Parasitic diseases of the central nervous system: lessons for clinicians and policy makers

Parasitic diseases of the central nervous system are associated with high mortality and morbidity, especially in resource-limited settings. The burden of these diseases is amplified as survivors are often left with neurologic sequelae affecting mobility, sensory organs, and cognitive functions, as well as seizures/epilepsy. These diseases inflict suffering by causing lifelong disabilities, reducing economic productivity, and causing social stigma. The complexity of parasitic life cycles and geographic specificities, as well as overlapping clinical manifestations in the host reflecting the diverse pathogenesis of parasites, can present diagnostic challenges. We herein provide an overview of these parasitic diseases and summarize clinical aspects, diagnosis, therapeutic strategies and recent milestones, and aspects related to prevention and control

Offering Self-administered Oral HIV Testing as a Choice to Truck Drivers in Kenya: Predictors of Uptake and Need for Guidance While Self-testing

We assessed predictors of choosing self-administered oral HIV testing in the clinic with supervision versus the standard provider-administered blood test when offered the choice among 149 Kenyan truck drivers, described the types of guidance participants needed during self-testing and predictors of needing guidance. Overall, 56.38% of participants chose the self-test, 23.49% the provider-administered test, and 20.13% refused testing. In the adjusted regression models, each additional unit on the fatalism and self-efficacy scales was associated with 0.97 (p = 0.003) and 0.83 (p = 0.008) times lower odds of choosing the self-test, respectively. Overall, 52.38% of self-testers did so correctly without questions, 47.61% asked questions, and 13.10% required unsolicited correction from the provider. Each additional unit on the fatalism scale was associated with 1.07 times higher odds of asking for guidance when self-testing (p\0.001). Self-administered oral HIV testing seems to be acceptable and feasible among Kenyan truck drivers, especially if given the opportunity to ask questions

Evaluating effect modification by HIV testing history to understand the mechanisms behind the impact of announcing HIV self-testing availability in a clinic system in Kenya

BackgroundIn sub-Saharan Africa, truckers and female sex workers (FSWs) have high HIV risk and face challenges accessing HIV testing. Adding HIV self-testing (HIVST) to standard of care (SOC) programs increases testing rates. However, the underlying mechanisms are not fully understood. HIVST may decrease barriers (inconvenient clinic hours, confidentiality concerns) and thus we would expect a greater impact among those not accessing SOC testing (barriers prevented previous testing). As a new biomedical technology, HIVST may also be a cue to action (the novelty of a new product motivates people to try it), in which case we might expect the impact to be similar by testing history.MethodsWe used data from two randomized controlled trials evaluating the announcement of HIVST availability via text-message to male truckers (n = 2,260) and FSWs (n = 2,196) in Kenya. Log binomial regression was used to estimate the risk ratio (RR) for testing ≤ 2 months post-announcement in the intervention vs. SOC overall and by having tested in the previous 12-months (12m-tested); and we assessed interaction between the intervention and 12m-tested. We also estimated risk differences (RD) per 100 and tested additive interaction using linear binomial regression.ResultsWe found no evidence that 12m-tested modified the HIVST impact. Among truckers, those in the intervention were 3.1 times more likely to test than the SOC (p < 0.001). Although testing was slightly higher among those not 12m-tested (RR = 3.5, p = 0.001 vs. RR = 2.7, p = 0.020), the interaction was not significant (p = 0.683). Among FSWs, results were similar (unstratified RR = 2.6, p < 0.001; 12m-tested: RR = 2.7, p < 0.001; not 12m-tested: RR = 2.5, p < 0.001; interaction p = 0.795). We also did not find significant interaction on the additive scale (truckers: unstratified RD = 2.8, p < 0.001; 12m-tested RD = 3.8, p = 0.037; not 12m-tested RD = 2.5, p = 0.003; interaction p = 0.496. FSWs: unstratified RD = 9.7, p < 0.001; 12m-tested RD = 10.7, p < 0.001, not 12m-tested RD = 9.1, p < 0.001; interaction p = 0.615).ConclusionThe impact of HIVST was not significantly modified by 12m-tested among truckers and FSWs on the multiplicative or additive scales. Announcing the availability of HIVST likely served primarily as a cue to action and testing clinics might maximize the HIVST benefits by holding periodic HIVST events to maintain the cue to action impact rather than making HIVST continually available

Costing analysis of an SMS-based intervention to promote HIV self-testing amongst truckers and sex workers in Kenya

Objective HIV testing rates in many sub-Saharan African countries have remained suboptimal, and there is an urgent need to explore strategic yet cost-effective approaches to increase the uptake of HIV testing, especially among high-risk populations. Methods A costing analysis was conducted for a randomized controlled trial (RCT) with male truckers and female sex workers (FSWs) registered in the electronic health record system (EHRS) of the North Star Alliance, which offers healthcare services at major transit hubs in Southern and East Africa. The RCT selected a sample of truckers and FSWs who were irregular HIV testers, according to the EHRS, and evaluated the effect of SMSs promoting the availability of HIV self-testing (HIVST) kits in Kenyan clinics (intervention program) versus a general SMS reminding clients to test for HIV (enhanced and standard program) on HIV testing rates. In this paper, we calculated costs from a provider perspective using a mixed-methods approach to identify, measure, and value the resources utilized within the intervention and standard programs. The results of the analysis reflect the cost per client tested. Results The cost of offering HIVST was calculated to be double that of routine facility-based testing (USD 10.13 versus USD 5.01 per client tested), primarily due to the high price of the self-test kit. In the two study arms that only offered provider-administered HIV testing in the clinic, only 1% of truckers and 6% of FSWs tested during the study period, while in the intervention arm, which also offered HST, approximately 4% of truckers and 11% of FSWs tested. These lower than expected outcomes resulted in relatively high cost per client estimates for all three study arms. Within the intervention arm, 65% of truckers and 72% of FSWs who tested chose the HIVST option. However, within the intervention arm, the cost per additional client tested was lower for FSWs than for truckers, at USD 0.15 per additional client tested versus USD 0.58 per additional client tested, driven primarily by the higher response rates. Conclusion Whilst the availability of HIVST increased HIV testing among both truckers and FSWs, the cost of providing HIVST is higher than that of a routine health facility-based test, driven primarily by the price of the HIV self-test kit. Future research needs to identify strategies which increase demand for HIVST, and determine whether these strategies and the subsequent increased demand for HIVST are cost-effective in relation to the conventional facility based testing currently available

The impact on HIV testing over 6 months when free oral HIV self-test kits were available to truck drivers in Kenya: a randomized controlled trial.

HEARD, 2021.Background: Studies suggest that offering HIV self-testing (HIVST) increases short-term HIV testing rates, but few have looked at long-term outcomes. Methods: We conducted a randomized controlled trial (RIDIE 55847d64a454f) on the impact of offering free oral HIVST to 305 truck drivers recruited from two clinics in Kenya. We previously reported that those offered HIVST were more likely to accept testing. Here we report on the 6-month follow-up during which intervention participants could pick-up HIVST kits from eight clinics. Results: There was no difference in HIV testing during 6-month follow-up between participants in the intervention and the standard of care (SOC) arms (OR = 1.0, p = 0.877). The most common reasons given for not testing were lack of time (69.6%), low risk (27.2%), fear of knowing HIV status (20.8%), and had tested recently (8.0%). The null association was not modified by having tested at baseline (interaction p = 0.613), baseline risk behaviors (number of partners in past 6 months, interaction p = 0.881, had transactional sex in past 6 months, interaction p = 0.599), nor having spent at least half of the past 30 nights away from home for work (interaction p = 0.304). Most participants indicated a preference for the characteristics associated with the SOC [preference for blood-based tests (69.4%), provider-administered testing (74.6%) testing in a clinic (70.1%)]. However, those in the intervention arm were more likely to prefer an oral swab test than those in the SOC (36.6 vs. 24.6%, p = 0.029). Conclusions: Offering HIVST kits to truck drivers through a clinic network had little impact on testing rates over the 6-month follow-up when participants had to return to the clinic to access HIVST. Clinic-based distribution of HIVST kits may not address some major barriers to testing, such as lack of time to go to a clinic, fear of knowing one’s status and low risk perception. Preferred HIV testing attributes were consistent with the SOC for most participants, but oral swab preference was higher among those in the intervention arm, who had seen the oral HIVST and had the opportunity to try it. This suggests that preferences may change with exposure to different testing modalities

Real-world use and outcomes of dolutegravir-containing antiretroviral therapy in HIV and tuberculosis co-infection: a site survey and cohort study in sub-Saharan Africa.

INTRODUCTION Dolutegravir is being scaled up globally as part of antiretroviral therapy (ART), but for people with HIV and tuberculosis co-infection, its use is complicated by a drug-drug interaction with rifampicin requiring an additional daily dose of dolutegravir. This represents a disadvantage over efavirenz, which does not have a major drug-drug interaction with rifampicin. We sought to describe HIV clinic practices for prescribing concomitant dolutegravir and rifampicin, and characterize virologic outcomes among patients with tuberculosis co-infection receiving dolutegravir or efavirenz. METHODS Within the four sub-Saharan Africa regions of the International epidemiology Databases to Evaluate AIDS consortium, we conducted a site survey (2021) and a cohort study (2015-2021). The cohort study used routine clinical data and included patients newly initiating or already receiving dolutegravir or efavirenz at the time of tuberculosis diagnosis. Patients were followed from tuberculosis diagnosis until viral suppression (<1000 copies/ml), a competing event (switching ART regimen; loss to program/death) or administrative censoring at 12 months. RESULTS In the survey, 86 of 90 (96%) HIV clinics in 18 countries reported prescribing dolutegravir to patients who were receiving rifampicin as part of tuberculosis treatment, with 77 (90%) reporting that they use twice-daily dosing of dolutegravir, of which 74 (96%) reported having 50 mg tablets available to accommodate twice-daily dosing. The cohort study included 3563 patients in 11 countries, with 67% newly or recently initiating ART. Among patients receiving dolutegravir (n = 465), the cumulative incidence of viral suppression was 58.9% (95% confidence interval [CI]: 54.3-63.3%), switching ART regimen was 4.1% (95% CI: 2.6-6.2%) and loss to program/death was 23.4% (95% CI: 19.7-27.4%). Patients receiving dolutegravir had improved viral suppression compared with patients receiving efavirenz who had a tuberculosis diagnosis before site dolutegravir availability (adjusted subdistribution hazard ratio [aSHR]: 1.47, 95% CI: 1.28-1.68) and after site dolutegravir availability (aSHR 1.28, 95% CI: 1.08-1.51). CONCLUSIONS At a programmatic level, dolutegravir was being widely prescribed in sub-Saharan Africa for people with HIV and tuberculosis co-infection with a dose adjustment for the drug-drug interaction with rifampicin. Despite this more complex regimen, our cohort study revealed that dolutegravir did not negatively impact viral suppression

Varespladib and cardiovascular events in patients with an acute coronary syndrome: the VISTA-16 randomized clinical trial

IMPORTANCE: Secretory phospholipase A2(sPLA2) generates bioactive phospholipid products implicated in atherosclerosis. The sPLA2inhibitor varespladib has favorable effects on lipid and inflammatory markers; however, its effect on cardiovascular outcomes is unknown. OBJECTIVE: To determine the effects of sPLA2inhibition with varespladib on cardiovascular outcomes. DESIGN, SETTING, AND PARTICIPANTS: A double-blind, randomized, multicenter trial at 362 academic and community hospitals in Europe, Australia, New Zealand, India, and North America of 5145 patients randomized within 96 hours of presentation of an acute coronary syndrome (ACS) to either varespladib (n = 2572) or placebo (n = 2573) with enrollment between June 1, 2010, and March 7, 2012 (study termination on March 9, 2012). INTERVENTIONS: Participants were randomized to receive varespladib (500 mg) or placebo daily for 16 weeks, in addition to atorvastatin and other established therapies. MAIN OUTCOMES AND MEASURES: The primary efficacy measurewas a composite of cardiovascular mortality, nonfatal myocardial infarction (MI), nonfatal stroke, or unstable angina with evidence of ischemia requiring hospitalization at 16 weeks. Six-month survival status was also evaluated. RESULTS: At a prespecified interim analysis, including 212 primary end point events, the independent data and safety monitoring board recommended termination of the trial for futility and possible harm. The primary end point occurred in 136 patients (6.1%) treated with varespladib compared with 109 patients (5.1%) treated with placebo (hazard ratio [HR], 1.25; 95%CI, 0.97-1.61; log-rank P = .08). Varespladib was associated with a greater risk of MI (78 [3.4%] vs 47 [2.2%]; HR, 1.66; 95%CI, 1.16-2.39; log-rank P = .005). The composite secondary end point of cardiovascular mortality, MI, and stroke was observed in 107 patients (4.6%) in the varespladib group and 79 patients (3.8%) in the placebo group (HR, 1.36; 95% CI, 1.02-1.82; P = .04). CONCLUSIONS AND RELEVANCE: In patients with recent ACS, varespladib did not reduce the risk of recurrent cardiovascular events and significantly increased the risk of MI. The sPLA2inhibition with varespladib may be harmful and is not a useful strategy to reduce adverse cardiovascular outcomes after ACS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01130246. Copyright 2014 American Medical Association. All rights reserved

Phagocytosis is the main CR3-mediated function affected by the lupus-associated variant of CD11b in human myeloid cells.

The CD11b/CD18 integrin (complement receptor 3, CR3) is a surface receptor on monocytes, neutrophils, macrophages and dendritic cells that plays a crucial role in several immunological processes including leukocyte extravasation and phagocytosis. The minor allele of a non-synonymous CR3 polymorphism (rs1143679, conversation of arginine to histidine at position 77: R77H) represents one of the strongest genetic risk factor in human systemic lupus erythematosus, with heterozygosity (77R/H) being the most common disease associated genotype. Homozygosity for the 77H allele has been reported to reduce adhesion and phagocytosis in human monocytes and monocyte-derived macrophages, respectively, without affecting surface expression of CD11b. Herein we comprehensively assessed the influence of R77H on different CR3-mediated activities in monocytes, neutrophils, macrophages and dendritic cells. R77H did not alter surface expression of CD11b including its active form in any of these cell types. Using two different iC3b-coated targets we found that the uptake by heterozygous 77R/H macrophages, monocytes and neutrophils was significantly reduced compared to 77R/R cells. Allele-specific transduced immortalized macrophage cell lines demonstrated that the minor allele, 77H, was responsible for the impaired phagocytosis. R77H did not affect neutrophil adhesion, neutrophil transmigration in vivo or Toll-like receptor 7/8-mediated cytokine release by monocytes or dendritic cells with or without CR3 pre-engagement by iC3b-coated targets. Our findings demonstrate that the reduction in CR3-mediated phagocytosis associated with the 77H CD11b variant is not macrophage-restricted but demonstrable in other CR3-expressing professional phagocytic cells. The association between 77H and susceptibility to systemic lupus erythematosus most likely relates to impaired waste disposal, a key component of lupus pathogenesis

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure