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The Pacific ocean–atmosphere system exerts an important influence on the climate of Asia and North America, but the limited length of the observational record prevents a complete understanding of its bidecadal and multidecadal time scales. Paleoclimate reconstructions provide one source of information on longer time scales, although they differ in their estimation of the behavior of the Pacific decadal oscillation (PDO) prior to the instrumental period. Forced general circulation model simulations offer complementary long-term perspectives on both the history and dynamics of this important mode of variability. Here, we analyze the PDO in the ensemble of CMIP5/PMIP3 last millennium (past1000 + historical) simulations. We evaluate the modeled spatial, temporal, and spectral characteristics of this mode, as well as teleconnections between North Pacific variability and global climate. All models produce a mode of North Pacific variability over the last millennium with spatial patterns and spectral power density similar to observations. CCSM, FGOALS, and IPSL best reproduce observed spatial patterns, spectral characteristics, and teleconnections to terrestrial regions used in paleoclimate proxy reconstructions. In these simulations, the PDO shows no consistent response to solar or volcanic forcing.

Human genome resequencing typically involves mapping reads to a reference genome to call variants; however, this approach suffers from both technical and reference biases, leaving many duplicated and structurally polymorphic regions of the genome unmapped. Consequently, existing variant benchmarks, generated by the same methods, fail to assess these complex regions. To address this limitation, we present a telomere-to-telomere genome benchmark that achieves near-perfect accuracy (i.e. no detectable errors) across 99.4% of the complete, diploid HG002 genome. This benchmark adds 701.4 Mb of autosomal sequence and both sex chromosomes (216.8 Mb), totaling 15.3% of the genome that was absent from prior benchmarks. We also provide a diploid annotation of genes, transposable elements, segmental duplications, and satellite repeats, including 39,144 protein-coding genes across both haplotypes. To facilitate application of the benchmark, we developed tools for measuring the accuracy of sequencing reads, phased variant call sets, and genome assemblies against a diploid reference. Genome-wide analyses show that state-of-the-art de novo assembly methods resolve 2-7% more sequence and outperform variant calling accuracy by an order of magnitude, yielding just one error per 100 kb across 99.9% of the benchmark regions. Adoption of genome-based benchmarking is expected to accelerate the development of cost-effective methods for complete genome sequencing, expanding the reach of genomic medicine to the entire genome and enabling a new era of personalized genomics.

The inappropriate use of antibiotics can increase the likelihood of antibiotic resistance and adverse events. In the United States, nearly a third of antibiotic prescriptions in outpatient settings are unnecessary, and the selection of antibiotics and duration of treatment are also often inappropriate. Evidence shows that antibiotic prescribing is influenced by psychosocial factors, including lack of accountability, perceived patient expectations, clinician workload, and habit. A varied and growing body of evidence, including meta-analyses and randomized controlled trials, has evaluated interventions to optimize the use of antibiotics. Interventions informed by behavioral science—such as communication skills training, audit and feedback with peer comparison, public commitment posters, and accountable justification—have been associated with improved antibiotic prescribing. In addition, delayed prescribing, active monitoring, and the use of diagnostics are guideline recommended practices that improve antibiotic use for some conditions. In 2016, the Centers for Disease Control and Prevention released the Core Elements of Outpatient Antibiotic Stewardship , which provides a framework for implementing these interventions in outpatient settings. This review summarizes the varied evidence on drivers of inappropriate prescription of antibiotics in outpatient settings and potential interventions to improve their use in such settings.

Abstract Background While antibiotics are life-saving drugs, their use is not without risk, including adverse events and antibiotic resistance. The majority of US antibiotic prescriptions are prescribed in outpatient settings, making outpatient antibiotic prescribing an important antibiotic stewardship target. The primary objective of this study was to describe trends in US outpatient oral antibiotic prescriptions from 2011–2016. Methods We estimated annual oral antibiotic prescription rates using national prescription dispensing count data from IQVIA Xponent, divided by census estimates for 2011–2016. We calculated the ratio of broad- to narrow-spectrum prescriptions by dividing broad-spectrum prescription rates by narrow-spectrum prescription rates. We used Poisson models to estimate prevalence rate ratios, comparing 2011 and 2016 antibiotic prescription rates, and linear models to evaluate temporal trends throughout the study period. Results Oral antibiotic prescription rates decreased 5%, from 877 prescriptions per 1000 persons in 2011 to 836 per 1000 persons in 2016. During this period, rates of prescriptions dispensed to children decreased 13%, while adult rates increased 2%. The ratio of broad- to narrow-spectrum antibiotics decreased from 1.62 in 2011 to 1.49 in 2016, driven by decreases in macrolides and fluoroquinolones. The proportion of prescriptions written by nurse practitioners and physician assistants increased during the study period; in 2016, these providers prescribed over one-quarter of all antibiotic prescriptions. Conclusions Outpatient antibiotic prescription rates, especially of broad-spectrum agents, have decreased in recent years. Clinicians who prescribe to adults, including nurse practitioners and physician assistants, are important targets for antibiotic stewardship. Population-based outpatient oral antibiotic prescription rates decreased significantly from 2011 to 2016. Antibiotic prescription rate decreases were greatest among broad-spectrum antibiotics, driven by macrolides and fluoroquinolones. The proportion of antibiotics prescribed by advanced practice providers increased during this period.

The discovery of the involvement of alpha-synuclein (α-syn) in Parkinson's disease (PD) pathogenesis has resulted in the development and use of viral vector-mediated α-syn overexpression rodent models. The goal of these series of experiments was to characterize the neurodegeneration and functional deficits resulting from injection of recombinant adeno-associated virus (rAAV) serotype 2/5-expressing human wildtype α-syn in the rat substantia nigra (SN). Rats were unilaterally injected into two sites in the SN with either rAAV2/5-expressing green fluorescent protein (GFP, 1.2 x 10(13)) or varying titers (2.2 x 10(12), 1.0 x 10(13), 5.9 x 10(13), or 1.0 x 10(14)) of rAAV2/5-α-syn. Cohorts of rats were euthanized 4, 8, or 12 weeks following vector injection. The severity of tyrosine hydroxylase immunoreactive (THir) neuron death in the SN pars compacta (SNpc) was dependent on vector titer. An identical magnitude of nigrostriatal degeneration (60-70% SNpc THir neuron degeneration and 40-50% loss of striatal TH expression) was observed four weeks following 1.0 x 10(14) titer rAAV2/5-α-syn injection and 8 weeks following 1.0 x 10(13) titer rAAV2/5-α-syn injection. THir neuron degeneration was relatively uniform throughout the rostral-caudal axis of the SNpc. Despite equivalent nigrostriatal degeneration between the 1.0 x 10(13) and 1.0 x 10(14) rAAV2/5-α-syn groups, functional impairment in the cylinder test and the adjusting steps task was only observed in rats with the longer 8 week duration of α-syn expression. Motor impairment in the cylinder task was highly correlated to striatal TH loss. Further, 8 weeks following 5.9 x 10(13) rAAV2/5-α-syn injection deficits in ultrasonic vocalizations were observed. In conclusion, our rAAV2/5-α-syn overexpression model demonstrates robust nigrostriatal α-syn overexpression, induces significant nigrostriatal degeneration that is both vector and duration dependent and under specific parameters can result in motor impairment that directly relates to the level of striatal TH denervation.

Disentangling the impact of the weather on transmission of infectious diseases is crucial for health protection, preparedness and prevention. Because weather factors are co-incidental and partly correlated, we have used geography to separate out the impact of individual weather parameters on other seasonal variables using campylobacteriosis as a case study. Campylobacter infections are found worldwide and are the most common bacterial food-borne disease in developed countries, where they exhibit consistent but country specific seasonality. We developed a novel conditional incidence method, based on classical stratification, exploiting the long term, high-resolution, linkage of approximately one-million campylobacteriosis cases over 20 years in England and Wales with local meteorological datasets from diagnostic laboratory locations. The predicted incidence of campylobacteriosis increased by 1 case per million people for every 5° (Celsius) increase in temperature within the range of 8°–15°. Limited association was observed outside that range. There were strong associations with day-length. Cases tended to increase with relative humidity in the region of 75–80%, while the associations with rainfall and wind-speed were weaker. The approach is able to examine multiple factors and model how complex trends arise, e.g . the consistent steep increase in campylobacteriosis in England and Wales in May-June and its spatial variability. This transparent and straightforward approach leads to accurate predictions without relying on regression models and/or postulating specific parameterisations. A key output of the analysis is a thoroughly phenomenological description of the incidence of the disease conditional on specific local weather factors. The study can be crucially important to infer the elusive mechanism of transmission of campylobacteriosis; for instance, by simulating the conditional incidence for a postulated mechanism and compare it with the phenomenological patterns as benchmark. The findings challenge the assumption, commonly made in statistical models, that the transformed mean rate of infection for diseases like campylobacteriosis is a mere additive and combination of the environmental variables.

The ocean provides resources key to human health and well-being, including food, oxygen, livelihoods, blue spaces, and medicines. The global threat to these resources posed by accelerating ocean acidification is becoming increasingly evident as the world’s oceans absorb carbon dioxide emissions. While ocean acidification was initially perceived as a threat only to the marine realm, here we argue that it is also an emerging human health issue. Specifically, we explore how ocean acidification affects the quantity and quality of resources key to human health and well-being in the context of: (1) malnutrition and poisoning, (2) respiratory issues, (3) mental health impacts, and (4) development of medical resources. We explore mitigation and adaptation management strategies that can be implemented to strengthen the capacity of acidifying oceans to continue providing human health benefits. Importantly, we emphasize that the cost of such actions will be dependent upon the socioeconomic context; specifically, costs will likely be greater for socioeconomically disadvantaged populations, exacerbating the current inequitable distribution of environmental and human health challenges. Given the scale of ocean acidification impacts on human health and well-being, recognizing and researching these complexities may allow the adaptation of management such that not only are the harms to human health reduced but the benefits enhanced.

The feasibility and efficacy of virtual reality job interview training (VR-JIT) was assessed in a single-blinded randomized controlled trial. Adults with autism spectrum disorder were randomized to VR-JIT ( n  = 16) or treatment-as-usual (TAU) ( n  = 10) groups. VR-JIT consisted of simulated job interviews with a virtual character and didactic training. Participants attended 90 % of laboratory-based training sessions, found VR-JIT easy to use and enjoyable, and they felt prepared for future interviews. VR-JIT participants had greater improvement during live standardized job interview role-play performances than TAU participants ( p  = 0.046). A similar pattern was observed for self-reported self-confidence at a trend level ( p  = 0.060). VR-JIT simulation performance scores increased over time ( R 2  = 0.83). Results indicate preliminary support for the feasibility and efficacy of VR-JIT, which can be administered using computer software or via the internet.

Background: Bridge-enhanced anterior cruciate ligament repair (BEAR) combines suture repair of the anterior cruciate ligament (ACL) with a specific extracellular matrix scaffold (the BEAR scaffold) that is placed in the gap between the torn ends of the ACL to facilitate ligament healing. Purpose/Hypothesis: The purpose of this study was to report the 12- and 24-month outcomes of patients who underwent the BEAR procedure compared with a nonrandomized concurrent control group who underwent ACL reconstruction (ACLR) with an autograft. We hypothesized that the BEAR group would have physical examination findings, patient-reported outcomes, and adverse events that were similar to those of the ACLR group. Study Design: Cohort study; Level of evidence, 2. Methods: Ten patients underwent BEAR, and 10 underwent ACLR with a 4-stranded hamstring autograft. At 24 months, 9 of the 10 BEAR patients and 7 of the 10 ACLR patients completed a study visit. Outcomes reported included International Knee Documentation Committee (IKDC) subjective and objective results, knee anteroposterior (AP) laxity findings via an arthrometer, and functional outcomes. Results: There were no graft or repair failures in the first 24 months after surgery. The IKDC subjective scores in both groups improved significantly from baseline (P < .0001) at 12 and 24 months, to 84.6 ± 17.2 in the ACLR group and to 91.7 ± 11.7 in the BEAR group. An IKDC objective grade of A (normal) was found in 44% of patients in the BEAR group and in 29% of patients in the ACLR group at 24 months; no patients in either group had C (abnormal) or D (severely abnormal) grades. Arthrometer testing demonstrated mean side-to-side differences in AP laxity that were similar in the 2 groups at 24 months (BEAR, 1.94 ± 2.08 mm; ACLR, 3.14 ± 2.66 mm). Functional hop testing results were similar in the 2 groups at 12 and 24 months after surgery. Hamstring strength indices were significantly higher in the BEAR group compared with the ACLR group (P = .0001). Conclusion: In this small, first-in-human study, BEAR produced similar outcomes to ACLR with a hamstring autograft. BEAR may result in knee stability and patient-reported outcomes at 2 years sufficient to warrant longer term studies of efficacy in larger groups of patients.

Gliomas account for approximately 80 % of all primary malignant brain tumors and, despite improvements in clinical care over the last 20 years, remain among the most lethal tumors, underscoring the need for gaining new insights that could translate into clinical advances. Recent genome-wide association studies (GWAS) have identified seven new susceptibility regions. We conducted a new independent GWAS of glioma using 1,856 cases and 4,955 controls (from 14 cohort studies, 3 case–control studies, and 1 population-based case-only study) and found evidence of strong replication for three of the seven previously reported associations at 20q13.33 ( RTEL ), 5p15.33 ( TERT ), and 9p21.3 ( CDKN2BAS ), and consistent association signals for the remaining four at 7p11.2 ( EGFR both loci), 8q24.21 ( CCDC26 ) and 11q23.3 ( PHLDB1 ). The direction and magnitude of the signal were consistent for samples from cohort and case–control studies, but the strength of the association was more pronounced for loci rs6010620 (20q,13.33; RTEL ) and rs2736100 (5p15.33, TERT ) in cohort studies despite the smaller number of cases in this group, likely due to relatively more higher grade tumors being captured in the cohort studies. We further examined the 85 most promising single nucleotide polymorphism (SNP) markers identified in our study in three replication sets (5,015 cases and 11,601 controls), but no new markers reached genome-wide significance. Our findings suggest that larger studies focusing on novel approaches as well as specific tumor subtypes or subgroups will be required to identify additional common susceptibility loci for glioma risk.