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Background/objectivesHigh salt intake has been linked to several diseases including obesity and an increased risk of death; however, fecal salinity and the ability of salt to alter the gut microbiota, which was recently identified as an instrumental factor for health and disease, remains poorly explored.Methods/subjectsWe analyzed the fecal samples of 1326 human individuals for salinity by refractometry, 572 for gut microbiota by culturomics, and 164 by 16S rRNA-targeted metagenomics. Geographical origin, age, gender, and obesity were tested as predictors of fecal salinity and halophilic diversity. All halophilic isolates were characterized by taxonogenomics and their genome sequenced.ResultsFecal salinity was associated with obesity independently of geographical origin, gender, and age. The first 2 human-associated halophilic archaeal members were isolated along with 64 distinct halophilic species, including 21 new species and 41 known in the environment but not in humans. No halophiles grow in less than 1.5% salinity. Above this threshold, the richness of the halophilic microbiota was correlated with fecal salinity (r = 0.58, p < 0.0001). 16S metagenomics linked high fecal salinity to decreased diversity (linear regression, p < .035) and a depletion in anti-obesity Akkermansia muciniphila and Bifidobacterium, specifically B. longum and B. adolescentis. Genomics analysis suggested that halophilic microbes are not only transient passengers but may be residents of the human gut.ConclusionsHigh salt levels are associated with alteration of the gut microbial ecosystem and halophilic microbiota, as discovered during this study. Further studies should clarify if the gut microbiota alterations associated with high salt levels and the human halophilic microbiota could be causally related to human disease, such as obesity.

Background/objectivesHigh salt intake has been linked to several diseases including obesity and an increased risk of death; however, fecal salinity and the ability of salt to alter the gut microbiota, which was recently identified as an instrumental factor for health and disease, remains poorly explored.Methods/subjectsWe analyzed the fecal samples of 1326 human individuals for salinity by refractometry, 572 for gut microbiota by culturomics, and 164 by 16S rRNA-targeted metagenomics. Geographical origin, age, gender, and obesity were tested as predictors of fecal salinity and halophilic diversity. All halophilic isolates were characterized by taxonogenomics and their genome sequenced.ResultsFecal salinity was associated with obesity independently of geographical origin, gender, and age. The first 2 human-associated halophilic archaeal members were isolated along with 64 distinct halophilic species, including 21 new species and 41 known in the environment but not in humans. No halophiles grow in less than 1.5% salinity. Above this threshold, the richness of the halophilic microbiota was correlated with fecal salinity (r = 0.58, p < 0.0001). 16S metagenomics linked high fecal salinity to decreased diversity (linear regression, p < .035) and a depletion in anti-obesity Akkermansia muciniphila and Bifidobacterium, specifically B. longum and B. adolescentis. Genomics analysis suggested that halophilic microbes are not only transient passengers but may be residents of the human gut.ConclusionsHigh salt levels are associated with alteration of the gut microbial ecosystem and halophilic microbiota, as discovered during this study. Further studies should clarify if the gut microbiota alterations associated with high salt levels and the human halophilic microbiota could be causally related to human disease, such as obesity.

Many communities in low- and middle-income countries globally lack sustainable, cost-effective and mutually beneficial solutions for infectious disease, food, water and poverty challenges, despite their inherent interdependence 1 – 7 . Here we provide support for the hypothesis that agricultural development and fertilizer use in West Africa increase the burden of the parasitic disease schistosomiasis by fuelling the growth of submerged aquatic vegetation that chokes out water access points and serves as habitat for freshwater snails that transmit Schistosoma parasites to more than 200 million people globally 8 – 10 . In a cluster randomized controlled trial (ClinicalTrials.gov: NCT03187366) in which we removed invasive submerged vegetation from water points at 8 of 16 villages (that is, clusters), control sites had 1.46 times higher intestinal Schistosoma infection rates in schoolchildren and lower open water access than removal sites. Vegetation removal did not have any detectable long-term adverse effects on local water quality or freshwater biodiversity. In feeding trials, the removed vegetation was as effective as traditional livestock feed but 41 to 179 times cheaper and converting the vegetation to compost provided private crop production and total (public health plus crop production benefits) benefit-to-cost ratios as high as 4.0 and 8.8, respectively. Thus, the approach yielded an economic incentive—with important public health co-benefits—to maintain cleared waterways and return nutrients captured in aquatic plants back to agriculture with promise of breaking poverty–disease traps. To facilitate targeting and scaling of the intervention, we lay the foundation for using remote sensing technology to detect snail habitats. By offering a rare, profitable, win–win approach to addressing food and water access, poverty alleviation, infectious disease control and environmental sustainability, we hope to inspire the interdisciplinary search for planetary health solutions 11 to the many and formidable, co-dependent global grand challenges of the twenty-first century. By harvesting aquatic vegetation that provides habitat for snails that harbour  Schistosoma parasites and converting it to compost and animal feed, a trial reduced schistosomiasis prevalence in children while providing wider economic benefits.

In 2005, the Government of Senegal embarked on a campaign to eliminate a Glossina palpalis gambiensis population from the Niayes area (∼ 1000 km(2)) under the umbrella of the Pan African Tsetse and Trypanosomosis Eradication Campaign (PATTEC). The project was considered an ecologically sound approach to intensify cattle production. The elimination strategy includes a suppression phase using insecticide impregnated targets and cattle, and an elimination phase using the sterile insect technique, necessary to eliminate tsetse in this area. Three main cattle farming systems were identified: a traditional system using trypanotolerant cattle and two \"improved\" systems using more productive cattle breeds focusing on milk and meat production. In improved farming systems herd size was 45% lower and annual cattle sales were €250 (s.d. 513) per head as compared to €74 (s.d. 38) per head in traditional farming systems (p<10-3). Tsetse distribution significantly impacted the occurrence of these farming systems (p = 0.001), with 34% (s.d. 4%) and 6% (s.d. 4%) of improved systems in the tsetse-free and tsetse-infested areas, respectively. We calculated the potential increases of cattle sales as a result of tsetse elimination considering two scenarios, i.e. a conservative scenario with a 2% annual replacement rate from traditional to improved systems after elimination, and a more realistic scenario with an increased replacement rate of 10% five years after elimination. The final annual increase of cattle sales was estimated at ∼ €2800/km(2) for a total cost of the elimination campaign reaching ∼ €6400/km(2). Despite its high cost, the benefit-cost analysis indicated that the project was highly cost-effective, with Internal Rates of Return (IRR) of 9.8% and 19.1% and payback periods of 18 and 13 years for the two scenarios, respectively. In addition to an increase in farmers' income, the benefits of tsetse elimination include a reduction of grazing pressure on the ecosystems.

Background The cardiovascular (CV) safety of linagliptin was evaluated in subjects with type 2 diabetes (T2DM). Methods Pre-specified patient-level pooled analysis of all available double-blind, randomized, controlled trials, ≥12 weeks’ duration (19 trials, 9459 subjects) of linagliptin versus placebo/active treatment. Primary end point: composite of prospectively adjudicated CV death, non-fatal myocardial infarction, non-fatal stroke, and hospitalization for unstable angina (4P-MACE). Hospitalization for congestive heart failure (CHF) was also evaluated; adjudication of CHF was introduced during the phase 3 program (8 trials; 3314 subjects). 4P-MACE was assessed in placebo-controlled trials (subgroup of 18 trials; 7746 subjects). Investigator-reported events suggestive of CHF from 24 placebo-controlled trials (including trials <12 weeks’ duration, 8778 subjects) were also analyzed. Results 5847 patients received linagliptin (5 mg: 5687, 10 mg: 160) and 3612 comparator (glimepiride: 775, voglibose: 162, placebo: 2675); cumulative exposure, 4421.3 and 3254.7 patient-years, respectively. 4P-MACE incidence rates: 13.4 per 1000 patient-years, linagliptin (60 events), 18.9, total comparators (62 events); overall hazard ratio (HR), 0.78 (95% confidence interval [CI], 0.55–1.12). HR for adjudicated hospitalization for CHF (n = 21): 1.04 (0.43–2.47). For placebo-controlled trials, 4P-MACE incidence rates: 14.9 per 1000 patient-years, linagliptin (43 events), 16.4, total comparators (29 events); overall HR, 1.09 (95% CI, 0.68–1.75). Occurrence of investigator-reported events suggestive of CHF was low for linagliptin- (26 events, 0.5%; serious: 16 events, 0.3%) and placebo-treated (8 events, 0.2%; serious: 6 events, 0.2%) patients. Conclusions Linagliptin is not associated with increased CV risk versus pooled active comparators or placebo in patients with T2DM.

According to the CPT theorem, which states that the combined operation of charge conjugation, parity transformation and time reversal must be conserved, particles and their antiparticles should have the same mass and lifetime but opposite charge and magnetic moment. Here, we test CPT symmetry in a nucleus containing a strange quark, more specifically in the hypertriton. This hypernucleus is the lightest one yet discovered and consists of a proton, a neutron and a Λ hyperon. With data recorded by the STAR detector 1 – 3 at the Relativistic Heavy Ion Collider, we measure the Λ hyperon binding energy B Λ for the hypertriton, and find that it differs from the widely used value 4 and from predictions 5 – 8 , where the hypertriton is treated as a weakly bound system. Our results place stringent constraints on the hyperon–nucleon interaction 9 , 10 and have implications for understanding neutron star interiors, where strange matter may be present 11 . A precise comparison of the masses of the hypertriton and the antihypertriton allows us to test CPT symmetry in a nucleus with strangeness, and we observe no deviation from the expected exact symmetry. The STAR collaboration reports a measurement of the mass difference and binding energy of the hypertriton and its antiparticle. This work constrains the hyperon–nucleon interaction and allows us to test the CPT theorem in a nucleus with strangeness.

About 10 μs after the Big Bang, the universe was filled—in addition to photons and leptons—with strong-interaction matter consisting of quarks and gluons, which transitioned to hadrons at temperatures close to kT = 150 MeV and densities several times higher than those found in nuclei. This quantum chromodynamics (QCD) matter can be created in the laboratory as a transient state by colliding heavy ions at relativistic energies. The different phases in which QCD matter may exist depend for example on temperature, pressure or baryochemical potential, and can be probed by studying the emission of electromagnetic radiation. Electron–positron pairs emerge from the decay of virtual photons, which immediately decouple from the strong interaction, and thus provide information about the properties of QCD matter at various stages. Here, we report the observation of virtual photon emission from baryon-rich QCD matter. The spectral distribution of the electron–positron pairs is nearly exponential, providing evidence for a source of temperature in excess of 70 MeV with constituents whose properties have been modified, thus reflecting peculiarities of strong-interaction QCD matter. Its bulk properties are similar to the dense matter formed in the final state of a neutron star merger, as apparent from recent multimessenger observation.

Apical membrane antigen 1 from Plasmodium is a leading malaria vaccine candidate. The protein is essential for host-cell invasion, but its molecular function is unknown. The crystal structure of the three domains comprising the ectoplasmic region of the antigen from P. vivax, solved at 1.8 angstrom resolution, shows that domains I and II belong to the PAN motif, which defines a superfamily of protein folds implicated in receptor binding. We also mapped the epitope of an invasion-inhibitory monoclonal antibody specific for the P. falciparum ortholog and modeled this to the structure. The location of the epitope and current knowledge on structure-function correlations for PAN domains together suggest a receptor-binding role during invasion in which domain II plays a critical part. These results are likely to aid vaccine and drug design.

ObjectivesBiologics treatment with antitumour necrosis factor alpha (TNFα) is efficacious in patients with juvenile idiopathic arthritis (JIA). Despite displaying clinical inactivity during treatment, many patients will flare on cessation of therapy. The inability to definitively discriminate patients who will relapse or continue to remain in remission after therapy withdrawal is currently a major unmet medical need. CD4 T cells have been implicated in active disease, yet how they contribute to disease persistence despite treatment is unknown.MethodsWe interrogated the circulatory reservoir of CD4+ immune subsets at the single-cell resolution with mass cytometry (cytometry by time of flight) of patients with JIA (n=20) who displayed continuous clinical inactivity for at least 6 months with anti-TNFα and were subsequently withdrawn from therapy for 8 months, and scored as relapse or remission. These patients were examined prior to therapy withdrawal for putative subsets that could discriminate relapse from remission. We verified on a separate JIA cohort (n=16) the dysregulation of these circulatory subsets 8 months into therapy withdrawal. The immunological transcriptomic signature of CD4 memory in relapse/remission patients was examined with NanoString.ResultsAn inflammatory memory subset of CD3+CD4+CD45RA−TNFα+ T cells deficient in immune checkpoints (PD1−CD152−) was present in relapse patients prior to therapy withdrawal. Transcriptomic profiling reveals divergence between relapse and remission patients in disease-centric pathways involving (1) T-cell receptor activation, (2) apoptosis, (3) TNFα, (4) nuclear factor-kappa B and (5) mitogen-activated protein kinase signalling.ConclusionsA unique discriminatory immunomic and transcriptomic signature is associated with relapse patients and may explain how relapse occurs.