95% CI 66.7, 136.0; p < 0.001). The mean haemoglobin concentration at the end of the transmission season was higher in SMC than control villages, by 6.5 g/l (95% CI 2.0, 11; p = 0.007) among children under 5 years of age, and by 5.2 g/l (95% CI 0.4, 9.9; p = 0.035) among children 5-9 years of age. The prevalence of parasitaemia was 18% in children under 5 years of age and 25% in children 5-9 years of age in the control villages, and 5.7% and 5.8%, respectively, in these 2 age groups in the SMC villages, with prevalence differences of 12.5% (95% CI 6.8%, 18.2%; p < 0.001) in children under 5 years of age and 19.3% (95% CI 8.3%, 30.2%; p < 0.001) in children 5-9 years of age. The pfdhps-540E mutation associated with clinical resistance to sulfadoxine-pyrimethamine was found in 0.8% of samples from malaria cases but not in the final survey. Twelve children died in the control group and 14 in the SMC group, a rate difference of 0.096/1,000 child-months (95% CI 0.99, 1.18; p = 0.895). Limitations of this study include that we were not able to obtain blood smears for microscopy for all suspected malaria cases, such that we had to rely on RDTs for confirmation, which may have included false positives. In this study SMC for children under 10 years of age given over 5 months was feasible, well tolerated, and effective in preventing malaria episodes, and reduced the prevalence of parasitaemia and anaemia. SMC with CCM achieved high coverage and ensured children with malaria were promptly treated with artemether-lumefantrine. www.clinicaltrials.gov NCT01449045.

Background. Daily preexposure prophylaxis (PrEP) with oral emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) decreases the risk of human immunodeficiency virus (HIV) acquisition. Initiation of TDF decreases bone mineral density (BMD) in HIV-infected people. We report the effect of FTC/TDF on BMD in HIV-seronegative men who have sex with men and in transgender women. Methods. Dual-energy X-ray absorptiometry was performed at baseline and 24-week intervals in a substudy of iPrEx, a randomized, double-blind, placebo-controlled trial of FTC/TDF PrEP. Plasma and intracellular tenofovir concentrations were measured in participants randomized to FTC/TDF. Results. In 498 participants (247 FTC/TDF, 251 placebo), BMD in those randomized to FTC/TDF decreased modestly but statistically significantly by 24 weeks in the spine (net difference, −0.91% [95% confidence interval {CI}, −1.44% to −.38%]; P = .001) and hip (−0.61% [95% CI, −.96% to −.27%], P = .001). Changes within each subsequent 24-week interval were not statistically significant. Changes in BMD by week 24 correlated inversely with intracellular tenofovir diphosphate (TFV-DP), which was detected in 53% of those randomized to FTC/TDF. Net BMD loss by week 24 in participants with TFV-DP levels indicative of consistent dosing averaged −1.42% ± 29% and −0.85% ± 19% in the spine and hip, respectively (P < .001 vs placebo). Spine BMD tended to rebound following discontinuation of FTC/TDF. There were no differences in fractures (P = .62) or incidence of low BMD. Conclusions. In HIV-uninfected persons, FTC/TDF PrEP was associated with small but statistically significant decreases in BMD by week 24 that inversely correlated with TFV-DP, with more stable BMD thereafter. Clinical Trials Registration. NCT00458393.

Seasonal malaria chemoprevention (SMC) with sulfadoxine–pyrimethamine combined with amodiaquine (SPAQ) effectively protects eligible children from malaria in areas of high and seasonal transmission. However, concerns about parasite resistance to sulfadoxine–pyrimethamine in East and Southern Africa necessitate evaluating alternative drug regimens. This study assessed the effectiveness of SPAQ and dihydroartemisinin–piperaquine for SMC in Uganda. This three-arm, open-label, non-inferiority and superiority, cluster-randomised, controlled trial was conducted in Karamoja subregion, Uganda, among children aged 3–59 months and 6–59 months for SPAQ and dihydroartemisinin–piperaquine, respectively. Of 427 villages, 380 were randomly assigned (1:1) to the SPAQ group and dihydroartemisinin–piperaquine group, and 47 were assigned to the control group (no SMC). The superiority component compared the SPAQ and dihydroartemisinin–piperaquine groups with the control group, whereas the non-inferiority component compared the dihydroartemisinin–piperaquine group with the SPAQ group. The primary endpoint was confirmed malaria incidence using rapid diagnostic tests or microscopy. Survival analyses were done on an intention-to-treat basis (in all randomised participants), with adjustments made for covariate imbalances at baseline. Additionally, molecular markers associated with resistance to sulfadoxine–pyrimethamine and amodiaquine were analysed on 750 malaria-positive blood samples from children younger than 5 years before and after five SMC cycles. This trial was registered with ClinicalTrials.gov, NCT05323721, and has been completed. During June 18–30, 2022, 3881 children were enrolled; 1755 in SPAQ, 1736 in dihydroartemisinin–piperaquine, and 390 in control villages. Of these children, 3629 were analysed. Incidence rates were 0·90 cases per 100 person-months in the SPAQ group, 0·80 cases per 100 person-months in the dihydroartemisinin–piperaquine group, and 18·26 cases per 100 person-months in the control group. SPAQ and dihydroartemisinin–piperaquine reduced malaria risk by 94% (hazard ratio [HR] 0·06 [95% CI 0·04–0·08]; p<0·001) and 96% (0·04 [0·03–0·06]; p<0·001), respectively. Based on the prespecified non-inferiority margin of 1·4, there was non-inferiority between the protective effectiveness of dihydroartemisinin–piperaquine and that of SPAQ (HR 0·90 [95% CI 0·58–1·39]). Prevalence of mutations linked to moderate (Plasmodium falciparum dihydrofolate reductase [PfDHFR] and P falciparum dihydropteroate synthetase reductase [PfDHPS]) and high (PfDHFR Ile164Leu and PfDHPS Ala581Gly) sulfadoxine–pyrimethamine resistance were more than 88% and less than 5%, respectively. Mutations associated with 4-aminoquinolone resistance (P falciparum multidrug resistance protein-1 [PfMDR1] Asp1246Tyr and PfMDR1 Asn86Tyr) were less than 1%. There was no significant increase in the prevalence of antifolate and artemisinin partial resistance-associated mutations, but a decrease was observed for key aminoquinoline resistance-associated alleles: P falciparum chloroquine resistance transporter protein Lys76Thr, P falciparum multidrug resistance protein Asn86Tyr, and PfMDR1 Asp1246Tyr (p<0·001). No serious or fatal adverse events were reported. SPAQ and dihydroartemisinin–piperaquine effectively reduced malaria in children younger than 5 years, with no safety concerns. There was no evidence of resistance selection by SMC. Although these findings support SPAQ-based SMC in Eastern and Southern Africa, ongoing resistance surveillance and efficacy monitoring are essential for sustained impact. GiveWell. For the Swahili translation of the abstract see Supplementary Materials section.

Chronic infections with hepatitis C virus (HCV) and HIV are highly prevalent in the USA and concentrated in people who inject drugs. Treatment as prevention with highly effective new direct-acting antivirals is a prospective HCV elimination strategy. We used network-based modelling to analyse the effect of this strategy in HCV-infected people who inject drugs in a US city. Five graph models were fit using data from 1574 people who inject drugs in Hartford, CT, USA. We used a degree-corrected stochastic block model, based on goodness-of-fit, to model networks of injection drug users. We simulated transmission of HCV and HIV through this network with varying levels of HCV treatment coverage (0%, 3%, 6%, 12%, or 24%) and varying baseline HCV prevalence in people who inject drugs (30%, 60%, 75%, or 85%). We compared the effectiveness of seven treatment-as-prevention strategies on reducing HCV prevalence over 10 years and 20 years versus no treatment. The strategies consisted of treatment assigned to either a randomly chosen individual who injects drugs or to an individual with the highest number of injection partners. Additional strategies explored the effects of treating either none, half, or all of the injection partners of the selected individual, as well as a strategy based on respondent-driven recruitment into treatment. Our model estimates show that at the highest baseline HCV prevalence in people who inject drugs (85%), expansion of treatment coverage does not substantially reduce HCV prevalence for any treatment-as-prevention strategy. However, when baseline HCV prevalence is 60% or lower, treating more than 120 (12%) individuals per 1000 people who inject drugs per year would probably eliminate HCV within 10 years. On average, assigning treatment randomly to individuals who inject drugs is better than targeting individuals with the most injection partners. Treatment-as-prevention strategies that treat additional network members are among the best performing strategies and can enhance less effective strategies that target the degree (ie, the highest number of injection partners) within the network. Successful HCV treatment as prevention should incorporate the baseline HCV prevalence and will achieve the greatest benefit when coverage is sufficiently expanded. National Institute on Drug Abuse.

Available drugs against cytomegalovirus have adverse effects that compromise their prophylactic use in recipients of allogeneic stem-cell transplants. We assessed the safety, tolerability, and antiviral activity of oral maribavir in such patients. In this placebo-controlled, randomised, double-blind, multicentre phase 3 study, we enrolled adult patients recipient-seropositive or donor-seropositive for cytomegalovirus who had undergone allogeneic stem-cell transplantation. Patients were recruited from 90 centres in Canada, Europe, and the USA. After engraftment, patients were stratified by recipient cytomegalovirus serostatus and conditioning regimen (myeloablative or reduced-intensity) and assigned (2:1) by masked computer-generated randomisation sequence to receive maribavir 100 mg twice daily or placebo for up to 12 weeks, with weekly blood cytomegalovirus surveillance. If the virus was detected, administration of study drug was stopped and pre-emptive anticytomegalovirus treatment started. The primary endpoint was cytomegalovirus disease within 6 months of transplantation. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, NCT00411645. Between December, 2006, and May, 2008, 681 patients were enrolled and assigned to receive maribavir (454) or placebo (227). The incidence of cytomegalovirus disease within 6 months was 20 of 454 (4%) for the maribavir group and 11 of 227 (5%) for the placebo group (OR 0·90; 95% CI 0·42–1·92). During the 100 days following transplantation, cytomegalovirus infection rates as measured by pp65 antigenaemia were lower in the maribavir group (26·4%) than in the placebo group (34·8%; OR 0·67; 0·47–0·95), but not when measured by plasma cytomegalovirus DNA PCR (27·8% vs 30·4%; OR 0·88; 0·62–1·25), nor by initiation of treatment against cytomegalovirus (30·6% vs 37·4%; OR 0·73, 0·52–1·03). Maribavir was well tolerated: most adverse events, including incident acute graft-versus-host disease and neutropenia, affected both groups equally, except for taste disturbance (15% maribavir, 6% placebo). Compared with placebo, maribavir prophylaxis did not prevent cytomegalovirus disease when started after engraftment. Cytomegalovirus disease as a primary endpoint might not be sufficient to show improvements in cytomegalovirus prevention in recipients of allogeneic stem-cell transplants in the setting of pre-emptive antiviral treatment. Clinical and virological composite endpoints should be used in future trials. ViroPharma Incorporated.

Malaria-elimination interventions aim to extinguish hotspots and prevent transmission to nearby areas. Here, we re-analyzed a cluster-randomized trial of reactive, focal interventions (chemoprevention using artemether–lumefantrine and/or indoor residual spraying with pirimiphos-methyl) delivered within 500 m of confirmed malaria index cases in Namibia to measure direct effects (among intervention recipients within 500 m) and spillover effects (among non-intervention recipients within 3 km) on incidence, prevalence and seroprevalence. There was no or weak evidence of direct effects, but the sample size of intervention recipients was small, limiting statistical power. There was the strongest evidence of spillover effects of combined chemoprevention and indoor residual spraying. Among non-recipients within 1 km of index cases, the combined intervention reduced malaria incidence by 43% (95% confidence interval, 20–59%). In analyses among non-recipients within 3 km of interventions, the combined intervention reduced infection prevalence by 79% (6–95%) and seroprevalence, which captures recent infections and has higher statistical power, by 34% (20–45%). Accounting for spillover effects increased the cost-effectiveness of the combined intervention by 42%. Targeting hotspots with combined chemoprevention and vector-control interventions can indirectly benefit non-recipients up to 3 km away. In a re-analysis of a cluster-randomized trial on malaria-control measures, the combined intervention reduces infections up to 3 km from the point of intervention, increasing efficacy and cost-effectiveness of the intervention.

Background The use of cardiovascular medication for the primary prevention of cardiovascular disease (CVD) is potentially inappropriate when potential risks outweigh the potential benefits. It is unknown whether deprescribing preventive cardiovascular medication in patients without a strict indication for such medication is safe and cost-effective in general practice. Methods In this pragmatic cluster randomised controlled non-inferiority trial, we recruited 46 general practices in the Netherlands. Patients aged 40–70 years who were using antihypertensive and/or lipid-lowering drugs without CVD and with low risk of future CVD were followed for 2 years. The intervention was an attempt to deprescribe preventive cardiovascular medication. The primary outcome was the difference in the increase in predicted (10-year) CVD risk in the per-protocol (PP) population with a non-inferiority margin of 2.5 percentage points. An economic evaluation was performed in the intention-to-treat (ITT) population. We used multilevel (generalised) linear regression with multiple imputation of missing data. Results Of 1067 participants recruited between 7 November 2012 and 18 February 2014, 72% were female. Overall, their mean age was 55 years and their mean predicted CVD risk at baseline was 5%. Of 492 participants in the ITT intervention group, 319 (65%) quit the medication (PP intervention group); 135 (27%) of those participants were still not taking medication after 2 years. The predicted CVD risk increased by 2.0 percentage points in the PP intervention group compared to 1.9 percentage points in the usual care group. The difference of 0.1 (95% CI -0.3 to 0.6) fell within the non-inferiority margin. After 2 years, compared to the usual care group, for the PP intervention group, systolic blood pressure was 6 mmHg higher, diastolic blood pressure was 4 mmHg higher and total cholesterol and low-density lipoprotein-cholesterol levels were both 7 mg/dl higher (all P  < 0.05). Cost and quality-adjusted life years did not differ between the groups. Conclusions The results of the ECSTATIC study show that an attempt to deprescribe preventive cardiovascular medication in low-CVD-risk patients is safe in the short term when blood pressure and cholesterol levels are monitored after stopping. An attempt to deprescribe medication can be considered, taking patient preferences into consideration. Trial registration This study was registered with Dutch trial register on 20 June 2012 ( NTR3493 ).

In many sub-Saharan African countries, it is recommended that children with sickle cell anaemia receive malaria chemoprevention with monthly sulfadoxine–pyrimethamine or daily proguanil as the standard of care. However, the efficacy of these interventions is compromised by high-grade antifolate resistance of Plasmodium falciparum and poor adherence. We aimed to compare the efficacy of weekly dihydroartemisinin–piperaquine and monthly sulfadoxine–pyrimethamine for the prevention of clinical malaria in children with sickle cell anaemia in areas with high-grade sulfadoxine–pyrimethamine resistance of P falciparum in Uganda and Malawi. We did an individually randomised, parallel group, double-blind, placebo-controlled trial at two hospitals in Uganda and two hospitals in Malawi. Children (aged 6 months to 15 years) with sickle cell anaemia with a bodyweight of at least 5kg were randomly assigned (1:1) by computer-generated block randomisation, stratified by site and weight category, to receive either weekly dihydroartemisinin–piperaquine (approximately 2·5 mg per kg bodyweight dihydroartemisinin and 20 mg per kg bodyweight per day piperaquine) or monthly sulfadoxine–pyrimethamine (approximately 25 mg per kg bodyweight sulfadoxine and 1·25 mg per kg bodyweight). Placebos matching the alternative treatment were used in each treatment group to maintain masking of the different dosing schedules from the participants and caregivers, study staff, investigators, and data analysts. All children younger than 5 years received penicillin twice daily as standard of care. The primary endpoint was the incidence of clinical malaria, defined as a history of fever in the preceding 48 h or documented axillary temperature of 37·5°C or higher plus the detection of P falciparum parasites on microscopy (any parasite density). Secondary efficacy outcomes were any malaria parasitaemia (on either microscopy or malaria rapid diagnostic test), all-cause unscheduled clinic visits, all-cause and malaria-specific hospitalisation, sickle cell anaemia-related events (including vaso-occlusive crises, acute chest syndrome, stroke), need for blood transfusion, and death. All primary and secondary outcomes were assessed in the modified intention-to-treat population, which included all participants who were randomly assigned for whom endpoint data were available. Safety was assessed in in all children who received at least one dose of the study drug. Complete case analysis was conducted using negative-binomial regression. This study was registered with Clinicaltrials.gov, NCT04844099. Between April 17, 2021, and May 30, 2022, 725 participants were randomly assigned; of whom 724 were included in the primary analysis (367 participants in the dihydroartemisinin–piperaquine group and 357 participants in the sulfadoxine–pyrimethamine group). The median follow-up time was 14·7 months (IQR 11·2–18·2). The incidence of clinical malaria was 8·8 cases per 100 person-years in the dihydroartemisinin–piperaquine group and 43.7 events per 100 person-years in the sulfadoxine–pyrimethamine group (incidence rate ratio [IRR] 0·20 [95% CI 0·14–0·30], p<0·0001). The incidence of hospitalisation with any malaria was lower in the dihydroartemisinin–piperaquine group than the sulfadoxine–pyrimethamine group (10·4 vs 37·0 events per 100 person-years; IRR 0·29 [0·20–0·42], p<0·0001) and the number of blood transfusions was also lower in the dihydroartemisinin–piperaquine group than the sulfadoxine–pyrimethamine group (52·1 vs 72·5 events per 100 person-years; IRR 0·70 [0·54–0·90], p=0·006). The incidence of all-cause unscheduled clinic visits and all-cause hospitalisations were similar between the two groups, however, participants in the dihydroartemisinin–piperaquine group had more clinic visits unrelated to malaria (IRR 1·12 [1·00–1·24], p=0·042) and more hospitalisations with lower respiratory tract events (16·5 vs 8·5 events per 100 person-years; IRR 1·99 [1·25–3·16], p=0·0036) than participants in the sulfadoxine–pyrimethamine group. The number of serious adverse events in the dihydroartemisinin–piperaquine group was similar to that in the sulfadoxine–pyrimethamine group (vaso-occlusive crisis [154 of 367 participants dihydroartemisinin–piperaquine group vs 132 of 357 participants in the sulfadoxine–pyrimethamine group] and suspected sepsis [115 participants vs 92 participants]), with the exception of acute chest syndrome or pneumonia (51 participants vs 32 participants). The number of deaths were similar between groups (six [2%] of 367 participants in the dihydroartemisinin–piperaquine group and eight (2%) of 357 participants in the sulfadoxine–pyrimethamine group). Malaria chemoprophylaxis with weekly dihydroartemisinin–piperaquine in children with sickle cell anaemia is safe and considerably more efficacious than monthly sulfadoxine–pyrimethamine. However, monthly sulfadoxine–pyrimethamine was associated with fewer episodes of non-malaria-related illnesses, especially in children 5 years or older not receiving penicillin prophylaxis, which might reflect its antimicrobial effects. In areas with high P falciparum antifolate resistance, dihydroartemisinin–piperaquine should be considered as an alternative to sulfadoxine–pyrimethamine for malaria chemoprevention in children younger than 5 years with sickle cell anaemia receiving penicillin-V prophylaxis. However, there is need for further studies in children older than 5 years. Research Council of Norway and UK Medical Research Council. For the Chichewa, Acholi, Lusoga and Luganda translations of the abstract see Supplementary Materials section.