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Trapped ions (TIs) are at the forefront of quantum computing implementation, offering unparalleled coherence, fidelity, and connectivity. However, the scalability of TI systems is hampered by the limited capacity of individual ion traps, necessitating intricate ion shuttling for advanced computational tasks. The quantum charge-coupled device (QCCD) framework has emerged as a promising solution, facilitating ion mobility for universal quantum computation. Current QCCD architectures predominantly feature a linear topology, which is increasingly recognized as inefficient for complex quantum operations. Anticipating the shift toward more efficacious designs, this article introduces an innovative quantum scheduling strategy optimized for parallel QCCD topologies. Our strategy proposes a probabilistic formula for ion movement, alongside ingenious methods for local layer generation and layer compression, yielding a significant reduction in ion shuttle times. Through simulations, we demonstrate that our strategy not only substantially outstrips the linear model but also exhibits better performance over other parallel strategies that employ greedy algorithms. This is achieved through our nuanced resolution of complexities, such as traffic blocks and trap capacity limitations. The consequent reduction in shuttle operations leads to lower energy consumption and an enhancement in the quantum computer's fidelity, ultimately accelerating program execution times.

Background The rapid global emergence of the COVID-19 pandemic in early 2020 created urgent demand for leading indicators to track the spread of the virus and assess the consequences of public health measures designed to limit transmission. Public transit mobility, which has been shown to be responsive to previous societal disruptions such as disease outbreaks and terrorist attacks, emerged as an early candidate. Methods We conducted a longitudinal ecological study of the association between public transit mobility reductions and COVID-19 transmission using publicly available data from a public transit app in 40 global cities from March 16 to April 12, 2020. Multilevel linear regression models were used to estimate the association between COVID-19 transmission and the value of the mobility index 2 weeks prior using two different outcome measures: weekly case ratio and effective reproduction number. Results Over the course of March 2020, median public transit mobility, measured by the volume of trips planned in the app, dropped from 100% (first quartile (Q1)–third quartile (Q3) = 94–108%) of typical usage to 10% (Q1–Q3 = 6–15%). Mobility was strongly associated with COVID-19 transmission 2 weeks later: a 10% decline in mobility was associated with a 12.3% decrease in the weekly case ratio (exp(β) = 0.877; 95% confidence interval (CI): [0.859–0.896]) and a decrease in the effective reproduction number (β = −0.058; 95% CI: [−0.068 to −0.048]). The mobility-only models explained nearly 60% of variance in the data for both outcomes. The adjustment for epidemic timing attenuated the associations between mobility and subsequent COVID-19 transmission but only slightly increased the variance explained by the models. Discussion Our analysis demonstrated the value of public transit mobility as a leading indicator of COVID-19 transmission during the first wave of the pandemic in 40 global cities, at a time when few such indicators were available. Factors such as persistently depressed demand for public transit since the onset of the pandemic limit the ongoing utility of a mobility index based on public transit usage. This study illustrates an innovative use of “big data” from industry to inform the response to a global pandemic, providing support for future collaborations aimed at important public health challenges.

ABSTRACTTools to advance antimicrobial stewardship in the primary health care setting, where most antimicrobials are prescribed, are urgently needed. The aim of this study was to evaluate OPEN Stewarship (Online Platform for Expanding aNtibiotic Stewardship), an automated feedback intervention, among a cohort of primary care physicians. We performed a controlled, interrupted time-series study of 32 intervention and 725 control participants, consisting of primary care physicians from Ontario, Canada and Southern Israel, from October 2020 to December 2021. Intervention participants received three personalized feedback reports targeting several aspects of antibiotic prescribing. Study outcomes (overall prescribing rate, prescribing rate for viral respiratory conditions, prescribing rate for acute sinusitis, and mean duration of therapy) were evaluated using multilevel regression models. We observed a decrease in the mean duration of antibiotic therapy (IRR = 0.94; 95% CI: 0.90, 0.99) in intervention participants during the intervention period. We did not observe a significant decline in overall antibiotic prescribing (OR = 1.01; 95% CI: 0.94, 1.07), prescribing for viral respiratory conditions (OR = 0.87; 95% CI: 0.73, 1.03), or prescribing for acute sinusitis (OR = 0.85; 95% CI: 0.67, 1.07). In this antimicrobial stewardship intervention among primary care physicians, we observed shorter durations of therapy per antibiotic prescription during the intervention period. The COVID-19 pandemic may have hampered recruitment; a dramatic reduction in antibiotic prescribing rates in the months before our intervention may have made physicians less amenable to further reductions in prescribing, limiting the generalizability of the estimates obtained.IMPORTANCEAntibiotic overprescribing contributes to antibiotic resistance, a major threat to our ability to treat infections. We developed the OPEN Stewardship (Online Platform for Expanding aNtibiotic Stewardship) platform to provide automated feedback on antibiotic prescribing in primary care, where most antibiotics for human use are prescribed but where the resources to improve antibiotic prescribing are limited. We evaluated the platform among a cohort of primary care physicians from Ontario, Canada and Southern Israel from October 2020 to December 2021. The results showed that physicians who received personalized feedback reports prescribed shorter courses of antibiotics compared to controls, although they did not write fewer antibiotic prescriptions. While the COVID-19 pandemic presented logistical and analytical challenges, our study suggests that our intervention meaningfully improved an important aspect of antibiotic prescribing. The OPEN Stewardship platform stands as an automated, scalable intervention for improving antibiotic prescribing in primary care, where needs are diverse and technical capacity is limited.

The escalating threat of antimicrobial resistance (AMR) necessitates impactful, reproducible, and scalable antimicrobial stewardship strategies. This review addresses the critical need to enhance the quality of antimicrobial stewardship intervention research. We propose five considerations for authors planning and evaluating antimicrobial stewardship initiatives. Antimicrobial stewards should consider the following mnemonic ABCDE: (A) plan Ahead using implementation science; (B) Be clear and thoroughly describe the intervention by using the TidIER checklist; (C) Use a Checklist to comprehensively report study components; (D) Select a study Design carefully; and (E) Assess Effectiveness and implementation by selecting meaningful outcomes. Incorporating these recommendations will help strengthen the evidence base of antimicrobial stewardship literature and support optimal implementation of strategies to mitigate AMR.

Background: Pertussis is a reportable disease in many countries, but ascertainment bias has limited data accuracy. This study aims to validate pertussis data measures using a reference standard that incorporates different suspected case severities, allowing for the impact of case severity on accuracy and detection to be explored. Methods: We evaluated 25 pertussis detection algorithms in a primary care electronic medical record database between January 1, 1986 and December 30, 2016. We estimated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV). We used sensitivity analyses to explore areas of uncertainty and evaluated reasons for lack of detection. Results: The algorithm including all data measures achieved the highest sensitivity at 20.6%. Sensitivity increased to 100% after reclassifying symptom-only cases as non-cases, but the PPV remained low. Age at first episode was significantly associated with detection in half of the tested scenarios, and false negatives often had some history of immunization. Conclusions: Sensitivity improved by reclassifying symptom-only cases but remained low unless multiple data sources were used. Results demonstrate a trade-off between PPV and sensitivity. EMRs can enhance detection through patient history and clinical note data. It is essential to improve case identification of older individuals with vaccination history to reduce ascertainment bias.

Summary: Background: COVID-19 and antimicrobial resistance (AMR) are two intersecting public health crises. Antimicrobial overuse in patients with COVID-19 threatens to worsen AMR. Guidelines are fundamental in encouraging antimicrobial stewardship. We sought to assess the quality of antibiotic prescribing guidelines and recommendations in the context of COVID-19, and whether they incorporate principles of antimicrobial stewardship. Methods: We performed a systematic survey which included a search using the concepts “antibiotic/antimicrobial” up to November 15, 2022 of the eCOVID-19 living map of recommendations (RecMap) which aggregates guidelines across a range of international sources and all languages. Guidelines providing explicit recommendations regarding antibacterial use in COVID-19 were eligible for inclusion. Guideline and recommendation quality were assessed using the AGREE II and AGREE-REX instruments, respectively. We extracted guideline characteristics including panel representation and the presence or absence of explicit statements related to antimicrobial stewardship (i.e., judicious antibiotic use, antimicrobial resistance or adverse effects as a consequence of antibiotic use). We used logistic regression to evaluate the relationship between guideline characteristics including quality and incorporation of antimicrobial stewardship principles. Protocol registration (OSF): https://osf.io/4pgtc. Findings: Twenty-eight guidelines with 63 antibiotic prescribing recommendations were included. Recommendations focused on antibiotic initiation (n = 52, 83%) and less commonly antibiotic selection (n = 13, 21%), and duration of therapy (n = 15, 24%). Guideline and recommendation quality varied widely. Twenty (71%) guidelines incorporated at least one concept relating to antimicrobial stewardship. Including infectious diseases expertise on the guideline panel (OR 9.44, 97.5% CI: 1.09–81.59) and AGREE-REX score (OR 3.26, 97.5% CI: 1.14–9.31 per 10% increase in overall score) were associated with a higher odds of guidelines addressing antimicrobial stewardship. Interpretation: There is an opportunity to improve antibiotic prescribing guidelines in terms of both quality and incorporation of antimicrobial stewardship principles. These findings can help guideline developers better address antibiotic stewardship in future recommendations beyond COVID-19. Funding: This project was funded by Michael G. DeGroote Cochrane Canada and McMaster GRADE centres.

Abstract We estimated the effectiveness of booster doses of monovalent mRNA COVID-19 vaccines against Omicron-associated severe outcomes among adults in Ontario, Canada. We used a test-negative design to estimate vaccine effectiveness (VE) against hospitalization or death among SARS-CoV-2-tested adults aged ≥50 years from January 2 to October 1, 2022, stratified by age and time since vaccination. We also compared VE during BA.1/BA.2 and BA.4/BA.5 sublineage predominance. We included 11,160 cases and 62,880 tests for test-negative controls. Depending on the age group, compared to unvaccinated adults, VE was 91–98% 7–59 days after a third dose, waned to 76–87% after ≥240 days, was restored to 92–97% 7–59 days after a fourth dose, and waned to 86–89% after ≥120 days. VE was lower and declined faster during BA.4/BA.5 versus BA.1/BA.2 predominance, particularly after ≥120 days. Here we show that booster doses of monovalent mRNA COVID-19 vaccines restored strong protection against severe outcomes for at least 3 months after vaccination. Across the entire study period, protection declined slightly over time, but waned more during BA.4/BA.5 predominance.

Summary: Background: Global estimates suggest millions of deaths annually are associated with antimicrobial resistance (AMR) but these are generated from scarce data on the relative risk of death attributable to drug-resistant versus drug-sensitive infections. Methods: We examined all episodes of E. coli bloodstream infection in Ontario, Canada between 2017 and 2020, and measured 90 day mortality among those with resistant versus sensitive isolates for each of 8 commonly used antibiotic classes and a category of difficult to treat resistance (DTTR). We used multivariable logistic regression to calculate an adjusted odds of mortality associated with AMR, after accounting for patient demographics, comorbidities, and prior healthcare exposure. Findings: Among 14,548 eligible episodes of E. coli bloodstream infection, resistance was most common to aminopenicillins (46.8%), followed by first generation cephalosporins (38.8%), fluoroquinolones (26.5%), sulfonamides (24.1%), third generation cephalosporins (13.8%), aminoglycosides (11.7%), beta-lactam-beta-lactamase-inhibitors (9.1%) and carbapenems (0.2%). Only 18 (0.1%) episodes exhibited DTTR. For each antibiotic class, the unadjusted odds of mortality (OR) were higher among resistant isolates, but after accounting for patient characteristics the adjusted odds (aOR) of mortality were attenuated: aminopenicillins (OR 1.22, 95% CI 1.12–1.33; aOR 1.09, 95% CI 0.99–1.20), first generation cephalosporins (OR 1.24, 95% CI 1.14–1.35; aOR 1.07, 95% CI 0.97–1.18), third generation cephalosporins (OR 1.64, 95% CI 1.47–1.82; aOR 1.29, 95% CI 1.15–1.46), beta-lactam-beta-lactamase-inhibitors (OR 1.69, 95% CI 1.52–1.89, aOR 1.28, 95% CI 1.13–1.45), carbapenems (OR 3.11, 95% CI 1.52–6.34; aOR 2.06, 95% CI 0.91–4.66), sulfonamides (OR 1.19, 95% CI 1.07–1.31, aOR 1.06, 95% CI 0.95–1.18), fluoroquinolones (OR 1.49, 95% CI 1.36–1.64, aOR 1.16, 95% CI 1.05–1.29), aminoglycosides (OR 1.43, 95% CI 1.27–1.62; aOR 1.27, 95% CI 1.11–1.46), and DTTR (OR 3.71, 95% CI 1.46–9.41; aOR 2.58, 95% CI 0.87–7.66). Interpretation: AMR is associated with substantial increased mortality among patients with E. coli bloodstream infection, particularly for resistance to classes commonly used as empiric treatment. Surveillance for AMR-associated mortality should incorporate adjustment for patient characteristics and prior healthcare utilization. Funding: This work was supported by a project grant from CIHR (grant number 159503). This study was also supported by ICES, which is funded by an annual grant from Ontario Ministry of Health and Long-Term Care (MOHLTC).

Abstract Objective: To evaluate inter-physician variability and predictors of changes in antibiotic prescribing before (2019) and during (2020/2021) the coronavirus disease 2019 (COVID-19) pandemic. Methods: We conducted a retrospective cohort analysis of physicians in Ontario, Canada prescribing oral antibiotics in the outpatient setting between January 1, 2019 and December 31, 2021 using the IQVIA Xponent data set. The primary outcome was the change in the number of antibiotic prescriptions between the prepandemic and pandemic period. Secondary outcomes were changes in the selection of broad-spectrum agents and long-duration (>7 d) antibiotic use. We used multivariable linear regression models to evaluate predictors of change. Results: There were 17,288 physicians included in the study with substantial inter-physician variability in changes in antibiotic prescribing (median change of −43.5 antibiotics per physician, interquartile range −136.5 to −5.0). In the multivariable model, later career stage (adjusted mean difference [aMD] −45.3, 95% confidence interval [CI] −52.9 to −37.8, p < .001), family medicine (aMD −46.0, 95% CI −62.5 to −29.4, p < .001), male patient sex (aMD −52.4, 95% CI −71.1 to −33.7, p < .001), low patient comorbidity (aMD −42.5, 95% CI −50.3 to −34.8, p < .001), and high prescribing to new patients (aMD −216.5, 95% CI −223.5 to −209.5, p < .001) were associated with decreases in antibiotic initiation. Family medicine and high prescribing to new patients were associated with a decrease in selection of broad-spectrum agents and prolonged antibiotic use. Conclusions: Antibiotic prescribing changed throughout the COVID-19 pandemic with overall decreases in antibiotic initiation, broad-spectrum agents, and prolonged antibiotic courses with inter-physician variability. These findings present opportunities for community antibiotic stewardship interventions.

Objectives We aimed to estimate associations between COVID-19 incidence and mortality with neighbourhood-level immigration, race, housing, and socio-economic characteristics. Methods We conducted a population-based study of 28,808 COVID-19 cases in the provincial reportable infectious disease surveillance systems (Public Health Case and Contact Management System) which includes all known COVID-19 infections and deaths from Ontario, Canada reported between January 23, 2020 and July 28, 2020. Residents of congregate settings, Indigenous communities living on reserves or small neighbourhoods with populations Results Neighbourhoods with the highest proportion of immigrants (relative risk (RR): 4.0, 95%CI:3.5–4.5) and visible minority residents (RR: 3.3, 95%CI:2.9–3.7) showed the strongest association with COVID-19 incidence in adjusted models. Among individual race groups, COVID-19 incidence was highest among neighbourhoods with the high proportions of Black (RR: 2.4, 95%CI:2.2–2.6), South Asian (RR: 1.9, 95%CI:1.8–2.1), Latin American (RR: 1.8, 95%CI:1.6–2.0) and Middle Eastern (RR: 1.2, 95%CI:1.1–1.3) residents. Neighbourhoods with the highest average household size (RR: 1.9, 95%CI:1.7–2.1), proportion of multigenerational families (RR: 1.8, 95%CI:1.7–2.0) and unsuitably crowded housing (RR: 2.1, 95%CI:2.0–2.3) were associated with COVID-19 incidence. Neighbourhoods with the highest proportion of residents with less than high school education (RR: 1.6, 95%CI:1.4–1.8), low income (RR: 1.4, 95%CI:1.2–1.5) and unaffordable housing (RR: 1.6, 95%CI:1.4–1.8) were associated with COVID-19 incidence. Similar inequities were observed across neighbourhood-level sociodemographic characteristics and COVID-19 mortality. Conclusions Neighbourhood-level inequities in COVID-19 incidence and mortality were observed in Ontario, with excess burden experienced in neighbourhoods with a higher proportion of immigrants, racialized populations, large households and low socio-economic status.

Epidemic curves are used by decision makers and the public to infer the trajectory of the COVID-19 pandemic and to understand the appropriateness of response measures. Symptom onset date is commonly used to date incident cases on the epidemic curve in public health reports and dashboards; however, third-party trackers date cases by the date they were publicly reported by the public health authority. These two curves create very different impressions of epidemic progression. On April 1, 2020, the epidemic curve based on public reporting date for Ontario, Canada showed an accelerating epidemic, whereas the curve based on a proxy variable for symptom onset date showed a rapidly declining epidemic. This illusory downward trend is a feature of epidemic curves anchored using date variables earlier in time than the date a case was publicly reported, such as the symptom onset date. Delays between the onset of symptoms and the detection of a case by the public health authority mean that recent days will always have incomplete case data, creating a downward bias. Public reporting date is not subject to this bias and can be used to visualize real-time epidemic curves meant to inform the public and decision makers.

scPipeline is a single-cell data analysis toolbox that builds on existing methods and offers modular workflows for multi-level cellular annotation and user-friendly analysis reports.

Summary: Eye color is highly variable in populations with European ancestry, ranging from low to high quantities of melanin in the iris. Polymorphisms in the HERC2/OCA2 locus have the largest effect on eye color in these populations, although other genomic regions also influence eye color. We performed genome-wide association studies of eye color in a Canadian cohort of European ancestry (N = 5,641) and investigated candidate causal variants. We uncovered several candidate causal signals in the HERC2/OCA2 region, whereas other loci likely harbor a single causal signal. We observed colocalization of eye color signals with the expression or methylation profiles of cultured primary melanocytes. Genetic correlations of eye and hair color suggest high genome-wide pleiotropy, but locus-level differences in the genetic architecture of both traits. Overall, we provide a better picture of the polymorphisms underpinning eye color variation, which may be a consequence of specific molecular processes in the iris melanocytes.

Summary: Background: Assessing relatedness of pathogen sequences in clinical samples is a core goal in molecular epidemiology. Tools for Bayesian analysis of phylogeny, such as the BEAST software package, have been typically used in the analysis of sequence/time data in public health. However, they are computationally-, time-, and knowledge-intensive, demanding resources that many laboratories do not have available or cannot allocate frequently. Methods: To evaluate a faster and simpler alternative method to support the routine interpretation of sequence data for epidemiology, we obtained sequences for two regions in the measles virus genome, N-450 and MF-NCR, from patient samples of genotypes B3, D4 and D8 taken between 2011 and 2017 in the UK and Romania. A mathematical model incorporating time, possible shared ancestry and the Poisson distribution describing the number of expected substitutions at a given time point was developed to exclude epidemiological relatedness between pairs of sequences. The model was validated against the commonly used Bayesian phylogenetic method using an independent dataset collected in 2017–19. Findings: We demonstrate that our model, using time and sequence information to predict whether two samples may be related within a given time frame, minimises the risk of erroneous exclusion of relatedness. An easy-to-use implementation in the form of a guide and spreadsheet is provided for convenient application. Interpretation: The proposed model only requires a previously calculated substitution rate for the locus and pathogen of interest. It allows for an informed but quick decision on the likelihood of relatedness between two samples within a time frame, without the need for phylogenetic reconstruction, thus facilitating rapid epidemiological interpretation of sequence data. Funding: This work was funded by the United Kingdom Health Security Agency (UKHSA). The World Health Organization European Regional Office funded Aurora Fernández-García and Mihaela Lazar training visits to UKHSA.

The presence of immune cells in the tumor microenvironment has been associated with response to immunotherapies across several cancer types, including melanoma. Despite its therapeutic relevance, characterization of the melanoma immune microenvironments remains insufficiently explored. To distinguish the immune microenvironment in a cohort of 180 metastatic melanoma clinical specimens, we developed a method using promoter CpG methylation of immune cell type‐specific genes extracted from genome‐wide methylation arrays. Unsupervised clustering identified three immune methylation clusters with varying levels of immune CpG methylation that are related to patient survival. Matching protein and gene expression data further corroborated the identified epigenetic characterization. Exploration of the possible immune exclusion mechanisms at play revealed likely dependency on MITF protein level and PTEN loss‐of‐function events for melanomas unresponsive to immunotherapies (immune‐low). To understand whether melanoma tumors resemble other solid tumors in terms of immune methylation characteristics, we explored 15 different solid tumor cohorts from TCGA. Low‐dimensional projection based on immune cell type‐specific methylation revealed grouping of the solid tumors in line with melanoma immune methylation clusters rather than tumor types. Association of survival outcome with immune cell type‐specific methylation differed across tumor and cell types. However, in melanomas immune cell type‐specific methylation was associated with inferior patient survival. Exploration of the immune methylation patterns in a pan‐cancer context suggested that specific immune microenvironments might occur across the cancer spectrum. Together, our findings underscore the existence of diverse immune microenvironments, which may be informative for future immunotherapeutic applications.

Toxoplasma gondii has evolved different developmental stages for disseminating during acute infection (i.e., tachyzoites) and establishing chronic infection (i.e., bradyzoites). Calcium ion (Ca2+) signaling tightly regulates the lytic cycle of tachyzoites by controlling microneme secretion and motility to drive egress and cell invasion. However, the roles of Ca2+ signaling pathways in bradyzoites remain largely unexplored. Here, we show that Ca2+ responses are highly restricted in bradyzoites and that they fail to egress in response to agonists. Development of dual-reporter parasites revealed dampened Ca2+ responses and minimal microneme secretion by bradyzoites induced in vitro or harvested from infected mice and tested ex vivo. Ratiometric Ca2+ imaging demonstrated lower Ca2+ basal levels, reduced magnitude, and slower Ca2+ kinetics in bradyzoites compared with tachyzoites stimulated with agonists. Diminished responses in bradyzoites were associated with downregulation of Ca2+-ATPases involved in intracellular Ca2+ storage in the endoplasmic reticulum (ER) and acidocalcisomes. Once liberated from cysts by trypsin digestion, bradyzoites incubated in glucose plus Ca2+ rapidly restored their intracellular Ca2+ and ATP stores, leading to enhanced gliding. Collectively, our findings indicate that intracellular bradyzoites exhibit dampened Ca2+ signaling and lower energy levels that restrict egress, and yet upon release they rapidly respond to changes in the environment to regain motility.

Abstract Background Association studies in recently admixed populations are extremely useful to identify the genetic architecture of pigmentation, due to their high genotypic and phenotypic variation. However, to date only four Genome-Wide Association Studies (GWAS) have been carried out in these populations. Results We present a GWAS of skin pigmentation in an admixed sample from Cuba (N = 762). Additionally, we conducted a meta-analysis including the Cuban sample, and admixed samples from Cape Verde, Puerto Rico and African-Americans from San Francisco. This meta-analysis is one of the largest efforts so far to characterize the genetic basis of skin pigmentation in admixed populations (N = 2,104). We identified five genome-wide significant regions in the meta-analysis, and explored if the markers observed in these regions are associated with the expression of relevant pigmentary genes in human melanocyte cultures. In three of the regions identified in the meta-analysis (SLC24A5, SLC45A2, and GRM5/TYR), the association seems to be driven by non-synonymous variants (rs1426654, rs16891982, and rs1042602, respectively). The rs16891982 polymorphism is strongly associated with the expression of the SLC45A2 gene. In the GRM5/TYR region, in addition to the rs1042602 non-synonymous SNP located on the TYR gene, variants located in the nearby GRM5 gene have an independent effect on pigmentation, possibly through regulation of gene expression of the TYR gene. We also replicated an association recently described near the MFSD12 gene on chromosome 19 (lead variant rs112332856). Additionally, our analyses support the presence of multiple signals in the OCA2/HERC2/APBA2 region on chromosome 15. A clear causal candidate is the HERC2 intronic variant rs12913832, which has a profound influence on OCA2 expression. This variant has pleiotropic effects on eye, hair, and skin pigmentation. However, conditional and haplotype-based analyses indicate the presence of other variants with independent effects on melanin levels in OCA2 and APBA2. Finally, a follow-up of genome-wide signals identified in a recent GWAS for tanning response indicates that there is a substantial overlap in the genetic factors influencing skin pigmentation and tanning response. Conclusions Our meta-analysis of skin pigmentation GWAS in recently admixed populations provides new insights about the genetic architecture of this complex trait.

Abstract Background Systemic sclerosis (SSc) is a rare connective tissue disease with a heterogeneous clinical course. Interstitial lung disease (ILD) is a common manifestation of SSc and a leading cause of death. Main body All patients newly diagnosed with SSc should receive a comprehensive clinical evaluation, including assessment of respiratory symptoms, a high-resolution computed tomography (HRCT) scan of the chest, and pulmonary function tests. ILD can develop in any patient with SSc, including those with pulmonary hypertension, but the risk is increased in those with diffuse (rather than limited) cutaneous SSc, those with anti-Scl-70/anti-topoisomerase I antibody, and in the absence of anti-centromere antibody. While it can occur at any time, the risk of developing ILD is greatest early in the course of SSc, so patients should be monitored closely in the first few years after diagnosis. An increased extent of lung fibrosis on HRCT and a low forced vital capacity (FVC) are predictors of early mortality. While not all patients will require treatment, current approaches to the treatment of progressive SSc-ILD focus on immunosuppressant therapies, including cyclophosphamide and mycophenolate mofetil. In patients with severe and/or rapidly progressive disease, both haematopoietic stem cell transplantation (HSCT) and lung transplantation have been successfully used. A number of medications, including the two drugs approved for the treatment of idiopathic pulmonary fibrosis (IPF), are under active investigation as potential new therapies for SSc-ILD. Conclusions Physicians managing patients with SSc should maintain a high level of suspicion and regularly monitor for ILD, particularly in the first few years after diagnosis.

One of the largest warm water anomalies (marine heat waves [MHWs]) ever recorded occurred in the northeast Pacific during 2014–2016. This MHW was caused by large-scale atmospheric ridging and affected fisheries and ecosystems from Alaska through California, including a bloom of toxic algae spanning the entire coastline. Regional variations in MHW severity are common along coastlines worldwide but are generally unexplained. During the 2014–16 MHW, the summertime sea-surface temperature (SST) anomalies were often stronger along the southern half of the coastline off the western continental United States. The reason for this north-south difference in severity of the MHW within the California Current System (CCS) has remained unclear. The scientific community's lack of understanding of regional variations within MHWs prevents accurate prediction of SST anomalies and resulting ecological and economic impacts. We show the north-south difference in SST anomalies was due to a known wind pattern determined by the coastline shape. The wind anomalies in summer have a quasi-dipole structure: the northern lobe extends southwest from Washington/Oregon, and the southern lobe has opposite sign and extends south from Cape Mendocino in a triangle due to a hydraulic expansion fan in the marine boundary layer. The alternating wind intensifications and relaxations typically last several days. However, the large-scale ridging during the MHW was associated with unusual persistence in this pattern: in summer 2015 a single wind relaxation in the southern lobe lasted 2 weeks. These wind anomalies induce changes in SST, likely via changes in wind-driven vertical entrainment of cold water from below the mixed layer, and mixed-layer shoaling; the net air-sea heat flux anomaly is small. The July 2015 wind relaxation persisted so long that the changes in SST exceeded pre-existing SST variations. The resulting SST anomalies have a dipole pattern similar to the wind anomalies. These dipole SST anomalies explain the north-south asymmetry in the CCS MHW. We suggest that during future persistent ridging events, the SST anomalies off the western continental U.S. will develop a north-south split structure similar to July 2015.

Summary: BRAF fusions are detected in numerous neoplasms, but their clinical management remains unresolved. We identified six melanoma lines harboring BRAF fusions representative of the clinical cases reported in the literature. Their unexpected heterogeneous responses to RAF and MEK inhibitors could be categorized upon specific features of the fusion kinases. Higher expression level correlated with resistance, and fusion partners containing a dimerization domain promoted paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway and hyperproliferation in response to first- and second-generation RAF inhibitors. By contrast, next-generation αC-IN/DFG-OUT RAF inhibitors blunted paradoxical activation across all lines and had their therapeutic efficacy further increased in vitro and in vivo by combination with MEK inhibitors, opening perspectives in the clinical management of tumors harboring BRAF fusions. : Botton et al. shed light on the heterogeneity of BRAF fusions encountered in melanocytic tumors and characterize features influencing their signaling and drug response. These findings unveil the singularities of BRAF fusions and establish general principles to guide their clinical management in melanoma and other malignancies. Keywords: BRAF fusion, melanoma, paradoxical activation, RAF inhibitor, MEK inhibitor, sequencing, rearrangement, translocation, kinase, pre-clinical

The effects of interstitial lung disease (ILD) create a significant burden on patients, unsettling almost every domain of their lives, disrupting their physical and emotional well-being and impairing their quality of life (QoL). Because many ILDs are incurable, and there are limited reliably-effective, life-prolonging treatment options available, the focus of many therapeutic interventions has been on improving or maintaining how patients with ILD feel and function, and by extension, their QoL. Such patient-centred outcomes are best assessed by patients themselves through tools that capture their perceptions, which inherently incorporate their values and judgements. These patient-reported outcome measures (PROs) can be used to assess an array of constructs affected by a disease or the interventions implemented to treat it. Here, we review the impact of ILD that may present with a progressive-fibrosing phenotype on patients' lives and examine how PROs have been used to measure that impact and the effectiveness of therapeutic interventions.

PTEN mutation occurs in a variety of aggressive cancers and is associated with poor patient outcomes. Recent studies have linked mutational loss of PTEN to reduced RAD51 expression and function, a key factor involved in the homologous recombination (HR) pathway. However, these studies remain controversial, as they fail to establish a definitive causal link to RAD51 expression that is PTEN-dependent, while other studies have not been able to recapitulate the relationship between the PTEN expression and the RAD51/HR function. Resolution of this apparent conundrum is essential due to the clinically-significant implication that PTEN-deficient tumors may be sensitive to poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) commonly used in the clinical management of BRCA-mutated and other HR-deficient (HRD) tumors. Methods: Primary Pten-deficient (and corresponding wild-type) mouse embryonic fibroblasts (MEFs) and astrocytes and PTEN-null human tumor cell lines and primary cells were assessed for RAD51 expression (via the Western blot analysis) and DNA damage repair analyses (via alkali comet and γH2AX foci assays). RAD51 foci analysis was used to measure HR-dependent DNA repair. Xrcc2-deficient MEFs served as an HR-deficient control, while the stable knockdown of RAD51 (shRAD51) served to control for the relative RAD51/HR-mediated repair and the phospho-53BP1 foci analysis served to confirm and measure non-homologous end joining (NHEJ) activity in PTEN-deficient and shRAD51-expressing (HRD) lines. Cell proliferation studies were used to measure any potential added sensitivity of PTEN-null cells to the clinically-relevant PARPi, olaparib. RAD51 levels and DNA damage response signaling were assessed in PTEN-mutant brain tumor initiating cells (BTICs) derived from primary and recurrent glioblastoma multiforme (GBM) patients, while expression of RAD51 and its paralogs were examined as a function of the PTEN status in the RNA expression datasets isolated from primary GBM tumor specimens and BTICs. Results: Pten knockout primary murine cells display unaltered RAD51 expression, endogenous and DNA strand break-induced RAD51 foci and robust DNA repair activity. Defective HR was only observed in the cells lacking Xrcc2. Likewise, human glioblastoma multiforme (GBM) cell lines with known PTEN deficiency (U87, PTEN-mutated; U251 and U373, PTEN-null) show apparent expression of RAD51 and display efficient DNA repair activity. Only GBM cells stably expressing shRNAs against RAD51 (shRAD51) display dysfunctional DNA repair activity and reduced proliferative capacity, which is exacerbated by PARPi treatment. Furthermore, GBM patient-derived BTICs displayed robust RAD51 expression and intact DNA damage response signaling in spite of PTEN-inactivating mutations. RNA expression analysis of primary GBM tissue specimens and BTICs demonstrate stable levels of RAD51 and its paralogs (RAD51B, RAD51C, RAD51D, XRCC2, XRCC3, and DMC1), regardless of the PTEN mutational status. Conclusions: Our findings demonstrate definitively that PTEN loss does not alter the RAD51 expression, its paralogs, or the HR activity. Furthermore, deficiency in PTEN alone is not sufficient to impart enhanced sensitivity to PARPi associated with HRD. This study is the first to unequivocally demonstrate that PTEN deficiency is not linked to the RAD51 expression or the HR activity amongst primary neural and non-neural Pten-null cells, PTEN-deficient tumor cell lines, and primary PTEN-mutant GBM patient-derived tissue specimens and BTICs.

Melanoma is one of the most lethal cutaneous malignancies, characterized by chemoresistance and a striking propensity to metastasize. The transcription factor ATF2 elicits oncogenic activities in melanoma, and its inhibition attenuates melanoma development. Here, we show that expression of a transcriptionally inactive form of Atf2 (Atf2Δ8,9) promotes development of melanoma in mouse models. Atf2Δ8,9-driven tumors show enhanced pigmentation, immune infiltration, and metastatic propensity. Similar to mouse Atf2Δ8,9, we have identified a transcriptionally inactive human ATF2 splice variant 5 (ATF2SV5) that enhances the growth and migration capacity of cultured melanoma cells and immortalized melanocytes. ATF2SV5 expression is elevated in human melanoma specimens and is associated with poor prognosis. These findings point to an oncogenic function for ATF2 in melanoma development that appears to be independent of its transcriptional activity.

Objective: This study was designed to demonstrate that alendronate (ALN)/vitamin D3 combination tablets (ALN/D5600) are bioequivalent to corresponding doses of ALN and vitamin D3 as individual tablets in healthy Taiwanese volunteers. Methods: In this open-label, randomized, 2-period, crossover study, 68 volunteers were randomized to a single ALN/D5600 combination tablet or corresponding doses of 70 mg ALN + 5600 IU vitamin D3 (2 × 2800 IU), followed by a 12-day washout period and administration of the alternate formulation. Plasma ALN levels were measured using a newly developed assay. Geometric mean ratios of ALN AUC0–last, AUC0–∞, and Cmax, and unadjusted vitamin D3 AUC0–80h and Cmax were compared and considered bioequivalent if the 90% CI was within 0.8 to 1.25. Results: The geometric mean ratios were: AUC0–last, 1.084 (90% CI, 0.937–1.253); AUC0–∞, 1.081 (90% CI, 0.935–1.249); and Cmax, 1.112 (90% CI, 0.959–1.289) for ALN, and AUC0–80h 0.953 (90% CI, 0.827–1.098) and Cmax, 0.982 (90% CI, 0.854–1.130) for vitamin D3 unadjusted for endogenous levels. Conclusions: The combination tablet was considered bioequivalent to coadministration based on ALN AUC0–∞ and unadjusted vitamin D3 parameters. Slight differences for ALN AUC0–last and Cmax (upper 90% CIs outside the bounds) were not considered clinically significant. The combination tablet was well tolerated. No serious adverse experiences were reported. © 2015. The Authors. Published by Elsevier Inc. All rights reserved.

Epithelial ovarian cancer (EOC) has a unique mode of metastasis, where cells shed from the primary tumour, form aggregates called spheroids to evade anoikis, spread through the peritoneal cavity, and adhere to secondary sites. We previously showed that the master kinase Liver kinase B1 (LKB1) is required for EOC spheroid viability and metastasis. We have identified novel (nua) kinase 1 (NUAK1) as a top candidate LKB1 substrate in EOC cells and spheroids using a multiplex inhibitor beads-mass spectrometry approach. We confirmed that LKB1 maintains NUAK1 phosphorylation and promotes its stabilization. We next investigated NUAK1 function in EOC cells. Ectopic NUAK1-overexpressing EOC cell lines had increased adhesion, whereas the reverse was seen in OVCAR8-NUAK1KO cells. In fact, cells with NUAK1 loss generate spheroids with reduced integrity, leading to increased cell death after long-term culture. Following transcriptome analysis, we identified reduced enrichment for cell interaction gene expression pathways in OVCAR8-NUAK1KO spheroids. In fact, the FN1 gene, encoding fibronectin, exhibited a 745-fold decreased expression in NUAK1KO spheroids. Fibronectin expression was induced during native spheroid formation, yet this was completely lost in NUAK1KO spheroids. Co-incubation with soluble fibronectin restored the compact spheroid phenotype to OVCAR8-NUAK1KO cells. In a xenograft model of intraperitoneal metastasis, NUAK1 loss extended survival and reduced fibronectin expression in tumours. Thus, we have identified a new mechanism controlling EOC metastasis, through which LKB1-NUAK1 activity promotes spheroid formation and secondary tumours via fibronectin production.

A FDA clinical trial was carried out to evaluate the potential benefit of cochlear implant (CI) use for adults with unilateral moderate-to-profound sensorineural hearing loss. Subjects were 20 adults with moderate-to-profound unilateral sensorineural hearing loss and normal or near-normal hearing on the other side. A MED-EL standard electrode was implanted in the impaired ear. Outcome measures included: (a) sound localization on the horizontal plane (11 positions, −90° to 90°), (b) word recognition in quiet with the CI alone, and (c) masked sentence recognition with the target at 0° and the masker at −90°, 0°, or 90°. This battery was completed preoperatively and at 1, 3, 6, 9, and 12 months after CI activation. Normative data were also collected for 20 age-matched control subjects with normal or near-normal hearing bilaterally. The CI improved localization accuracy and reduced side bias. Word recognition with the CI alone was similar to performance of traditional CI recipients. The CI improved masked sentence recognition when the masker was presented from the front or from the side of normal or near-normal hearing. The binaural benefits observed with the CI increased between the 1- and 3-month intervals but appeared stable thereafter. In contrast to previous reports on localization and speech perception in patients with unilateral sensorineural hearing loss, CI benefits were consistently observed across individual subjects, and performance was at asymptote by the 3-month test interval. Cochlear implant settings, consistent CI use, and short duration of deafness could play a role in this result.

Carbonic anhydrases (CAs) have been linked to tumor progression, particularly membrane-bound CA isoform IX (CA IX). The role of CA IX in the context of breast cancer is to regulate the pH of the tumor microenvironment. In contrast to CA IX, expression of CA XII, specifically in breast cancer, is associated with better outcome despite performing the same catalytic function. In this study, we have structurally modeled the orientation of bound ureido-substituted benzene sulfonamides (USBs) within the active site of CA XII, in comparison to CA IX and cytosolic off-target CA II, to understand isoform specific inhibition. This has identified specific residues within the CA active site, which differ between isoforms that are important for inhibitor binding and isoform specificity. The ability of these sulfonamides to block CA IX activity in breast cancer cells is less effective than their ability to block activity of the recombinant protein (by one to two orders of magnitude depending on the inhibitor). The same is true for CA XII activity but now they are two to three orders of magnitude less effective. Thus, there is significantly greater specificity for CA IX activity over CA XII. While the inhibitors block cell growth, without inducing cell death, this again occurs at two orders of magnitude above the Ki values for inhibition of CA IX and CA XII activity in their respective cell types. Surprisingly, the USBs inhibited cell growth even in cells where CA IX and CA XII expression was ablated. Despite the potential for these sulfonamides as chemotherapeutic agents, these data suggest that we reconsider the role of CA activity on growth potentiation.

Contaminated surfaces serve as an important reservoir for Clostridium difficile transmission. Current strategies to detect environmental contamination of C. difficile rely heavily on culture, and often only indicate presence versus absence of spores. The goal of this study was to compare quantitative PCR (qPCR) to culture for the detection and quantification of C. difficile from inert surfaces. First, we compared the limit of detection (LOD) of a 16S rRNA gene and toxin B gene qPCR assay for detection of C. difficile in solution. Second, we compared the LODs of 16S rRNA gene qPCR versus culture for detection of C. difficile from surfaces. Solution experiments were performed by direct seeding of spores into neutralizing broth, whereas surface experiments involved seeding of spores onto plastic test surfaces, and recovery using sponge swabs. Both experiments were conducted using spores expressing short (NAP1) and long (NAP4) hair lengths. Combining data from both strains, the overall LOD for C. difficile cells in solution was 1.4 cells for 16S rRNA gene and 23.6 cells for toxin B gene qPCR (p

Despite the remarkable clinical response of melanoma harboring BRAF mutations to BRAF inhibitors (BRAFi), most tumors become resistant. Here, we identified the downregulation of the ubiquitin ligase RNF125 in BRAFi-resistant melanomas and demonstrated its role in intrinsic and adaptive resistance to BRAFi in cultures as well as its association with resistance in tumor specimens. Sox10/MITF expression correlated with and contributed to RNF125 transcription. Reduced RNF125 was associated with elevated expression of receptor tyrosine kinases (RTKs), including EGFR. Notably, RNF125 altered RTK expression through JAK1, which we identified as an RNF125 substrate. RNF125 bound to and ubiquitinated JAK1, prompting its degradation and suppressing RTK expression. Inhibition of JAK1 and EGFR signaling overcame BRAFi resistance in melanoma with reduced RNF125 expression, as shown in culture and in in vivo xenografts. Our findings suggest that combination therapies targeting both JAK1 and EGFR could be effective against BRAFi-resistant tumors with de novo low RNF125 expression.

Recognising recent advances, the definition and diagnostic criteria for acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) have been updated by an international working group. The new definition describes any acute, clinically significant respiratory deterioration (both idiopathic and triggered events) characterised by evidence of new widespread alveolar abnormality. The new criteria require a previous or concurrent diagnosis of IPF, an acute worsening or development of dyspnoea typically less than 1 month in duration, chest imaging evidence on computed tomography (CT) of new bilateral ground-glass opacity and/or consolidation superimposed on a background imaging pattern of usual interstitial pneumonia not fully explained by cardiac failure or fluid overload. Due to high in-hospital mortality rates, current treatment guidelines say that the majority of patients with AE-IPF should not receive mechanical ventilation. However, new data suggest that the prognosis may have improved. This modest improvement in overall survival seen in more recent studies may be the result of differences in the diagnostic criteria, study design, baseline clinical risk factors and/or improvements in management. Based on our updated knowledge of possible preventive and therapeutic measures, including mechanical ventilation and pharmacological therapies, the current approach to the treatment of AE-IPF requires careful decision-making.

Auditory neuropathy spectrum disorder (ANSD) is characterized by an apparent discrepancy between measures of cochlear and neural function based on auditory brainstem response (ABR) testing. Clinical indicators of ANSD are a present cochlear microphonic (CM) with small or absent wave V. Many identified ANSD patients have speech impairment severe enough that cochlear implantation (CI) is indicated. To better understand the cochleae identified with ANSD that lead to a CI, we performed intraoperative round window electrocochleography (ECochG) to tone bursts in children (n = 167) and adults (n = 163). Magnitudes of the responses to tones of different frequencies were summed to measure the “total response” (ECochG-TR), a metric often dominated by hair cell activity, and auditory nerve activity was estimated visually from the compound action potential (CAP) and auditory nerve neurophonic (ANN) as a ranked “Nerve Score”. Subjects identified as ANSD (45 ears in children, 3 in adults) had higher values of ECochG-TR than adult and pediatric subjects also receiving CIs not identified as ANSD. However, nerve scores of the ANSD group were similar to the other cohorts, although dominated by the ANN to low frequencies more than in the non-ANSD groups. To high frequencies, the common morphology of ANSD cases was a large CM and summating potential, and small or absent CAP. Common morphologies in other groups were either only a CM, or a combination of CM and CAP. These results indicate that responses to high frequencies, derived primarily from hair cells, are the main source of the CM used to evaluate ANSD in the clinical setting. However, the clinical tests do not capture the wide range of neural activity seen to low frequency sounds.

Toxoplasma gondii contains an expanded number of calmodulin (CaM)-like proteins whose functions are poorly understood. Using a combination of CRISPR/Cas9-mediated gene editing and a plant-like auxin-induced degron (AID) system, we examined the roles of three apically localized CaMs. CaM1 and CaM2 were individually dispensable, but loss of both resulted in a synthetic lethal phenotype. CaM3 was refractory to deletion, suggesting it is essential. Consistent with this prediction auxin-induced degradation of CaM3 blocked growth. Phenotypic analysis revealed that all three CaMs contribute to parasite motility, invasion, and egress from host cells, and that they act downstream of microneme and rhoptry secretion. Super-resolution microscopy localized all three CaMs to the conoid where they overlap with myosin H (MyoH), a motor protein that is required for invasion. Biotinylation using BirA fusions with the CaMs labeled a number of apical proteins including MyoH and its light chain MLC7, suggesting they may interact. Consistent with this hypothesis, disruption of MyoH led to degradation of CaM3, or redistribution of CaM1 and CaM2. Collectively, our findings suggest these CaMs may interact with MyoH to control motility and cell invasion.

Independent component analysis (ICA) is a ubiquitous method for decomposing complex signal mixtures into a small set of statistically independent source signals. However, in cases in which the signal mixture consists of both nongaussian and Gaussian sources, the Gaussian sources will not be recoverable by ICA and will pollute estimates of the nongaussian sources. Therefore, it is desirable to have methods for mixed ICA/PCA which can separate mixtures of Gaussian and nongaussian sources. For mixtures of purely Gaussian sources, principal component analysis (PCA) can provide a basis for the Gaussian subspace. We introduce a new method for mixed ICA/PCA which we call Mixed ICA/PCA via Reproducibility Stability (MIPReSt). Our method uses a repeated estimations technique to rank sources by reproducibility, combined with decomposition of multiple subsamplings of the original data matrix. These multiple decompositions allow us to assess component stability as the size of the data matrix changes, which can be used to determinine the dimension of the nongaussian subspace in a mixture. We demonstrate the utility of MIPReSt for signal mixtures consisting of simulated sources and real-word (speech) sources, as well as mixture of unknown composition.

Over the past 40 years, the United States has engaged in various policies to integrate otherwise segregated black and white households within a shared space. However, little work has been done to fully articulate a moral argument for residential integration among black and white households. This paper offers what I refer to as the normative argument, which possesses two morally-impelled arguments for residential integration. Since the ethical appeal to integrate is often couched in the language of justice, I begin with a framework—based upon the work of the late philosopher John Rawls—for considering the moral aspects of residential integration. However, I go on to point out intractable problems related to the Rawlsian framework that would fail to flesh out all ethical considerations of the normative argument. From here, I provide a revised, or neo-Rawlsian, framework for understanding residential integration which addresses the aforementioned problems. This exercise is both important and necessary for the future of residential mixing, as better understanding the moral and ethical attributes of this discussion is, perhaps, the best means to lubricate the fundamental shift from 'spatial' to 'social' integration.

Background: The introduction of the inactivated poliovirus vaccine (IPV) represents a crucial step in the polio eradication endgame. This trial examined the safety and immunogenicity of IPV given alongside the measles–rubella and yellow fever vaccines at 9 months and when given as a full or fractional dose using needle and syringe or disposable-syringe jet injector. Methods: We did a phase 4, randomised, non-inferiority trial at three periurban government clinics in west Gambia. Infants aged 9–10 months who had already received oral poliovirus vaccine were randomly assigned to receive the IPV, measles–rubella, and yellow fever vaccines, singularly or in combination. Separately, IPV was given as a full intramuscular or fractional intradermal dose by needle and syringe or disposable-syringe jet injector at a second visit. The primary outcomes were seroprevalence rates for poliovirus 4–6 weeks post-vaccination and the rate of seroconversion between baseline and post-vaccination serum samples for measles, rubella, and yellow fever; and the post-vaccination antibody titres generated against each component of the vaccines. We did a per-protocol analysis with a non-inferiority margin of 10% for poliovirus seroprevalence and measles, rubella, and yellow fever seroconversion, and (1/3) log2 for log2-transformed antibody titres. This trial is registered with ClinicalTrials.gov, number NCT01847872. Findings: Between July 10, 2013, and May 8, 2014, we assessed 1662 infants for eligibility, of whom 1504 were enrolled into one of seven groups for vaccine interference and one of four groups for fractional dosing and alternative route of administration. The rubella and yellow fever antibody titres were reduced by co-administration but the seroconversion rates achieved non-inferiority in both cases (rubella, −4·5% [95% CI −9·5 to −0·1]; yellow fever, 1·2% [–2·9 to 5·5]). Measles and poliovirus responses were unaffected (measles, 6·8% [95% CI −1·4 to 14·9]; poliovirus serotype 1, 1·6% [–6·7 to 4·7]; serotype 2, 0·0% [–2·1 to 2·1]; serotype 3, 0·0% [–3·8 to 3·9]). Poliovirus seroprevalence was universally high (>97%) after vaccination, but the antibody titres generated by fractional intradermal doses of IPV did not achieve non-inferiority compared with full dose. The number of infants who seroconverted or had a four-fold rise in titres was also lower by the intradermal route. There were no safety concerns. Interpretation: The data support the future co-administration of IPV, measles–rubella, and yellow fever vaccines within the Expanded Programme on Immunization schedule at 9 months. The administration of single fractional intradermal doses of IPV by needle and syringe or disposable-syringe jet injector compromises the immunity generated, although it results in a high post-vaccination poliovirus seroprevalence. Funding: Bill & Melinda Gates Foundation.

A new strain of measles virus, D4-Hamburg, was imported from London to Hamburg in December 2008 and subsequently spread to Bulgaria, where an outbreak of >24,300 cases was observed. We analyzed spread of the virus to demonstrate the importance of addressing hard-to-reach communities within the World Health Organization European Region regarding access to medical care and vaccination campaigns. The D4-Hamburg strain appeared during 2009–2011 in Poland, Ireland, Northern Ireland, Austria, Greece, Romania, Turkey, Macedonia, Serbia, Switzerland, and Belgium and was repeatedly reimported to Germany. The strain was present in Europe for >27 months and led to >25,000 cases in 12 countries. Spread of the virus was prevalently but not exclusively associated with travel by persons in the Roma ethnic group; because this travel extends beyond the borders of any European country, measures to prevent the spread of measles should be implemented by the region as a whole.

Em pacientes com miosite, é comum o comprometimento pulmonar, e a presença de anticorpos anti-aminoacil-RNAt sintetase (anti-ARS) é preditora da presença ou do desenvolvimento de doença pulmonar intersticial (DPI). Uma entidade clínica distinta - a síndrome antissintetase - é caracterizada pela presença de anticorpos anti-ARS, miosite, DPI, artrite, fenômeno de Raynaud e "mãos de mecânico". O mais comum anticorpo anti-ARS é o anti-Jo-1. Anticorpos anti-ARS mais recentemente descritos podem conferir um fenótipo que é distinto daquele de pacientes com positividade para anti-Jo-1, sendo caracterizado por uma menor incidência de miosite e uma maior incidência de DPI. Nos pacientes com DPI relacionada à síndrome antissintetase, a resposta a medicações imunossupressoras é em geral favorável.In patients with myositis, the lung is commonly involved, and the presence of anti-aminoacyl-tRNA synthetase (anti-ARS) antibodies marks the presence or predicts the development of interstitial lung disease (ILD). A distinct clinical entity-antisynthetase syndrome-is characterized by the presence of anti-ARS antibodies, myositis, ILD, fever, arthritis, Raynaud's phenomenon, and mechanic's hands. The most common anti-ARS antibody is anti-Jo-1. More recently described anti-ARS antibodies might confer a phenotype that is distinct from that of anti-Jo-1-positive patients and is characterized by a lower incidence of myositis and a higher incidence of ILD. Among patients with antisynthetase syndrome-related ILD, the response to immunosuppressive medications is generally, but not universally, favorable.

Surveillance of rubella in England and Wales has included immunoglobulin M testing of oral (crevicular) fluid from reported case-patients since 1994. The need for laboratory confirmation to monitor rubella elimination is emphasized by poor sensitivity (51%, 95% confidence interval 48.9%–54.0%) and specificity (55%, 95% confidence interval 53.7%–55.6%) of the clinical case definition. During 1999–2008, oral fluid from 11,709 (84%) of 13,952 reported case-patients was tested; 143 (1.0%) cases were confirmed and 11,566 (99%) were discarded (annual investigation and discard rate of clinically suspected rubella cases was 2,208/100,000 population). Incidence of confirmed rubella increased from 0.50 to 0.77/1 million population when oral fluid testing was included. Oral fluid tests confirmed that cases were more likely to be in older, unvaccinated men. Testing of oral fluid has improved ascertainment of confirmed rubella in children and men and provided additional information for assessing UK progress toward the World Health Organization elimination goal.

To determine the origin of the virus associated with a measles outbreak in Menglian County, Yunnan Province, People’s Republic of China, in 2009, we conducted genetic analyses. Phylogenetic analyses based on nucleoprotein (N) and hemagglutinin (H) gene sequences showed that these Menglian viruses were not closely related to sequences of any World Health Organization (WHO) reference strains representing the 23 currently recognized genotypes. The minimum nucleotide divergence between the Menglian viruses and the most closely related reference strain, genotype D7, was 3.3% for the N gene and 3.0% for the H gene. A search of the databases of GenBank, WHO, and the Health Protection Agency Measles Nucleotide Surveillance showed that the Menglian viruses, together with the 2 older non-Menglian viruses, could be members of a new proposed measles genotype, d11. The new genotype designation will allow for better description of measles transmission patterns, especially in the Southeast Asian and Western Pacific regions.

During 2005–2006, nine measles virus (MV) genotypes were identified throughout the World Health Organization European Region. All major epidemics were associated with genotypes D4, D6, and B3. Other genotypes (B2, D5, D8, D9, G2, and H1) were only found in limited numbers of cases after importation from other continents. The genetic diversity of endemic D6 strains was low; genotypes C2 and D7, circulating in Europe until recent years, were no longer identified. The transmission chains of several indigenous MV strains may thus have been interrupted by enhanced vaccination. However, multiple importations from Africa and Asia and virus introduction into highly mobile and unvaccinated communities caused a massive spread of D4 and B3 strains throughout much of the region. Thus, despite the reduction of endemic MV circulation, importation of MV from other continents caused prolonged circulation and large outbreaks after their introduction into unvaccinated and highly mobile communities.

Quantitative computational models play an increasingly important role in modern biology. Such models typically involve many free parameters, and assigning their values is often a substantial obstacle to model development. Directly measuring in vivo biochemical parameters is difficult, and collectively fitting them to other experimental data often yields large parameter uncertainties. Nevertheless, in earlier work we showed in a growth-factor-signaling model that collective fitting could yield well-constrained predictions, even when it left individual parameters very poorly constrained. We also showed that the model had a "sloppy" spectrum of parameter sensitivities, with eigenvalues roughly evenly distributed over many decades. Here we use a collection of models from the literature to test whether such sloppy spectra are common in systems biology. Strikingly, we find that every model we examine has a sloppy spectrum of sensitivities. We also test several consequences of this sloppiness for building predictive models. In particular, sloppiness suggests that collective fits to even large amounts of ideal time-series data will often leave many parameters poorly constrained. Tests over our model collection are consistent with this suggestion. This difficulty with collective fits may seem to argue for direct parameter measurements, but sloppiness also implies that such measurements must be formidably precise and complete to usefully constrain many model predictions. We confirm this implication in our growth-factor-signaling model. Our results suggest that sloppy sensitivity spectra are universal in systems biology models. The prevalence of sloppiness highlights the power of collective fits and suggests that modelers should focus on predictions rather than on parameters.

Understanding the signals used by plants to attract seed disperses is a pervasive quest in evolutionary and sensory biology. Fruit size, colour, and odour variation have long been discussed in the controversial context of dispersal syndromes targeting olfactory-oriented versus visually-oriented foragers. Trade-offs in signal investment could impose important physiological constraints on plants, yet have been largely ignored. Here, we measure the reflectance and volatile organic compounds of a community of Malagasy plants and our results indicate that extant plant signals may represent a trade-off between olfactory and chromatic signals. Blue pigments are the most visually-effective--blue is a colour that is visually salient to all known seed dispersing animals within the study system. Additionally, plants with blue-reflecting fruits are less odiferous than plants that reflect primarily in other regions of the colour spectrum.

BACKGROUND:Measles is a highly infectious disease caused by measles virus (MeV). Despite the availability of a safe and cost-effective vaccine, measles is one of the world-leading causes of death in young children. Within Europe, there is a target for eliminating endemic measles in 2015, with molecular epidemiology required on 80% of cases for inclusion/exclusion of outbreak transmission chains. Currently, MeV is genotyped on the basis of a 450 nucleotide region of the nucleoprotein gene (N-450) and the hemagglutinin gene (H). However, this is not sufficiently informative for distinguishing endemic from imported MeV. We have developed an amplicon-based method for obtaining whole genome sequences (WGS) using NGS or Sanger methodologies from cell culture isolates or oral fluid specimens, and have sequenced over 60 samples, including 42 from the 2012 outbreak in the UK. RESULTS:Overall, NGS coverage was over 90% for approximately 71% of the samples tested. Analysis of 32 WGS excluding 3' and 5' termini (WGS-t) obtained from the outbreak indicates that the single nucleotide difference found between the two major groups of N-450 sequences detected during the outbreak is most likely a result of stochastic viral mutation during endemic transmission rather than of multiple importation events: earlier strains appear to have evolved into two distinct strain clusters in 2013, one containing strains with both outbreak-associated N-450 sequences. Additionally, phylogenetic analysis of each genomic region of MeV for the strains in this study suggests that the most information is acquired from the non-coding region located between the matrix and fusion protein genes (M/F NCR) and the N-450 genotyping sequence, an observation supported by entropy analysis across genotypes. CONCLUSIONS:We suggest that both M/F NCR and WGS-t could be used to complement the information from classical epidemiology and N-450 sequencing to address specific questions in the context of measles elimination.