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Although opioid-related harms have reached new heights across North America, the size of the gap in opioid agonist therapy (OAT) delivery for opioid-related health problems is unknown in most jurisdictions. This study sought to characterize the gap in OAT treatment using a cascade of care framework, and determine factors associated with engagement and retention in treatment.A population-based retrospective cohort study.Ontario, Canada.Individuals who sought medical care for opioid-related health problems or died from an opioid-related cause between 2005 and 2019.Monthly treatment status for buprenorphine/naloxone or methadone OAT between 2013 and 2019 (i.e., "off OAT", "retained on OAT6 months", "retained on OAT ≥6 months").Out of 122,811 individuals in the cohort, 97,516 (79.4%) received OAT at least once during the study period. There was decreasing 6-month treatment retention over time. Model results indicated that males had higher odds of being on OAT each month (odds ratio [OR]=1.26, 95% confidence interval [CI]: 1.23-1.28) but lower odds of OAT retention (OR=0.90, 95% CI: 0.88-0.92), while the reverse was observed for older individuals (monthly: OR=0.76 per 10-year increase, 95% CI: 0.76-0.77; retention: OR=1.36 per 10-year increase, 95% CI: 1.34-1.38) and individuals with higher neighbourhood income (e.g., highest income quintile, monthly: OR=0.79, 95% CI: 0.77-0.82; highest income quintile, retention: OR=1.15, 95% CI: 1.11-1.20). Individuals residing in rural areas and with a history of mental health diagnoses had poorer outcomes overall, including lower odds of being on OAT each month (rural: OR=0.75, 95% CI: 0.73-0.78; mental health: OR=0.89, 95% CI: 0.87-0.92) and OAT retention (rural: OR=0.79, 95% CI: 0.77-0.82; mental health: OR=0.81, 95% CI: 0.78-0.83), as well as higher risk of starting/stopping OAT (rural, starting OAT: HR=1.07, 95% CI: 1.05-1.10; mental health, starting OAT: HR=1.20, 95% CI: 1.18-1.23; rural, stopping OAT: HR=1.24, 95% CI: 1.22-1.26; mental health, stopping OAT: HR=1.11, 95% CI: 1.09-1.13). Individuals with a history of mental health diagnoses also had a higher risk of death, regardless of OAT status (off OAT death: HR=1.49, 95% CI: 1.33-1.66; on OAT death: HR=1.20, 95% CI: 1.09-1.31).Factors influencing engagement and declining retention in treatment with opioid agonist therapy in Ontario's health system include age, sex and neighbourhood income, as well as mental health diagnoses or residing in rural regions..

Purpose of Review The acute management of pain using regional anesthesia techniques may prevent the development of persistent postsurgical pain (PPP), ultimately improving patient outcomes and enhancing overall quality of life in postsurgical patients. The purpose of this review is to describe the current literature regarding the role of regional anesthesia techniques in the perioperative setting to address and prevent PPP. Recent Findings Data was collected and analyzed using results from randomized controlled studies stratified into categories based on different surgical subspecialties. Conclusions were drawn from each surgical category regarding the role of regional anesthesia and/or local analgesia in acute and chronic pain management on the long-term results seen in the studies analyzed. Summary Preoperative consultations and optimized perioperative analgesia using regional anesthesia and local analgesia play a fundamental role preventing and treating postoperative pain after many types of surgery by managing pain in the acute setting to mitigate the future development of PPP. Additional studies in different surgical subspecialties are needed to confirm the role regional anesthesia plays in chronic postsurgical pain (CPSP) prevention.

Introduction: Carbapenem-resistant Enterobacteriaceae (CRE) are problematic pathogens because infections caused by these organisms are associated with significant morbidity and mortality. These organisms often harbor multiple resistance mechanisms, which makes it difficult to treat their associated infections. Treatment typically consists of intravenous antibiotics that are selected based on the specific susceptibility pattern for the pathogen. Data on the use of oral antibiotics for the treatment of infections caused by CRE are sparse. Case Presentation: In this case, a 62-year-old female presented with a chronic left leg wound infection. She previously underwent surgical debridement and skin grafting, which were unsuccessful. She was initially prescribed minocycline for the infection, but the wound got re-infected. At this time, the wound had significant surrounding erythema, drainage, and slough. A wound culture was obtained and demonstrated growth of carbapenem-resistant Enterobacter cloacae and methicillin-resistant Staphylococcus aureus. The patient was initiated on oral omadacycline, and she responded with resolution of the cellulitis and wound drainage. Conclusion: This case demonstrates that omadacycline may be beneficial as an oral medication for the treatment of complicated acute bacterial skin and skin structure infections caused by carbapenem-resistant Enterobacter cloacae.

We developed lipid-like ionic liquids, containing 2-mercaptoimidazolium and 2-mercaptothiazolinium headgroups tethered to two long saturated alkyl chains, as carriers for in vitro delivery of plasmid HEK DNA into 293T cells. We employed a combination of modular design, synthesis, X-ray analysis, and computational modeling to rationalize the self-assembly and desired physicochemical and biological properties. The results suggest that thioamide-derived ionic liquids may serve as a modular platform for lipid-mediated gene delivery. This work represents a step toward understanding the structure-function relationships of these amphiphiles with long-range ordering and offering insight into design principles for synthetic vectors based on self-assembly behavior.

Background Within-household transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection has been identified as one of the main sources of spread of coronavirus disease 2019 (COVID-19) after lockdown restrictions and self-isolation guidelines are implemented. Secondary attack rates among household contacts are estimated to be 5–10 times higher than among non-household contacts, but it is unclear which individuals are more prone to transmit infection within their households. Methods Using address matching, a cohort was assembled of all individuals with laboratory-confirmed COVID-19 residing in private households in Ontario, Canada. Descriptive analyses were performed to compare characteristics of cases in households that experienced secondary transmission versus those that did not. Logistic regression models were fit to determine index case characteristics and neighborhood characteristics associated with transmission. Results Between January and July 2020, there were 26 714 individuals with COVID-19 residing in 21 226 households. Longer testing delays (≥5 vs 0 days; odds ratio [OR], 3.02; 95% confidence interval [CI], 2.53–3.60) and male gender (OR, 1.28; 95% CI, 1.18–1.38) were associated with greater odds of household secondary transmission, while being a healthcare worker (OR, .56; 95% CI, .50–.62) was associated with lower odds of transmission. Neighborhoods with larger average family size and a higher proportion of households with multiple persons per room were also associated with greater odds of transmission. Conclusions It is important for individuals to get tested for SARS-CoV-2 infection as soon as symptoms appear, and to isolate away from household contacts; this is particularly important in neighborhoods with large family sizes and/or crowded households.

Introduction Whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be detected in semen and transmitted sexually is a vital question that has, thus far, been inconclusive. Prior studies, with limited numbers, have included men in various stages of infection with most in the recovery phase of the illness. The timing of test results and severity of illness has made recruiting study participants a significant challenge. Our pilot study will examine semen from men with a recent diagnosis of COVID-19 as well as those in the convalescent phase to determine if SARS-CoV-2 can be detected and its relationship, if any, with the severity of the disease. Methods Eighteen men with a median age of 32 (range, 24-57) who tested positive for COVID-19 by rt-PCR analysis were enrolled and provided a semen sample. The study group demonstrated symptoms of COVID-19 ranging from asymptomatic to moderate and none required hospitalization. Samples were subjected to viral RNA extraction and then processed by real-time RT-PCR using the US Centers for Disease Control and Prevention (CDC, USA) panel of 2019-Novel Coronavirus (2019-nCoV) primers and probes to detect the presence of SARS-CoV-2 RNA. Results Length of time from diagnosis to providing a specimen ranged from 1 to 28 days (median, 6 days). Fifteen participants were symptomatic and three were asymptomatic, including recovering men, at the time of semen collection. No SARS-CoV-2 was detected in any of the semen samples. Conclusion Based on these preliminary results and consistent with prior findings, we suggest SARS-CoV-2 is not present in semen during the acute or convalescent phase of COVID-19.

Background Opioid-related mortality continues to rise across North America, and mortality rates have been further exacerbated by the COVID-19 pandemic. This study sought to provide an updated picture of trends of opioid-related mortality for Ontario, Canada between January 2003 and December 2020, in relation to age and sex. Methods Using mortality data from the Office of the Chief Coroner for Ontario, we applied Bayesian Poisson regression to model age/sex mortality per 100,000 person-years, including random walks to flexibly capture age and time effects. Models were also used to explore how trends might continue into 2022, considering both pre- and post-COVID-19 courses. Results From 2003 to 2020, there were 11,633 opioid-related deaths in Ontario. A shift in the age distribution of mortality was observed, with the greatest mortality rates now among younger individuals. In 2003, mortality rates reached maximums at 5.5 deaths per 100,000 person-years (95% credible interval: 4.0–7.6) for males around age 44 and 2.2 deaths per 100,000 person-years (95% CI: 1.5–3.2) for females around age 51. As of 2020, rates have reached maximums at 67.2 deaths per 100,000 person-years (95% CI: 55.3–81.5) for males around age 35 and 16.8 deaths per 100,000 person-years (95% CI: 12.8–22.0) for females around age 37. Our models estimate that opioid-related mortality among the younger population will continue to grow, and that current conditions could lead to male mortality rates that are more than quadruple those of pre-pandemic estimations. Conclusions This analysis may inform a refocusing of public health strategy for reducing rising rates of opioid-related mortality, including effectively reaching both older and younger males, as well as young females, with health and social supports such as treatment and harm reduction measures.

Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. Here we present CATCH, a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa. CATCH designs optimal probe sets, with a specified number of oligonucleotides, that achieve full coverage of, and scale well with, known sequence diversity. We focus on applying CATCH to capture viral genomes in complex metagenomic samples. We design, synthesize, and validate multiple probe sets, including one that targets the whole genomes of the 356 viral species known to infect humans. Capture with these probe sets enriches unique viral content on average 18-fold, allowing us to assemble genomes that could not be recovered without enrichment, and accurately preserves within-sample diversity. We also use these probe sets to recover genomes from the 2018 Lassa fever outbreak in Nigeria and to improve detection of uncharacterized viral infections in human and mosquito samples. The results demonstrate that CATCH enables more sensitive and cost-effective metagenomic sequencing.

BACKGROUNDAs a result of low numbers of pediatric cases early in the COVID-19 pandemic, pediatric household transmission of SARS-CoV-2 remains an understudied topic. This study sought to determine whether there are differences in the odds of household transmission for younger children compared to older children.METHODSWe assembled a cohort of all individuals in Ontario, Canada with laboratory-confirmed SARS-CoV-2 infection between June 1 and December 31, 2020. The cohort was restricted to individuals residing in private households (N=132,232 cases in 89,191 households), identified through an address matching algorithm. Analysis focused on households in which the index case was aged RESULTSA total of 6,280 households had pediatric index cases, and 1,717 (27.3%) experienced secondary transmission. Children aged 0-3 years had the highest odds of household transmission compared to children aged 14-17 years (model adjusted for gender, month of disease onset, testing delay, and average family size: 1.43, 95% CI: 1.17-1.75). This association was similarly observed in sensitivity analyses defining secondary cases as 2-14 days or 4-14 days after the index case, and stratified analyses by presence of symptoms, association with a school/childcare outbreak, or school/childcare reopening. Children aged 4-8 years and 9-13 years also had increased odds of transmission (4-8: 1.40, 95% CI: 1.18-1.67; 9-13: 1.13, 95% CI: 0.97-1.32).CONCLUSIONSThis study suggests that younger children are more likely to transmit SARS-CoV-2 infection compared to older children, and the highest odds of transmission was observed for children aged 0-3 years. Differential infectivity of pediatric age groups has implications for infection prevention controls within households, as well as schools/childcare, to minimize risk of household secondary transmission.

BackgroundMinimizing delays in disease identification and reporting improves the timeliness of surveillance data, and can reduce transmission of COVID-19. Our study investigates factors associated with timely testing and reporting of COVID-19 during the first pandemic wave in one province of Canada.MethodsWe identified all persons with confirmed SARS-CoV-2 infection residing in private households across the largest province of Canada, Ontario from the date of the first confirmed case in Ontario (January 25) to July 19, 2020. Our primary outcomes consisted of: (1) specimen collection within 1 day of symptom onset (test seeking), (2) test result reported to local public health within 1 day of specimen collection (test turnaround), and (3) entry of case data into the provincial database within 1 day of reporting test results (reporting). We examined 14 covariates including eight case characteristics, and six neighborhood characteristics. In addition to descriptive measures, logistic regression models were fitted. Unadjusted models included the covariate alone, while adjusted models included age, gender, month, and region.FindingsAmong 27,198 COVID-19 cases from January 25 2020 to July 19 2020, 28·7% had timely test seeking, 40·2% had timely test turnaround, and 75·5% had timely reporting. Male gender had lower odds of timely test seeking (adjusted odds ratio [aOR] 0·79 [95% CI: 0·74-0·85]) compared to females. Healthcare worker status (aOR 2·77 [95% CI: 2·52-3·05] compared to non-healthcare workers), and age ≥80 years (aOR 1·59 [95% CI: 1·33-1·91] compared to 40-59 year olds) were associated with timely test seeking. Specimen collection on Fridays and Saturdays (aOR 0·88 [95% CI: 0·79-0·98], aOR 0·83 [95% CI: 0·74-0·92] respectively, compared to Wednesdays) had lower odds of timely test turnaround. Urban areas (aOR 1·55 [95% CI: 1·41-1·70] compared to rural areas) were associated with timely test turnaround. Urban areas (aOR 0·79 [95% CI: 0·70-0·89] compared to rural areas) were less likely to have timely reporting.InterpretationIndividual, neighborhood, and administrative factors are associated with timely testing and reporting of SARS-CoV-2 infections. These findings present considerations for developing targeted strategies to minimize delays and improve timely testing and reporting of SARS-CoV-2 infections.FundingThis study was funded by Public Health Ontario.Research in ContextEvidence before this studyWe searched PubMed and medRxiv up to November 30 2020 to identify studies examining the impact of delays in the disease reporting process on the public health response to COVID-19. We used the search terms (“2019-nCoV” OR “COVID-19” OR “SARS-CoV-2”) AND (“delays” OR “timely” OR “reporting” OR “test” OR “turnaround”), and reviewed reference lists of any relevant articles in the original search. Numerous modeling studies have highlighted the importance of timely testing and reporting to effectively control the spread of COVID-19. Additional studies have also identified delays of only 1 day in testing were associated with increased risk of secondary transmission within households. However no study has described the multiple delays in the disease reporting process of COVID-19 and examined factors associated with timely disease reporting using a large population cohort.Added value of this studyOur study described timely test seeking, test turnaround, and reporting for laboratory-confirmed COVID-19 cases in Ontario, Canada and identified associated individual, neighbourhood, and administrative factors. To the best of our knowledge, this study is the first to describe detailed delays in the disease reporting process of COVID-19 and identified associated factors using a large population cohort.Implications of all the available evidenceNumerous individual, neighborhood, and administrative characteristics are associated with timely testing and reporting of COVID-19. These identified factors may be used to develop strategies such as broadened test access, prioritization of vulnerable populations, and increased testing capacity to reduce delays in testing and reporting and improve the effectiveness of public health response to COVID-19.

BACKGROUNDWithin-household transmission of SARS-CoV-2 infection has been identified as one of the main sources of spread of COVID-19 after lockdown restrictions and self-isolation guidelines are implemented. Secondary attack rates among household contacts are estimated to be five to ten times higher than among non-household contacts, but it is unclear which individuals are more prone to transmit infection within their households.METHODSUsing address matching, a cohort was assembled of all laboratory-confirmed cases of COVID-19 residing in private households in Ontario, Canada. Descriptive analyses were performed to compare characteristics of cases in households that experienced secondary transmission versus those that did not. Logistic regression models were fit to determine index case characteristics and neighbourhood characteristics associated with transmission.FINDINGSBetween January and July, 2020, there were 26,152 cases of COVID-19 residing in 21,226 households. Longer testing delays (≥5 days versus 0 days OR=3·02, 95% CI: 2·53 - 3·60) and male sex (OR=1·28, 95% CI: 1·18 - 1·38) were associated with greater odds of household secondary transmission, while being a healthcare worker (OR=0·56, 95% CI: 0·50 - 0·62) was associated with lower odds of transmission. Neighbourhoods with larger average economic family size and a higher proportion of households with multiple persons per room were also associated with greater odds of transmission.INTERPRETATIONIt is important for individuals to get tested for SARS-CoV-2 infection as soon as symptoms appear, and to isolate away from household contacts; this is particularly important in neighbourhoods with large family sizes and/or crowded households.FUNDINGThis study was supported by Public Health Ontario.Research in ContextEVIDENCE BEFORE THIS STUDYWe searched PubMed and Google Scholar up to September 3, 2020 to identify individual-level cohort studies or meta-analyses on household transmission of COVID-19. We used the search terms (“COVID” OR “SARS-CoV-2”) AND (“household” [Title]), and also reviewed the reference lists of any studies found during the search to identify additional studies. We considered studies that reported secondary attack rates and/or other measures of association (i.e., relative risk, odds ratio, or hazard ratio) for household transmission. We did not consider any modelling studies, studies that focused specifically on children, or small case studies that included less than three households. The search returned 53 studies, of which 51 were included in three meta-analyses. Pooled household secondary attack rates from the three meta-analyses were 19%, 27%, and 30%; secondary attack rates in households were estimated to be five to ten times as high as in non-household settings. Most studies were conducted in Asia and identified households from contact tracing, with individual studies reporting on fewer than 6000 households. Most studies did not consider households with no secondary transmission, and focused on a limited set of secondary case characteristics.ADDED VALUE OF THIS STUDYWe applied an address matching algorithm, which identified 21,226 private households of laboratory-confirmed cases of COVID-19 in Ontario, Canada. Ontario has the advantage of a universal healthcare system and population-wide data for the entire province. To our knowledge, this study contains the largest number of private households with at least one confirmed case of COVID-19. We compared a variety of individual- and neighbourhood-level characteristics of households with and without secondary transmission. We also applied logistic regression models to determine index case characteristics associated with transmission, which gave important insights into factors that may help reduce secondary transmission in households.IMPLICATIONS OF ALL THE AVAILABLE EVIDENCEFindings from this study and existing evidence suggest that testing delays and household crowding play important roles in whether household secondary transmission occurs. Odds of household transmission may be reduced by cases seeking testing as soon as symptoms appear, and self-isolating outside the home or in a room alone if possible. These strategies may be considered by public health officials to reduce household transmission and mitigate local spread of COVID-19. Future research should further investigate the role of children and youth in household transmission.

Importance As a result of low numbers of pediatric cases early in the COVID-19 pandemic, pediatric household transmission of SARS-CoV-2 remains an understudied topic. Objective To determine whether there are differences in the odds of household transmission by younger children compared with older children. Design, Setting, and Participants This population-based cohort study took place between June 1 and December 31, 2020, in Ontario, Canada. Private households in which the index case individual of laboratory-confirmed SARS-CoV-2 infection was younger than 18 years were included. Individuals were excluded if they resided in apartments missing suite information, in households with multiple index cases, or in households where the age of the index case individual was missing. Exposures Age group of pediatric index cases categorized as 0 to 3, 4 to 8, 9 to 13, and 14 to 17 years. Main Outcomes and Measures Household transmission, defined as households where at least 1 secondary case occurred 1 to 14 days after the pediatric index case. Results A total of 6280 households had pediatric index cases, and 1717 households (27.3%) experienced secondary transmission. The mean (SD) age of pediatric index case individuals was 10.7 (5.1) years and 2863 (45.6%) were female individuals. Children aged 0 to 3 years had the highest odds of transmitting SARS-CoV-2 to household contacts compared with children aged 14 to 17 years (odds ratio, 1.43; 95% CI, 1.17-1.75). This association was similarly observed in sensitivity analyses defining secondary cases as 2 to 14 days or 4 to 14 days after the index case and stratified analyses by presence of symptoms, association with a school/childcare outbreak, or school/childcare reopening. Children aged 4 to 8 years and 9 to 13 years also had increased odds of transmission (aged 4-8 years: odds ratio, 1.40; 95% CI, 1.18-1.67; aged 9-13 years: odds ratio, 1.13; 95% CI, 0.97-1.32). Conclusions and Relevance This study suggests that younger children may be more likely to transmit SARS-CoV-2 infection compared with older children, and the highest odds of transmission was observed for children aged 0 to 3 years. Differential infectivity of pediatric age groups has implications for infection prevention within households, as well as schools/childcare, to minimize risk of household secondary transmission. Additional population-based studies are required to establish the risk of transmission by younger pediatric index cases.

Purpose: Growing evidence implicates ambient air pollutants in the development of major chronic diseases and premature mortality. However, epidemiologic evidence linking air pollution to diabetes remains inconclusive. This study sought to determine the relationships between selected air pollutants (nitrogen dioxide [NO2], fine particulate matter [PM2.5], ozone [O3], and oxidant capacity [Ox; the redox-weighted average of O3 and NO2]) and the incidence of diabetes, as well as the risk of cardiovascular or diabetes mortality among individuals with prevalent diabetes. Research Design and Methods: We followed two cohorts, which included 4.8 million Ontario adults free of diabetes and 452,590 Ontario adults with prevalent diabetes, from 2001 to 2015. Area-level air pollution exposures were assigned to subjects’ residential areas, and outcomes were ascertained using health administrative data with validated algorithms. We estimated hazard ratios for the association between each air pollutant and outcome using Cox proportional hazards models, and modelled the shape of the concentration-response relationships. Results: Over the study period, 790,461 individuals were diagnosed with diabetes. Among those with prevalent diabetes, 26,653 died from diabetes and 64,773 died from cardiovascular diseases. For incident diabetes, each IQR increase in NO2 had a hazard ratio of 1.04 (95% CI: 1.03–1.05). This relationship was relatively robust to all sensitivity analyses considered, and exhibited a near-linear shape. There were also positive associations between incident diabetes and PM2.5, O3, and Ox, but these estimates were somewhat sensitive to different models considered. Among those with prevalent diabetes, almost all pollutants were associated with increased diabetes and cardiovascular mortality risk. The strongest association was observed between diabetes mortality and exposure to NO2 (HR = 1.08, 95% CI: 1.02–1.13). Conclusions: Selected air pollutants, especially NO2, were linked to an increased risk of incident diabetes, as well as risk of cardiovascular or diabetes mortality among persons with prevalent diabetes. As NO2 is frequently used as a proxy for road traffic exposures, this result may indicate that traffic-related air pollution has the strongest effect on diabetes etiology and survival after diabetes development. Keywords: Air pollution, Diabetes, Cardiovascular, Mortality, Incidence, Epidemiology

How viruses evolves within hosts can dictate infection outcomes; however, accurately reconstructing this process is challenging from samples with low virus concentrations. We evaluated our highly multiplexed amplicon approach - PrimalSeq - to enrich for viral RNA and demonstrate how virus concentration, sequencing coverage depth, primer mismatches, and technical replicates influence the accuracy of measuring intrahost virus diversity. Using this data, we developed an open source experimental protocol and computational tool (iVar; github.com/andersen-lab/ivar) for using PrimalSeq to measure intrahost virus diversity using Illumina and compared the results to Oxford Nanopore sequencing. Furthermore, we demonstrate the utility of our approach by measuring Zika and West Nile virus diversity from varied sample types, and show that the accumulation of genetic diversity is heavily influenced by experimental and biological systems.

Introduction It is unknown whether urban green space is associated with reduced risk of major neurological conditions, especially dementia and stroke. Methods Retrospective, population-based cohorts were created for each study outcome, including 1.7 and 4.3 million adults in Ontario, Canada for dementia and stroke, respectively. Residential green space was quantified using the satellite-derived Normalized Difference Vegetation Index. Incidence was ascertained using health administrative data with validated algorithms. Mixed-effects Cox models were used to estimate hazard ratios per interquartile range increase in green space exposure. Results Between 2001 and 2013, 219,013 individuals were diagnosed with dementia and 89,958 had a stroke. The hazard ratio per interquartile range increase in green space was 0.97 (95% CI: 0.96–0.98) for dementia and 0.96 (0.95–0.98) for stroke. Estimates remained generally consistent in sensitivity analyses. Discussion Increased exposure to urban green space was associated with reduced incidence of dementia and stroke. To our knowledge, this is the first population-based cohort study to assess these relationships.

Background Studies have reported increasing incidence rates of paediatric diabetes, especially among those aged 0–5 years. Epidemiological evidence linking ambient air pollution to paediatric diabetes remains mixed. Objective This study investigated the association between maternal and early-life exposures to common air pollutants (NO2, PM2.5, O3, and oxidant capacity [Ox; the redox-weighted average of O3 and NO2]) and the incidence of paediatric diabetes in children up to 6 years of age. Methods All registered singleton births in Ontario, Ca nada occurring between April 1st, 2006 and March 31st, 2012 were included through linkage from health administrative data. Monthly exposures to NO2, PM2.5, O3, and Ox were estimated across trimesters, the entire pregnancy period and during childhood. Random effects Cox proportional hazards models were used to assess the relationships with paediatric diabetes incidence while controlling for important covariates. We also modelled the shape of concentration-response (CR) relationships. Results There were 1094 children out of a cohort of 754,698 diagnosed with diabetes before the age of six. O3 exposures during the first trimester of pregnancy were associated with paediatric diabetes incidence (hazard ratio (HR) per interquartile (IQR) increase = 2.00, 95% CI: 1.04–3.86). The CR relationship between O3 during the first trimester and paediatric diabetes incidence appeared to have a risk threshold, in which there was little-to-no risk below 25 ppb of O3, while above this level risk increased sigmoidally. No other associations were observed. Conclusion O3 exposures during a critical period of development were associated with an increased risk of paediatric diabetes incidence.

Background/Aim: A growing body of epidemiologic evidence has identified urban green space as a potential modifiable factor that can improve human health, especially mental health. However, little i...

Background/Aim: Diabetes research has recently taken into consideration the potential influence of air pollution on diabetes risk. However, epidemiologic evidence linking air pollution to diabetes ...

Metagenomic sequencing has the potential to transform microbial detection and characterization, but new tools are needed to improve its sensitivity. We developed CATCH (Compact Aggregation of Targets for Comprehensive Hybridization), a computational method to enhance nucleic acid capture for enrichment of diverse microbial taxa. CATCH designs compact probe sets that achieve full coverage of known sequence diversity and that scale well with this diversity. To illustrate applications of CATCH, we focused on capturing viral genomes. We designed, synthesized, and validated multiple probe sets, including one that targets whole genomes of the 356 viral species known to infect humans. Capture with these probe sets enriched unique viral content on average 18× and allowed us to assemble genomes that we could not otherwise recover, while accurately preserving within-sample diversity. We used this approach to recover genomes from the 2018 Lassa fever outbreak in Nigeria and to improve detection of viral infections in samples with unknown content. Together, this work demonstrates a path toward more sensitive, cost-effective metagenomic sequencing.

Mitigating global infectious disease requires diagnostic tools that are sensitive, specific, and rapidly field deployable. In this study, we demonstrate that the Cas13-based SHERLOCK (specific high-sensitivity enzymatic reporter unlocking) platform can detect Zika virus (ZIKV) and dengue virus (DENV) in patient samples at concentrations as low as 1 copy per microliter. We developed HUDSON (heating unextracted diagnostic samples to obliterate nucleases), a protocol that pairs with SHERLOCK for viral detection directly from bodily fluids, enabling instrument-free DENV detection directly from patient samples in, NIH (Grants AI-100190, 1R01-HG009761, 1R01-MH110049, and 1DP1-HL141201)

This study introduces a novel class of imidazolium- and ammonium-based ionic liquids possessing two C12 and C14 tails and thioether linkers designed for lipoplex-mediated DNA delivery. Imidazolium-based ionic liquids displayed efficient gene delivery properties with low toxicity. Thiol-yne click chemistry was employed for the facile and robust synthesis of these thioether-based cationic lipioids with enhanced lipophilicity and low fluidity.

Zika virus (ZIKV) is currently causing an unprecedented pandemic linked to severe congenital syndromes1,2. In July 2016, mosquito-borne ZIKV transmission was first reported in the continental United States and since then, hundreds of locally acquired infections have been described3. To gain insights into the timing, source, and likely route(s) of introduction into the United States, we tracked the virus from its first detection in Miami, Florida by direct sequencing of ZIKV genomes from infected patients and Aedes aegypti mosquitoes. We detected at least four distinct ZIKV introductions and estimate that 11-52 introductions contributed to the outbreak in Florida. Furthermore, our data suggests that ZIKV transmission likely started in the spring of 2016 - several months before initial detection. By analyzing epidemiological, surveillance, and genetic data, we discovered that several spatially distinct ZIKV transmission zones were likely portions of the same outbreak, rather than isolated events. Our analyses show that most introductions are linked to the Caribbean, which is supported by the high incidence rates and traffic, especially via cruises, from the region into Miami. By comparing mosquito abundance and travel capacity across the United States, we find that southern Florida is especially vulnerable to ZIKV introductions and at risk of repeat occurrences. By tracking the virus from its initial introduction into the United States, we provide a deeper understanding of how ZIKV initiates and sustains transmission in new regions.

Although the recent Zika virus (ZIKV) epidemic in the Americas and its link to birth defects have attracted a great deal of attention1,2, much remains unknown about ZIKV disease epidemiology and ZIKV evolution, in part owing to a lack of genomic data. Here we address this gap in knowledge by using multiple sequencing approaches to generate 110 ZIKV genomes from clinical and mosquito samples from 10 countries and territories, greatly expanding the observed viral genetic diversity from this outbreak. We analysed the timing and patterns of introductions into distinct geographic regions; our phylogenetic evidence suggests rapid expansion of the outbreak in Brazil and multiple introductions of outbreak strains into Puerto Rico, Honduras, Colombia, other Caribbean islands, and the continental United States. We find that ZIKV circulated undetected in multiple regions for many months before the first locally transmitted cases were confirmed, highlighting the importance of surveillance of viral infections. We identify mutations with possible functional implications for ZIKV biology and pathogenesis, as well as those that might be relevant to the effectiveness of diagnostic tests., National Institutes of Health (U.S.) (Grant NIAID U19AI110818)

Oppositional defiant disorder (ODD) involves patterns of negativistic, defiant, disobedient, and hostile behavior toward authority figures that last for at least 6 months (American Psychiatric Association [APA], 2013). ODD is among the most prevalent and resource-demanding mental health problems for children and adolescents (Loeber, Burke, Lahey, Winters, & Zera, 2000), with 5% to 10% of children ages 8 to 16 years having notable ODD behavior problems (Fraser & Wray, 2008). Characteristics of ODD include persistent stubbornness and refusal to comply with instructions, unwillingness to compromise with adults or peers, persistently and deliberately testing limits, failing to accept responsibility for one's own actions and blaming others for one's own mistakes, deliberately annoying others, and frequently losing one's temper (APA, 2013). ODD has also been associated with excessive arguing, cognitive and social deficits, and significantly problematic adult-child and child-peer interactions (Greene et al., 2002). According to Finger et al. (2011), youth with ODD demonstrate high rates of aggressive and antisocial behaviors, with a subset displaying callousness and psychopathic traits, including a lack of guilt, empathy, and remorse. It is sometimes difficult to determine whether a child truly meets the criteria for having an ODD diagnosis because many of the behavioral qualifications are commonly seen among youth in early childhood and adolescence (Fraser & Wray, 2008). If a child's behaviors consistently cause distress to the family system and have an effect on his or her social and educational functioning, further evaluation is warranted. ODD has been linked to many other comorbid disorders, such as anxiety; depression; and, most commonly, attention-deficit/ hyperactivity disorder (ADHD; Biederman, Newcorn, & Feldman, 2007). Jensen et al. (2001) found that ODD occurred in 30% to 60% of children diagnosed with ADHD. ODD has historically been considered a male problem (Loeberet al., 2000), and the developmental factors that accounted for symptoms in girls were only partly understood (Hipwell et al., 2002; Messer, Goodman, Rowe, Meltzer, & Maughan, 2006). One study (Munkvold, Lundervold, & Manger, 2011) found that the impact of symptoms and the prevalence of ODD were higher in boys than in girls. Fraser and Wray (2008) found that girls were more likely to demonstrate symptoms after the onset of puberty, during the adolescent years, whereas boys more frequently showed symptoms in early childhood. The manifestation of ODD in boys also differed from the manifestation of ODD in girls in that boys were more likely to demonstrate physical aggression or threaten others (overt aggression), whereas girls were more likely to harm or disrupt relationships with others (Crick & Grotpeter, 1995), better known today as relational aggression. Individuals diagnosed with early-onset ODD were more likely to have been abused by their parents, drop out of school, engage in serious crimes, and have greater long-term involvement with the mental health system. Because ODD is such a serious and common disorder and is comorbid with other disorders, it is important to determine whether counseling and psychotherapy reduce symptoms in individuals diagnosed with ODD. Primary counseling strategies discussed in the literature include family interventions and individual and group counseling approaches with children and adolescents. Family interventions, especially parent training programs, have been empirically supported as efficacious (Lonigan, Elbert, & Johnson, 1998). Brestan and Eyberg's (1998) research indicated that families completing a parent training program achieved both short- and long-term treatment goals. In addition to their known effect on child conduct problems, parenting group interventions promoted both child and family competencies (Borden, Schultz, Herman, & Brooks, 2010). Participants in a study of self-administered videotape parent training reported significantly fewer child behavior problems, reduced levels of stress, and less use of physical punishment (Webster-Stratton, 1990). …

BackgroundFor decades, human infections with Zika virus (ZIKV), a mosquito-transmitted flavivirus, were sporadic, associated with mild disease, and went underreported since symptoms were similar to other acute febrile diseases endemic in the same regions. Recent reports of severe disease associated with ZIKV, including Guillain-Barré syndrome and severe fetal abnormalities, have greatly heightened awareness. Given its recent history of rapid spread in immune naïve populations, it is anticipated that ZIKV will continue to spread in the Americas and globally in regions where competent Aedes mosquito vectors are found. Globally, dengue virus (DENV) is the most common mosquito-transmitted human flavivirus and is both well-established and the source of outbreaks in areas of recent ZIKV introduction. DENV and ZIKV are closely related, resulting in substantial antigenic overlap. Through a mechanism known as antibody-dependent enhancement (ADE), anti-DENV antibodies can enhance the infectivity of DENV for certain classes of immune cells, causing increased viral production that correlates with severe disease outcomes. Similarly, ZIKV has been shown to undergo ADE in response to antibodies generated by other flaviviruses. However, response to DENV antibodies has not yet been investigated.Methodology / Principal FindingsWe tested the neutralizing and enhancing potential of well-characterized broadly neutralizing human anti-DENV monoclonal antibodies (HMAbs) and human DENV immune sera against ZIKV using neutralization and ADE assays. We show that anti-DENV HMAbs, cross-react, do not neutralize, and greatly enhance ZIKV infection in vitro. DENV immune sera had varying degrees of neutralization against ZIKV and similarly enhanced ZIKV infection.Conclusions / SignificanceOur results suggest that pre-existing DENV immunity will enhance ZIKV infection in vivo and may increase disease severity. A clear understanding of the interplay between ZIKV and DENV will be critical in informing public health responses in regions where these viruses co-circulate and will be particularly valuable for ZIKV and DENV vaccine design and implementation strategies.Author SummaryRecent reports of severe disease, including developmental problems in newborns, have greatly heightened public health awareness of Zika virus (ZIKV), a mosquito-transmitted virus for which there is no vaccine or treatment. It is anticipated that ZIKV will continue to spread in the Americas and globally in regions where competent mosquitoes are found. Dengue virus (DENV), a closely related mosquito-transmitted virus is well-established in regions of recent ZIKV introduction and spread. It is increasingly common that individuals living in these regions may have had a prior DENV infection or may be infected with DENV and ZIKV at the same time. However, very little is known about the impact of DENV infections on ZIKV disease severity. In this study, we tested the ability of antibodies against DENV to prevent or enhance ZIKV infection in cell culture-based assays. We found that DENV antibodies can greatly enhance ZIKV infection in cells.Our results suggest that ZIKV infection in individuals that had a prior DENV infection may experience more severe clinical manifestations. The results of this study provide a better understanding of the interplay between ZIKV and DENV infections that can serve to inform public health responses and vaccine strategies.

Marine actinomycetes in the genus Salinispora fail to grow when seawater is replaced with deionized (DI) water in complex growth media. While bioinformatic analyses have led to the identification of a number of candidate marine adaptation genes, there is currently no experimental evidence to support the genetic basis for the osmotic requirements associated with this taxon. One hypothesis is that the lineage-specific loss of mscL is responsible for the failure of strains to grow in media prepared with DI water. The mscL gene encodes a conserved transmembrane protein that reduces turgor pressure under conditions of acute osmotic downshock. In the present study, the mscL gene from a Micromonospora strain capable of growth on media prepared with DI water was transformed into S. tropica strain CNB-440. The single-copy, chromosomal genetic complementation yielded a recombinant Salinispora mscL + strain that demonstrated an increased capacity to survive osmotic downshock. The enhanced survival of the S. tropica transformant provides experimental evidence that the loss of mscL is associated with the failure of Salinispora spp. to grow in low-osmotic-strength media.

SummaryLow-nutrient media and long incubation times facilitated the cultivation of 20 taxonomically diverse Gram-negative marine bacteria within the phyla Bacteroidetes and Proteobacteria. These strains comprise as many as three new families and include members of clades that had only been observed using culture-independent techniques. Chemical studies of the type strains representing two new families within the order Cytophagales led to the isolation of nine new alkaloid secondary metabolites that can be grouped into four distinct structure classes, including azepinones, aziridines, quinolones, and pyrazinones. Several of these compounds possess antibacterial properties and appear, on structural grounds, to be produced by amino acid-based biosynthetic pathways. Our results demonstrate that relatively simple cultivation techniques can lead to the isolation of new bacterial taxa that are capable of the production of alkaloid secondary metabolites with antibacterial activities. These findings support continued investment in cultivation techniques as a method for natural product discovery.

The human infectious disease anthrax is caused by the sporeforming, Gram-positive bacterium Bacillus anthracis. The disease, which is most common in those that handle infected farm animals, has also been used as a bioterrorism weapon. In 2001, just a week after the World Trade Center attacks, anthrax was deliberately spread through the US postal system by sending letters with powdered B. anthracis spores. This caused 22 cases of anthrax infection and ultimately claimed five lives. [1] Depending upon the method of exposure (inhalation of spores and direct bacterial contact, among others) B. anthracis infections can require prolonged treatment often for six months with a variety of antibiotics. The pulmonary form of anthrax is considered a medical emergency that may require continuous intravenous therapy with potent antibiotics. In the event of a bioterrorism attack, individuals exposed to B. anthracis will be given antibiotics prior to the onset of the illness. A vaccine has been developed but is not yet available to the general public. [2] Given the severity of this disease, and the fact that it can be spread by aerosol dispersal, the development of effective new antibiotics remains a high priority. As a resource for developing microbial antibiotics, we have focused our efforts on marine microorganisms, particularly those that are in the deep oceans. Examination of a Streptomyces species (our strain CNH365), isolated from near-shore marine sediments found near Santa Barbara, CA, showed that culture extracts possessed significant activity against B. anthracis and methicillin-resistant Staphylococcus aureus in broth dilution assays. Subsequent fractionation of the extract following antibacterial activities yielded a pure

The isolation and structure elucidation of a new meroterpenoid, actinoranone (1), produced by a marine bacterium closely related to the genus Streptomyces is reported. Actinoranone is composed of an unprecedented dihydronaphthalenone polyketide linked to a bicyclic diterpenoid. The stereochemistry of 1 was defined by application of the advanced Mosher’s method and by interpretation of spectroscopic data. Actinoranone (1) is significantly cytotoxic to HCT-116 human colon cancer cells with an LD50 = 2.0 μg/mL.

The human infectious disease anthrax is caused by the sporeforming, Gram-positive bacterium Bacillus anthracis. The disease, which is most common in those that handle infected farm animals, has also been used as a bioterrorism weapon. In 2001, just a week after the World Trade Center attacks, anthrax was deliberately spread through the US postal system by sending letters with powdered B. anthracis spores. This caused 22 cases of anthrax infection and ultimately claimed five lives. [1] Depending upon the method of exposure (inhalation of spores and direct bacterial contact, among others) B. anthracis infections can require prolonged treatment often for six months with a variety of antibiotics. The pulmonary form of anthrax is considered a medical emergency that may require continuous intravenous therapy with potent antibiotics. In the event of a bioterrorism attack, individuals exposed to B. anthracis will be given antibiotics prior to the onset of the illness. A vaccine has been developed but is not yet available to the general public. [2] Given the severity of this disease, and the fact that it can be spread by aerosol dispersal, the development of effective new antibiotics remains a high priority. As a resource for developing microbial antibiotics, we have focused our efforts on marine microorganisms, particularly those that are in the deep oceans. Examination of a Streptomyces species (our strain CNH365), isolated from near-shore marine sediments found near Santa Barbara, CA, showed that culture extracts possessed significant activity against B. anthracis and methicillin-resistant Staphylococcus aureus in broth dilution assays. Subsequent fractionation of the extract following antibacterial activities yielded a pure

The isolation and structure elucidation of a new meroterpenoid, actinoranone (1), produced by a marine bacterium closely related to the genus Streptomyces is reported. Actinoranone is composed of an unprecedented dihydronaphthalenone polyketide linked to a bicyclic diterpenoid. The stereochemistry of 1 was defined by application of the advanced Mosher's method and by interpretation of spectroscopic data. Actinoranone (1) is significantly cytotoxic to HCT-116 human colon cancer cells with an LD50 = 2.0 μg/mL.

Bacterial strains CNX-216T and CNU-914T were isolated from marine sediment samples collected from Palmyra Atoll and off Catalina Island, respectively. Both strains were Gram-negative and aerobic and produce deep-orange to pink colonies and alkaloid secondary metabolites. Cells of strain CNX-216T were short, non-motile rods, whereas cells of strain CNU-914T were short, curved rods with gliding motility. The DNA G+C contents of CNX-216T and CNU-914T were respectively 57.7 and 44.4 mol%. Strains CNX-216T and CNU-914T contained MK-7 as the predominant menaquinone and iso-C15 : 0 and C16 : 1ω5c as the major fatty acids. Phylogenetic analyses revealed that both strains belong to the order Cytophagales in the phylum Bacteroidetes . Strain CNX-216T exhibited low 16S rRNA gene sequence identity (87.1 %) to the nearest type strain, Cesiribacter roseus 311T, and formed a well-supported lineage that is outside all currently described families in the order Cytophagales . Strain CNU-914T shared 97.6 % 16S rRNA gene sequence identity with ‘Porifericola rhodea’ N5EA6-3A2B and, together with ‘Tunicatimonas pelagia’ N5DB8-4 and four uncharacterized marine bacteria isolated as part of this study, formed a lineage that is clearly distinguished from other families in the order Cytophagales . Based on our polyphasic taxonomic characterization, we propose that strains CNX-216T and CNU-914T represent novel genera and species, for which we propose the names Mooreia alkaloidigena gen. nov., sp. nov. (type strain CNX-216T = DSM 25187T = KCCM 90102T) and Catalinimonas alkaloidigena gen. nov., sp. nov. (type strain CNU-914T = DSM 25186T = KCCM 90101T) within the new families Mooreiaceae fam. nov. and Catalimonadaceae fam. nov.

For decades, human infections with Zika virus (ZIKV), a mosquito-transmitted flavivirus, were sporadic, associated with mild disease, and went underreported since symptoms were similar to other acute febrile diseases. Recent reports of severe disease associated with ZIKV have greatly heightened awareness. It is anticipated that ZIKV will continue to spread in the Americas and globally where competent Aedes mosquito vectors are found. Dengue virus (DENV), the most common mosquito-transmitted human flavivirus, is both well-established and the source of outbreaks in areas of recent ZIKV introduction. DENV and ZIKV are closely related, resulting in substantial antigenic overlap. Through antibody-dependent enhancement (ADE), anti-DENV antibodies can enhance the infectivity of DENV for certain classes of immune cells, causing increased viral production that correlates with severe disease outcomes. Similarly, ZIKV has been shown to undergo ADE in response to antibodies generated by other flaviviruses. We tested the neutralizing and enhancing potential of well-characterized broadly neutralizing human anti-DENV monoclonal antibodies (HMAbs) and human DENV immune sera against ZIKV using neutralization and ADE assays. We show that anti-DENV HMAbs, cross-react, do not neutralize, and greatly enhance ZIKV infection in vitro. DENV immune sera had varying degrees of neutralization against ZIKV and similarly enhanced ZIKV infection. Our results suggest that pre-existing DENV immunity may enhance ZIKV infection in vivo and may lead to increased disease severity. Understanding the interplay between ZIKV and DENV will be critical in informing public health responses and will be particularly valuable for ZIKV and DENV vaccine design and implementation strategies.

Correction for ‘Biomimetic design of protic lipidic ionic liquids with enhanced fluidity’ by Richard A. O'Brien et al., New J. Chem., 2016, 40, 7795–7803.

Genome sequencing of Zika virus samples from infected patients and Aedes aegypti mosquitoes in Florida shows that the virus was probably introduced into the United States on multiple occasions, and that the Caribbean is the most likely source. Three papers in this issue present a wealth of new Zika virus (ZIKV) genome sequences and further insights into the genetic epidemiology of ZIKV. Nathan Grubaugh et al. provide 39 new ZIKV genome sequences from infected patients and Aedes aegypti mosquitoes in Florida. Phylogenetic analysis suggests that the virus has been introduced on multiple separate occasions, probably linked to travel from the Caribbean. They find a low probability of long-term persistence of ZIKV transmission chains within Florida, suggesting that the potential for future ZIKV outbreaks there will depend on transmission dynamics in the Americas. Nuno Faria et al. and Hayden Metsky et al. reconstruct the spread of ZIKV in Brazil and the Americas. Faria et al. provide 54 new ZIKV genomes, several sequenced in real time in a mobile genomics laboratory. They trace the spatial origins and spread of ZIKV in Brazil and the Americas and date the timing of the international spread of ZIKV from Brazil. They find that northeast Brazil had a crucial role in the establishment of the epidemic and the spread of the virus within Brazil and the Americas. Metsky et al. generate 110 ZIKV genomes from clinical and mosquito samples from ten regions. They also see rapid expansion of the epidemic within Brazil and multiple introductions to other geographic areas. In agreement with Faria et al., they find that ZIKV circulated unobserved for many months before transmission was detected. Metsky et al. additionally describe ZIKV evolution and discuss how the accumulation of mutations might affect the performance of diagnostic tests in the future. Zika virus (ZIKV) is causing an unprecedented epidemic linked to severe congenital abnormalities1,2. In July 2016, mosquito-borne ZIKV transmission was reported in the continental United States; since then, hundreds of locally acquired infections have been reported in Florida3,4. To gain insights into the timing, source, and likely route(s) of ZIKV introduction, we tracked the virus from its first detection in Florida by sequencing ZIKV genomes from infected patients and Aedes aegypti mosquitoes. We show that at least 4 introductions, but potentially as many as 40, contributed to the outbreak in Florida and that local transmission is likely to have started in the spring of 2016—several months before its initial detection. By analysing surveillance and genetic data, we show that ZIKV moved among transmission zones in Miami. Our analyses show that most introductions were linked to the Caribbean, a finding corroborated by the high incidence rates and traffic volumes from the region into the Miami area. Our study provides an understanding of how ZIKV initiates transmission in new regions.

International audience; Objective: To develop recommendations for the appropriate use of ultrasound in the management of rheumatoid arthritis (RA) in routine practice based on data from the literature and of experts opinion. Methods: Based on a systematic literature review, a scientific committee decided on themes and relevant questions to draw up an initial draft of recommendations. These recommendations were submitted to a group of experts in ultrasound in rheumatic and musculoskeletal diseases using a Delphi method, which produced preliminary recommendations. These were submitted to an expanded group of ultrasound experts for relevance, comprehensibility and comprehensiveness. The level of agreement of the experts were recorded during a face-to-face meeting. Results: Following two rounds of the Delphi, a consensus was reached on three overarching principles, including definitions of joints, tendons and articular sites to be examined, and 10 recommendations. These recommendations underline the benefit of ultrasound for the diagnosis of RA in cases of inflammatory arthralgia or undifferentiated arthritis as well as in assessing the extent of initial structural and inflammatory damage. They also define the role of ultrasound during follow-up or when considering treatment reduction once clinical remission has been achieved. Lastly, they illustrate the utility of ultrasound in facilitating technical procedures. Conclusion: These 10 consensus-based recommendations should harmonize and optimize clinical practice and thus improve the management of RA patients.