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The human T-lymphotropic viruses (HTLVs) types 1 and 2 originated independently and are related to distinct lineages of simian T-lymphotropic viruses (STLV-1 and STLV-2, respectively). These facts, along with the finding that HTLV-1 diversity appears to have resulted from multiple cross-species transmissions of STLV-1, suggest that contact between humans and infected nonhuman primates (NHPs) may result in HTLV emergence. We investigated the diversity of HTLV among central Africans reporting contact with NHP blood and body fluids through hunting, butchering, and keeping primate pets. We show that this population is infected with a wide variety of HTLVs, including two previously unknown retroviruses: HTLV-4 is a member of a phylogenetic lineage that is distinct from all known HTLVs and STLVs; HTLV-3 falls within the phylogenetic diversity of STLV-3, a group not previously seen in humans. We also document human infection with multiple STLV-1-like viruses. These results demonstrate greater HTLV diversity than previously recognized and suggest that NHP exposure contributes to HTLV emergence. Our discovery of unique and divergent HTLVs has implications for HTLV diagnosis, blood screening, and potential disease development in infected persons. The findings also indicate that cross-species transmission is not the rate-limiting step in pandemic retrovirus emergence and suggest that it may be possible to predict and prevent disease emergence by surveillance of populations exposed to animal reservoirs and interventions to decrease risk factors, such as primate hunting.

Frequent infection with zoonotic simian foamy virus (SFV) has been reported among HIV-negative primate hunters in rural Cameroon. Plasma samples obtained from urban commercial sex workers (CSWs; n = 139), patients with sexually transmitted diseases (n = 41), and blood donors (n = 179) in the Democratic Republic of Congo [formerly known as Zaire] and Cameroon were tested for SFV and HIV-1 infection. One CSW and one blood donor were found to be seropositive for both SFV and HIV-1, thereby documenting what are, to our knowledge, the first reported cases of dual SFV and HIV infection. The findings of the present study suggest opportunities for bloodborne and sexual transmission of SFV and highlight the importance of defining the clinical consequences of dual infections.

Simple and cost-effective approaches for HIV drug-resistance testing are highly desirable for managing increasingly expanding HIV-1 infected populations who initiate antiretroviral therapy (ART), particularly in resource-limited settings. Non-nucleoside reverse trancriptase inhibitor (NNRTI)-based regimens with an NRTI backbone containing lamivudine (3TC) or emtricitabine (FTC) are preferred first ART regimens. Failure with these drug combinations typically involves the selection of NNRTI- and/or 3TC/FTC-resistant viruses. Therefore, the availability of simple assays to measure both types of drug resistance is critical. We have developed a high throughput screening test for assessing enzymatic resistance of the HIV-1 RT in plasma to 3TC/FTC and NNRTIs. The test uses the sensitive \"Amp-RT\" assay with a newly-developed real-time PCR format to screen biochemically for drug resistance in single reactions containing either 3TC-triphosphate (3TC-TP) or nevirapine (NVP). Assay cut-offs were defined based on testing a large panel of subtype B and non-subtype B clinical samples with known genotypic profiles. Enzymatic 3TC resistance correlated well with the presence of M184I/V, and reduced NVP susceptibility was strongly associated with the presence of K103N, Y181C/I, Y188L, and G190A/Q. The sensitivity and specificity for detecting resistance were 97.0% and 96.0% in samples with M184V, and 97.4% and 96.2% for samples with NNRTI mutations, respectively. We further demonstrate the utility of an HIV capture method in plasma by using magnetic beads coated with CD44 antibody that eliminates the need for ultracentifugation. Thus our results support the use of this simple approach for distinguishing WT from NNRTI- or 3TC/FTC-resistant viruses in clinical samples. This enzymatic testing is subtype-independent and can assist in the clinical management of diverse populations particularly in resource-limited settings.

The human T-lymphotropic viruses (HTLVs) types 1 and 2 originated independently and are related to distinct lineages of simian T-lymphotropic viruses (STLV-1 and STLV-2, respectively). These facts, along with the finding that HTLV-1 diversity appears to have resulted from multiple cross-species transmissions of STLV-1, suggest that contact between humans and infected nonhuman primates (NHPs) may result in HTLV emergence. We investigated the diversity of HTLV among central Africans reporting contact with NHP blood and body fluids through hunting, butchering, and keeping primate pets. We show that this population is infected with a wide variety of HTLVs, including two previously unknown retroviruses: HTLV-4 is a member of a phylogenetic lineage that is distinct from all known HTLVs and STLVs; HTLV-3 falls within the phylogenetic diversity of STLV-3, a group not previously seen in humans. We also document human infection with multiple STLV-1-like viruses. These results demonstrate greater HTLV diversity than previously recognized and suggest that NHP exposure contributes to HTLV emergence. Our discovery of unique and divergent HTLVs has implications for HTLV diagnosis, blood screening, and potential disease development in infected persons. The findings also indicate that cross-species transmission is not the rate-limiting step in pandemic retrovirus emergence and suggest that it may be possible to predict and prevent disease emergence by surveillance of populations exposed to animal reservoirs and interventions to decrease risk factors, such as primate hunting. [PUBLICATION ABSTRACT]

Sunitinib is a tyrosine kinase inhibitor with proven efficacy in renal-cell carcinoma, but some patients do not respond or need dose reductions due to toxicity. Because there are no validated molecular predictors of response or toxicity to sunitinib, we aimed to identify genetic markers predictive of outcome and toxic effects. In our observational, prospective study we enrolled previously untreated adults (≥18 years) with clear-cell renal-cell carcinoma at 15 institutions in the Spanish Oncology Genitourinary Group in Spain. Patients received sunitinib according to local practice guidelines. We assessed RECIST response, progression-free survival (PFS), overall survival, and toxicity of sunitinib with 16 key polymorphisms in nine genes: VEGFR2 (rs2305948 and rs1870377), VEGFR3 (rs307826, rs448012, and rs307821), PDGFR-α (rs35597368), VEGF-A (rs2010963, rs699947, and rs1570360), IL8 (rs1126647), CYP3A4 (rs2740574), CYP3A5 (rs776746), ABCB1 (rs1045642, rs1128503, and rs2032582), and ABCB2 (rs2231142). We assessed associations with efficacy and toxicity by use of univariable and multivariable analyses (with clinical factors associated with outcomes as covariates). We adjusted for multiplicity using the Bonferroni method; p values of less than 0·0031 before adjustment were deemed to still be significant after adjustment. We enrolled 101 patients between Oct 10, 2007, and Dec 13, 2010. 95 of these patients were included in toxicity analyses and 89 in the efficacy analyses. Two VEGFR3 missense polymorphisms were associated with reduced PFS with sunitinib on multivariable analysis: rs307826 (hazard ratio [HR] per allele 3·57, 1·75–7·30; p unadjusted=0·00049, p adjusted=0·0079) and rs307821 (3·31, 1·64–6·68; p unadjusted=0·00085, p adjusted=0·014). The CYP3A5*1 (rs776746) high metabolising allele was associated in a multivariable analysis with an increased risk of dose reductions due to toxicity (HR per allele 3·75, 1·67–8·41; p unadjusted=0·0014, p adjusted=0·022). No other SNPs were associated with sunitinib response or toxicity. Polymorphisms in VEGFR3 and CYP3A5*1 might be able to define a subset of patients with renal-cell carcinoma with decreased sunitinib response and tolerability. If confirmed, these results should promote interventional studies testing alternative therapeutic approaches for patients with such variants. Pfizer.

Most patients with multiple sclerosis without previous optic neuritis have thinner retinal layers than healthy controls. We assessed the role of peripapillary retinal nerve fibre layer (pRNFL) thickness and macular volume in eyes with no history of optic neuritis as a biomarker of disability worsening in a cohort of patients with multiple sclerosis who had at least one eye without optic neuritis available. In this multicentre, cohort study, we collected data about patients (age ≥16 years old) with clinically isolated syndrome, relapsing-remitting multiple sclerosis, and progressive multiple sclerosis. Patients were recruited from centres in Spain, Italy, France, Germany, Czech Republic, Netherlands, Canada, and the USA, with the first cohort starting in 2008 and the latest cohort starting in 2013. We assessed disability worsening using the Expanded Disability Status Scale (EDSS). The pRNFL thickness and macular volume were assessed once at study entry (baseline) by optical coherence tomography (OCT) and was calculated as the mean value of both eyes without optic neuritis for patients without a history of optic neuritis or the value of the non-optic neuritis eye for patients with previous unilateral optic neuritis. Researchers who did the OCT at baseline were masked to EDSS results and the researchers assessing disability with EDSS were masked to OCT results. We estimated the association of pRNFL thickness or macular volume at baseline in eyes without optic neuritis with the risk of subsequent disability worsening by use of proportional hazards models that included OCT metrics and age, disease duration, disability, presence of previous unilateral optic neuritis, and use of disease-modifying therapies as covariates. 879 patients with clinically isolated syndrome (n=74), relapsing-remitting multiple sclerosis (n=664), or progressive multiple sclerosis (n=141) were included in the primary analyses. Disability worsening occurred in 252 (29%) of 879 patients with multiple sclerosis after a median follow-up of 2·0 years (range 0·5–5 years). Patients with a pRNFL of less than or equal to 87 μm or less than or equal to 88 μm (measured with Spectralis or Cirrus OCT devices) had double the risk of disability worsening at any time after the first and up to the third years of follow-up (hazard ratio 2·06, 95% CI 1·36–3·11; p=0·001), and the risk was increased by nearly four times after the third and up to the fifth years of follow-up (3·81, 1·63–8·91; p=0·002). We did not identify meaningful associations for macular volume. Our results provide evidence of the usefulness of monitoring pRNFL thickness by OCT for prediction of the risk of disability worsening with time in patients with multiple sclerosis. Instituto de Salud Carlos III.

Alpha-particle self-heating, the process of deuterium–tritium fusion reaction products depositing their kinetic energy locally within a fusion reaction region and thus increasing the temperature in the reacting region, is essential for achieving ignition in a fusion system. Here, we report new inertial confinement fusion experiments where the alpha-particle heating of the plasma is dominant with the fusion yield produced exceeding the fusion yield from the work done on the fuel (pressure times volume change) by a factor of two or more. These experiments have achieved the highest yield (26 ± 0.5 kJ) and stagnation pressures (≍220 ± 40 Gbar) of any facility-based inertial confinement fusion experiments, although they are still short of the pressures required for ignition on the National Ignition Facility (∼300–400 Gbar). These experiments put us in a new part of parameter space that has not been extensively studied so far because it lies between the no-alpha-particle-deposition regime and ignition. Inertial confinement fusion, based on laser-heating a deuterium–tritium mixture, is one of the approaches towards energy production from fusion reactions. Now, record energy-yield experiments are reported—bringing us closer to ignition conditions.

Sitting on an unstable surface is a common paradigm to investigate trunk postural control among individuals with low back pain (LBP), by minimizing the influence lower extremities on balance control. Outcomes of many small studies are inconsistent (e.g., some find differences between groups while others do not), potentially due to confounding factors such as age, sex, body mass index [BMI], or clinical presentations. We conducted a systematic review with an individual participant data (IPD) meta-analysis to investigate whether trunk postural control differs between those with and without LBP, and whether the difference between groups is impacted by vision and potential confounding factors. We completed this review according to PRISMA-IPD guidelines. The literature was screened (up to 7th September 2023) from five electronic databases: MEDLINE, CINAHL, Embase, Scopus, and Web of Science Core Collection. Outcome measures were extracted that describe unstable seat movements, specifically centre of pressure or seat angle. Our main analyses included: 1) a two-stage IPD meta-analysis to assess the difference between groups and their interaction with age, sex, BMI, and vision on trunk postural control; 2) and a two-stage IPD meta-regression to determine the effects of LBP clinical features (pain intensity, disability, pain catastrophizing, and fear-avoidance beliefs) on trunk postural control. Forty studies (1,821 participants) were included for the descriptive analysis and 24 studies (1,050 participants) were included for the IPD analysis. IPD meta-analyses revealed three main findings: (a) trunk postural control was worse (higher root mean square displacement [RMSdispl], range, and long-term diffusion; lower mean power frequency) among individuals with than without LBP; (b) trunk postural control deteriorated more (higher RMSdispl, short- and long-term diffusion) among individuals with than without LBP when vision was removed; and (c) older age and higher BMI had greater adverse impacts on trunk postural control (higher short-term diffusion; longer time and distance coordinates of the critical point) among individuals with than without LBP. IPD meta-regressions indicated no associations between the limited LBP clinical features that could be considered and trunk postural control. Trunk postural control appears to be inferior among individuals with LBP, which was indicated by increased seat movements and some evidence of trunk stiffening. These findings are likely explained by delayed or less accurate corrective responses. This review has been registered in PROSPERO (registration number: CRD42021124658).

The Sentinel-3 Mission Performance Centre (S3MPC) is tasked by the European Space Agency (ESA) to monitor the health of the Copernicus Sentinel-3 satellites and ensure a high data quality to the users. This paper deals exclusively with the effort devoted to the altimeter and microwave radiometer, both components of the Surface Topography Mission (STM). The altimeters on Sentinel-3A and -3B are the first to operate in delay-Doppler or SAR mode over all Earth surfaces, which enables better spatial resolution of the signal in the along-track direction and improved noise reduction through multi-looking, whilst the radiometer is a two-channel nadir-viewing system. There are regular routine assessments of the instruments through investigation of telemetered housekeeping data, calibrations over selected sites and comparisons of geophysical retrievals with models, in situ data and other satellite systems. These are performed both to monitor the daily production, assessing the uncertainties and errors on the estimates, and also to characterize the long-term performance for climate science applications. This is critical because an undetected drift in performance could be misconstrued as a climate variation. As the data are used by the Copernicus Services (e.g., CMEMS, Global Land Monitoring Services) and by the research community over open ocean, coastal waters, sea ice, land ice, rivers and lakes, the validation activities encompass all these domains, with regular reports openly available. The S3MPC is also in charge of preparing improvements to the processing, and of the development and tuning of algorithms to improve their accuracy. This paper is thus the first refereed publication to bring together the analysis of SAR altimetry across all these different domains to highlight the benefits and existing challenges.

One of the major determinants of exercise intolerance and limiting symptoms among patients with obstructive hypertrophic cardiomyopathy (HCM) is an elevated intracardiac pressure resulting from left ventricular outflow tract obstruction. Aficamten is an oral selective cardiac myosin inhibitor that reduces left ventricular outflow tract gradients by mitigating cardiac hypercontractility. In this phase 3, double-blind trial, we randomly assigned adults with symptomatic obstructive HCM to receive aficamten (starting dose, 5 mg; maximum dose, 20 mg) or placebo for 24 weeks, with dose adjustment based on echocardiography results. The primary end point was the change from baseline to week 24 in the peak oxygen uptake as assessed by cardiopulmonary exercise testing. The 10 prespecified secondary end points (tested hierarchically) were change in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS), improvement in the New York Heart Association (NYHA) functional class, change in the pressure gradient after the Valsalva maneuver, occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver, and duration of eligibility for septal reduction therapy (all assessed at week 24); change in the KCCQ-CSS, improvement in the NYHA functional class, change in the pressure gradient after the Valsalva maneuver, and occurrence of a gradient of less than 30 mm Hg after the Valsalva maneuver (all assessed at week 12); and change in the total workload as assessed by cardiopulmonary exercise testing at week 24. A total of 282 patients underwent randomization: 142 to the aficamten group and 140 to the placebo group. The mean age was 59.1 years, 59.2% were men, the baseline mean resting left ventricular outflow tract gradient was 55.1 mm Hg, and the baseline mean left ventricular ejection fraction was 74.8%. At 24 weeks, the mean change in the peak oxygen uptake was 1.8 ml per kilogram per minute (95% confidence interval [CI], 1.2 to 2.3) in the aficamten group and 0.0 ml per kilogram per minute (95% CI, -0.5 to 0.5) in the placebo group (least-squares mean between-group difference, 1.7 ml per kilogram per minute; 95% CI, 1.0 to 2.4; P<0.001). The results for all 10 secondary end points were significantly improved with aficamten as compared with placebo. The incidence of adverse events appeared to be similar in the two groups. Among patients with symptomatic obstructive HCM, treatment with aficamten resulted in a significantly greater improvement in peak oxygen uptake than placebo. (Funded by Cytokinetics; SEQUOIA-HCM ClinicalTrials.gov number, NCT05186818.).