Tectonic settings influence the geochemical and microbial diversity of Peru hot springs.

Tectonic processes control hot spring temperature and geochemistry, yet how this in turn shapes microbial community composition is poorly understood. Here, we present geochemical and 16 S rRNA gene sequencing data from 14 hot springs from contrasting styles of subduction along a convergent margin in the Peruvian Andes. We find that tectonic influence on hot spring temperature and geochemistry shapes microbial community composition. Hot springs in the flat-slab and back-arc regions of the subduction system had similar pH but differed in geochemistry and microbiology, with significant relationships between microbial community composition, geochemistry, and geologic setting. Flat-slab hot springs were chemically heterogeneous, had modest surface temperatures (up to 45 °C), and were dominated by members of the metabolically diverse phylum Proteobacteria. Whereas, back-arc hot springs were geochemically more homogenous, exhibited high concentrations of dissolved metals and gases, had higher surface temperatures (up to 81 °C), and host thermophilic archaeal and bacterial lineages.

Comparison of Radiation With or Without Concurrent Trastuzumab for HER2-Positive Ductal Carcinoma In Situ Resected by Lumpectomy: A Phase III Clinical Trial.

PURPOSE: Preclinical studies report that trastuzumab (T) can boost radiotherapy (RT) effectiveness. The primary aim of the B-43 trial was to assess the efficacy of RT alone vs concurrent RT plus T in preventing recurrence of ipsilateral breast cancer (IBTR) in women with ductal carcinoma in situ (DCIS). PATIENTS AND METHODS: Eligibility: Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, DCIS resected by lumpectomy, known estrogen receptor (ER) and/or progesterone receptor (PgR), and human epidermal growth factor receptor 2 (HER2) status by centralized testing. Whole-breast RT was given concurrently with T. Stratification was by menopausal status, adjuvant endocrine therapy plan, and nuclear grade. Definitive intent-to-treat primary analysis was to be conducted when either 163 IBTR events occurred or all accrued patients were on study ≥ 5 years. RESULTS: There were 2,014 participants who were randomly assigned. Median follow-up time as of December 31, 2019, was 79.2 months. At primary definitive analysis, 114 IBTR events occurred: RT arm, 63 and RT plus T arm, 51 (hazard ratio [HR], 0.81; 95% CI, 0.56 to 1.17; P value = .26). There were 34 who were invasive: RT arm, 18 and RT plus T arm, 20 (HR, 1.11; 95% CI, 0.59 to 2.10; P value = .71). Seventy-six were DCIS: RT arm, 45 and RT plus T arm, 31 (HR, 0.68; 95% CI, 0.43 to 1.08; P value = .11). Annual IBTR event rates were: RT arm, 0.99%/y and RT plus T arm, 0.79%/y. The study did not reach the 163 protocol-specified events, so the definitive analysis was triggered by all patients having been on study for ≥ 5 years. CONCLUSION: Addition of T to RT did not achieve the objective of 36% reduction in IBTR rate but did achieve a modest but statistically nonsignificant reduction of 19%. Nonetheless, this trial had negative results. Further exploration of RT plus T is needed in HER2-positive DCIS before its routine delivery in patients with DCIS resected by lumpectomy.

Precision clinical trials: a framework for getting to precision medicine for neurobehavioural disorders.

The goal of precision medicine (individually tailored treatments) is not being achieved for neurobehavioural conditions such as psychiatric disorders. Traditional randomized clinical trial methods are insufficient for advancing precision medicine because of the dynamic complexity of these conditions. We present a pragmatic solution: the precision clinical trial framework, encompassing methods for individually tailored treatments. This framework includes the following: (1) treatment-targeted enrichment, which involves measuring patients' response after a brief bout of an intervention, and then randomizing patients to a full course of treatment, using the acute response to predict long-term outcomes; (2) adaptive treatments, which involve adjusting treatment parameters during the trial to individually optimize the treatment; and (3) precise measurement, which involves measuring predictor and outcome variables with high accuracy and reliability using techniques such as ecological momentary assessment. This review summarizes precision clinical trials and provides a research agenda, including new biomarkers such as precision neuroimaging, transcranial magnetic stimulation-electroencephalogram digital phenotyping and advances in statistical and machine-learning models. Validation of these approaches - and then widespread incorporation of the precision clinical trial framework - could help achieve the vision of precision medicine for neurobehavioural conditions.

Achieving coordinated national immunity and cholera elimination in Haiti through vaccination: a modelling study.

BACKGROUND: Cholera was introduced into Haiti in 2010. Since then, more than 820 000 cases and nearly 10 000 deaths have been reported. Oral cholera vaccine (OCV) is safe and effective, but has not been seen as a primary tool for cholera elimination due to a limited period of protection and constrained supplies. Regionally, epidemic cholera is contained to the island of Hispaniola, and the lowest numbers of cases since the epidemic began were reported in 2019. Hence, Haiti may represent a unique opportunity to eliminate cholera with OCV. METHODS: In this modelling study, we assessed the probability of elimination, time to elimination, and percentage of cases averted with OCV campaign scenarios in Haiti through simulations from four modelling teams. For a 10-year period from January 19, 2019, to Jan 13, 2029, we compared a no vaccination scenario with five OCV campaign scenarios that differed in geographical scope, coverage, and rollout duration. Teams used weekly department-level reports of suspected cholera cases from the Haiti Ministry of Public Health and Population to calibrate the models and used common vaccine-related assumptions, but other model features were determined independently. FINDINGS: Among campaigns with the same vaccination coverage (70% fully vaccinated), the median probability of elimination after 5 years was 0-18% for no vaccination, 0-33% for 2-year campaigns focused in the two departments with the highest historical incidence, 0-72% for three-department campaigns, and 35-100% for nationwide campaigns. Two-department campaigns averted a median of 12-58% of infections, three-department campaigns averted 29-80% of infections, and national campaigns averted 58-95% of infections. Extending the national campaign to a 5-year rollout (compared to a 2-year rollout), reduced the probability of elimination to 0-95% and the proportion of cases averted to 37-86%. INTERPRETATION: Models suggest that the probability of achieving zero transmission of Vibrio cholerae in Haiti with current methods of control is low, and that bolder action is needed to promote elimination of cholera from the region. Large-scale cholera vaccination campaigns in Haiti would offer the opportunity to synchronise nationwide immunity, providing near-term population protection while improvements to water and sanitation promote long-term cholera elimination. FUNDING: Bill & Melinda Gates Foundation, Global Good Fund, Institute for Disease Modeling, Swiss National Science Foundation, and US National Institutes of Health.

Correction: Behavioral and synaptic alterations relevant to obsessivecompulsive disorder in mice with increased EAAT3 expression.

The original version of this Article contained an error in the spelling of the author Anna K Radke, which was incorrectly given as Anna R Radke. This has now been corrected in both the PDF and HTML versions of the Article.

Behavioral and synaptic alterations relevant to obsessive-compulsive disorder in mice with increased EAAT3 expression.

Obsessive-compulsive disorder (OCD) is a severe, chronic neuropsychiatric disorder with a strong genetic component. The SLC1A1 gene encoding the neuronal glutamate transporter EAAT3 has been proposed as a candidate gene for this disorder. Gene variants affecting SLC1A1 expression in human brain tissue have been associated with OCD. Several mouse models fully or partially lacking EAAT3 have shown no alterations in baseline anxiety-like or repetitive behaviors. We generated a transgenic mouse model (EAAT3glo) to achieve conditional, Cre-dependent EAAT3 overexpression and evaluated the overall impact of increased EAAT3 expression at behavioral and synaptic levels. Mice with EAAT3 overexpression driven by CaMKIIα-promoter (EAAT3glo/CMKII) displayed increased anxiety-like and repetitive behaviors that were both restored by chronic, but not acute, treatment with fluoxetine or clomipramine. EAAT3glo/CMKII mice also displayed greater spontaneous recovery of conditioned fear. Electrophysiological and biochemical analyses at corticostriatal synapses of EAAT3glo/CMKII mice revealed changes in NMDA receptor subunit composition and altered NMDA-dependent synaptic plasticity. By recapitulating relevant behavioral, neurophysiological, and psychopharmacological aspects, our results provide support for the glutamatergic hypothesis of OCD, particularly for the increased EAAT3 function, and provide a valuable animal model that may open novel therapeutic approaches to treat this devastating disorder.

Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric condition affecting 1-3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze) and compulsivity (marble burying), as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus-brain areas that are relevant to OCD. RESULTS: Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally) increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. CONCLUSIONS: Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

Neurochemical and behavioral characterization of neuronal glutamate transporter EAAT3 heterozygous mice

BACKGROUND: Obsessive-compulsive disorder (OCD) is a severe neuropsychiatric condition affecting 1-3% of the worldwide population. OCD has a strong genetic component, and the SLC1A1 gene that encodes neuronal glutamate transporter EAAT3 is a strong candidate for this disorder. To evaluate the impact of reduced EAAT3 expression in vivo, we studied male EAAT3 heterozygous and wild-type littermate mice using a battery of behavioral paradigms relevant to anxiety (open field test, elevated plus maze) and compulsivity (marble burying), as well as locomotor activity induced by amphetamine. Using high-performance liquid chromatography, we also determined tissue neurotransmitter levels in cortex, striatum and thalamus-brain areas that are relevant to OCD. RESULTS: Compared to wild-type littermates, EAAT3 heterozygous male mice have unaltered baseline anxiety-like, compulsive-like behavior and locomotor activity. Administration of acute amphetamine (5 mg/kg intraperitoneally) increased locomotion with no differences across genotypes. Tissue levels of glutamate, GABA, dopamine and serotonin did not vary between EAAT3 heterozygous and wild-type mice. CONCLUSIONS: Our results indicate that reduced EAAT3 expression does not impact neurotransmitter content in the corticostriatal circuit nor alter anxiety or compulsive-like behaviors.

Health-Related Quality of Life among Pediatric Hematopoietic Stem Cell Donors.

OBJECTIVES: To examine health-related quality of life (HRQoL) among sibling pediatric hematopoietic stem cell donors from predonation through 1 year postdonation, to compare donor-reported HRQoL scores with proxy-reports by parents/guardians and those of healthy norms, and to identify predonation factors (including donor age) potentially associated with postdonation HRQoL, to better understand the physical and psychosocial effects of pediatric hematopoietic stem cell donation. STUDY DESIGN: A random sample of 105 pediatric donors from US centers and a parent/guardian were interviewed by telephone predonation and 4 weeks and 1 year postdonation. The interview included sociodemographic, psychosocial, and HRQoL items. A sample of healthy controls matched to donors by age, gender, and race/ethnicity was generated. RESULTS: Key findings included (1) approximately 20% of donors at each time point had very poor HRQoL; (2) child self-reported HRQoL was significantly lower than parent proxy-reported HRQoL at all 3 time points and significantly lower than that of norms at predonation and 4 weeks postdonation; and (3) younger children were at particular risk of poor HRQoL. CONCLUSIONS: Additional research to identify the specific sources of poorer HRQoL among at-risk donors (eg, the donation experience vs having a chronically ill sibling) and the reasons that parents may be overestimating HRQoL in their donor children is critical and should lead to interventions and policy changes that ensure positive experiences for these minor donors.

Projected Impact of Dengue Vaccination in Yucatán, Mexico.

Dengue vaccines will soon provide a new tool for reducing dengue disease, but the effectiveness of widespread vaccination campaigns has not yet been determined. We developed an agent-based dengue model representing movement of and transmission dynamics among people and mosquitoes in Yucatán, Mexico, and simulated various vaccine scenarios to evaluate effectiveness under those conditions. This model includes detailed spatial representation of the Yucatán population, including the location and movement of 1.8 million people between 375,000 households and 100,000 workplaces and schools. Where possible, we designed the model to use data sources with international coverage, to simplify re-parameterization for other regions. The simulation and analysis integrate 35 years of mild and severe case data (including dengue serotype when available), results of a seroprevalence survey, satellite imagery, and climatological, census, and economic data. To fit model parameters that are not directly informed by available data, such as disease reporting rates and dengue transmission parameters, we developed a parameter estimation toolkit called AbcSmc, which we have made publicly available. After fitting the simulation model to dengue case data, we forecasted transmission and assessed the relative effectiveness of several vaccination strategies over a 20 year period. Vaccine efficacy is based on phase III trial results for the Sanofi-Pasteur vaccine, Dengvaxia. We consider routine vaccination of 2, 9, or 16 year-olds, with and without a one-time catch-up campaign to age 30. Because the durability of Dengvaxia is not yet established, we consider hypothetical vaccines that confer either durable or waning immunity, and we evaluate the use of booster doses to counter waning. We find that plausible vaccination scenarios with a durable vaccine reduce annual dengue incidence by as much as 80% within five years. However, if vaccine efficacy wanes after administration, we find that there can be years with larger epidemics than would occur without any vaccination, and that vaccine booster doses are necessary to prevent this outcome.

Modeling cholera outbreaks.

Mathematical modeling can be a valuable tool for studying infectious disease outbreak dynamics and simulating the effects of possible interventions. Here, we describe approaches to modeling cholera outbreaks and how models have been applied to explore intervention strategies, particularly in Haiti. Mathematical models can play an important role in formulating and evaluating complex cholera outbreak response options. Major challenges to cholera modeling are insufficient data for calibrating models and the need to tailor models for different outbreak scenarios.

A preliminary study of a Peruvian diet using dietary analysis and hair mineral content as indicators.

Observations among former American residents living long-term in Peru suggested that hair health improved while in Peru. To determine if a Peruvian diet correlates with hair composition, dietary intake of nutrients and mineral content of hair were measured among Peruvian and matched US residents. Selected foods from Peru were also analyzed for mineral and antioxidant content and compared with equivalent foods available in the USA. Statistically significant differences between Peruvian and US residents' hair were found for sodium (decreased in Peru, p = 0.007) and vanadium (decreased in Peru, p = 0.03). Differences in hair composition between residencies may be explained by lower dietary sodium and vanadium intake among Peruvian residents or by lower concentrations of these minerals in Peruvian drinking water. Many significant mineral differences were also identified between Peruvian foods and their US equivalents. Although no statistically significant correlations between dietary intake and hair mineral content were found, results indicate that a Peruvian diet contributes differently to hair composition than a US diet. More research is needed to elucidate the link between a Peruvian diet and specific aspects of hair health.

Inhibition of calcification of bovine pericardium after treatment with biopolymers, E-beam irradiation and in vitro endothelization.

This work has investigated the in vitro calcification of bovine pericardium (BP) treated with chitosan (C), silk fibroin (SF) and electron beam irradiation after its endothelization in vitro. For this purpose, freeze-dried BP membranes treated with mixtures of C and SF (1:3, 1:1 and 3:1) and then irradiated by electron beam irradiation were seeded with human umbilical vein endothelial cells (HUVEC) in vitro. After 3 weeks of cultivation these membranes were submitted to in vitro calcification tests using simulated body fluid as the calcifying agent. Control membranes were also studied (without endothelial cells exposure). The results have shown that the membrane compatibility with HUVECs in vitro prevent such biomaterial from calcifying, showing a potential application in biomaterial area, such as cardiac valves and repair patches.

Phenotypes and genotypes of erythromycin-resistant Streptococcus pyogenes strains isolated from invasive and non-invasive infections from Mexico and the USA during 1999-2010.

OBJECTIVE: To compare the prevalence, phenotypes, and genes responsible for erythromycin resistance among Streptococcus pyogenes isolates from Mexico and the USA. METHODS: Eighty-nine invasive and 378 non-invasive isolates from Mexico, plus 148 invasive, 21 non-invasive, and five unclassified isolates from the USA were studied. Susceptibilities to penicillin, erythromycin, clindamycin, ceftriaxone, and vancomycin were evaluated according to Clinical and Laboratory Standards Institute (CLSI) standards. Phenotypes of erythromycin resistance were identified by triple disk test, and screening for mefA, ermTR, and ermB genes was carried out by PCR. RESULTS: All isolates were susceptible to penicillin, ceftriaxone, and vancomycin. Erythromycin resistance was found in 4.9% of Mexican strains and 5.2% of USA strains. Phenotypes in Mexican strains were 95% M and 5% cMLS; in strains from the USA, phenotypes were 33.3% iMLS, 33.3% iMLS-D, and 33.3% M. Erythromycin resistance genes in strains from Mexico were mefA (95%) and ermB (5%); USA strains harbored ermTR (56%), mefA (33%), and none (11%). In Mexico, all erythromycin-resistant strains were non-invasive, whereas 89% of strains from the USA were invasive. CONCLUSIONS: Erythromycin resistance continues to exist at low levels in both Mexico and the USA, although the genetic mechanisms responsible differ between the two nations. These genetic differences may be related to the invasive character of the S. pyogenes isolated.