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Examine factors impacting U.S. parents' intention to vaccinate their children against COVID-19.Data were collected February-May 2021 from parents living in six geographically diverse locations. The COVID-19 Exposure and Family Impact Survey assessed perceived susceptibility and severity to adverse outcomes from the pandemic. Semi-structured interviews assessed perceptions about benefits and risks of vaccinating children.Fifty parents of 106 children (newborn-17 years) were included; half were Spanish-speaking and half English-speaking. 62% were hesitant about vaccinating their children against COVID-19. Efficacy and safety were the main themes that emerged: some parents perceived them as benefits while others perceived them as risks to vaccination. Parent hesitancy often relied on social media, and was influenced by narrative accounts of vaccination experiences. Many cited the lower risk of negative outcomes from COVID-19 among children, when compared with adults. Some also cited inaccurate and constantly changing information about COVID-19 vaccines.Main drivers of parent hesitancy regarding child COVID-19 vaccination include perceived safety and efficacy of the vaccines and lower severity of illness in children.Many vaccine-hesitant parents may be open to vaccination in the future and welcome additional discussion and data.

Minority physicians have been persistently underrepresented in medicine (URiM) when compared with their representation in the general U.S.There is evidence that diversifying the physician workforce would have a positive impact on healthcare delivery. While programs have been implemented to diversify the physician workforce, there has been less emphasis and progress in diversifying academic medical centers (AMCs) at the faculty level. This review sought to provide an update in the literature on the published outcomes and components of programs designed to increase the racial/ethnic diversity of faculty at AMCs.A scoping review study design was used. Search terms-academic medical faculty, diversity, and recruitment or retention-were used to search literature published from August 2012 through February 4, 2021. Eligible studies (1) evaluate structured organization/institutional programs to increase the representation of faculty who identify as URiM; (2) include faculty who identify as URiM as defined by the Association of American Medical Colleges (individuals who identify as African Americans and/or Black, Hispanic/Latino, Native American (American Indians, Alaska Natives, and Native Hawaiians), Pacific Islander, and mainland Puerto Rican); (3) describe interventions for the academic medicine setting; and (4) report either quantitative or qualitative data.Ten papers describing eight programs were included in the review. Program components were heterogeneous. Most studies described funded research-focused programs and fewer studies were institution-wide efforts or included institutional culture (i.e., rules, values, beliefs, behaviors, and customs that shape how people behave within an organization) or climate (i.e., perception regarding the culture) efforts. Four studies reported outcomes that included changes in faculty representation and six included faculty retention efforts such as promotion, leadership positions, grants, and scholarly productivity.This review summarizes and updates the literature on programs to improve the diversity of faculty at AMCs. It includes specific recommendations for components that can provide a foundation for programs to improve faculty diversity. Future research should use high quality methods to compare different interventions to improve the diversity of faculty in AMCs.

Shelter has been described as one of the most 'intractable problems' in humanitarian aid and yet there is little clarity on the over-arching definition of shelter. The terminology for shelter and housing is often conflated, and further to this, the most prominently used definition does not fully reflect the recent progress the shelter and settlements sector has made. These progressions include a movement from 'product' to 'process', and a recognition of the wider impacts of shelter, including livelihoods, health, economic stimulation, education, and reduction of vulnerability. This paper explores the varying terminology utilised in definitions of shelter within humanitarian aid since 1990, reflecting on the concepts of 'shelter' and 'housing', alongside the surrounding perceptions of 'house' vs 'home, and related measures of adequacy. The current, most prolific definition is also deconstructed, demonstrating the ambiguity in some of the terminology such as 'dignity' and 'privacy', and identifying that the interpretation of this definition is dependent on the knowledge of the reader. Finally, a new definition of 'sheltering' is proposed, encompassing five key reflections: the concept of process over object; inclusion of communities as well as individuals; the commonality of long-term sheltering; the wider impacts of shelter; the impact on host communities and environment. This definition is proposed in conjunction with the needs defined in the UN-HABITAT definition of 'adequate shelter', with the caveat that adequacy of those needs, and the sheltering response, should be determined by the affected population.

Immunocompromised patients are highly susceptible to invasive aspergillosis. Herein, we identified a homozygous deletion mutation (507 del C) resulting in a frameshift (N170I) and early stop codon in the fungal binding Dectin-2 receptor, in an immunocompromised patient. The mutated form of Dectin-2 was weakly expressed, did not form clusters at/near the cell surface and was functionally defective. Peripheral blood mononuclear cells from this patient were unable to mount a cytokine (tumor necrosis factor, interleukin 6) response to Aspergillus fumigatus, and this first identified Dectin-2–deficient patient died of complications of invasive aspergillosis., We identified a Dectin-2 N170I mutation in an immunocompromised patient who died of complications of invasive aspergillosis. This mutation results in an early stop codon and poor receptor expression and renders Dectin-2 functionally defective.

Aims To compare variations in metabolic target achievement by ethnicity (Europeans, Māori and Pasifika) among patients with type 2 diabetes (T2DM) in Auckland, New Zealand (NZ) between 1994-2013. Methods 32,237 patients were enrolled. Adjusted marginal difference (European as reference) of systolic blood pressure (SBP), body mass index (BMI), HbA1c and total cholesterol, alongside the proportion achieving metabolic targets were estimated using multivariable mixed effect models at baseline, 1-, 2-, 3-, 4-, and 5-years, adjusted for covariates. Results Compared with Europeans, Māori and Pasifika had continuously, significantly higher HbA1c (by 0.3% (+3.5mmol/mol) and 0.6% (+6.8 mmol/mol) respectively and BMI (+1.5 and +0.3 kg/m2 respectively) but lower SBP (-1.8 and -3.4 mmHg respectively) and TG (-0.03 and -0.34 mmol/L respectively), and insignificantly TC (+0.004 and +0.01 respectively), by 5-year of follow-up. While 49% Europeans were within target HbA1c, this was achieved by only 30% Māori and 27% Pasifika. Conversely, 41% Europeans, 46% Māori and 59% Pasifika achieved the SBP target (all P

OBJECTIVE Academic medicine diversity is important for addressing health disparities and training the next generation. A recent study highlighted the lack of diversity among pediatric trainees over time. However, trends in US pediatric faculty diversity have not been clearly illuminated. The aim of this study is to evaluate pediatric faculty diversity trends and compare racial/ethnic representation between pediatric faculty and the US population. METHODS Repeat cross-sectional study of the Association of American Medical Colleges Faculty Roster of pediatric faculty from 2000 to 2020. Trends in sex, race, ethnicity, and rank were compared with the Cochran-Armitage test. Data on faculty race/ethnicity were compared with the general and child population by using US Census Bureau data. RESULTS Trends in underrepresented in medicine (URiM) faculty representation significantly increased at all ranks: professor (+3.5%, P < .0001), associate professor (+3.0%, P = .0001), and assistant professor (+2.5%, P = .0001). URiM male representation remained unchanged (P = .14), whereas significantly increased trends occurred in URiM female representation (+3.4%, P < .0001). African American/Black males significantly decreased representation at associate (-0.4%, P = .04) and assistant professor levels (-0.6%, P < .0001), and American Indian/Alaska Native males significantly decreased representation at the assistant professor rank (-0.1%, P < .0001). The percentage of URiM pediatric faculty representation was considerably lower compared with 2020 US overall and longitudinal child population representation. CONCLUSION The stagnation of URiM male representation and lack of faculty diversity reflective of the US population may have a critical impact on the ability to recruit/retain a diverse pediatric workforce and promote equitable care.

Objective We examined associations between household food insecurity status and parental feeding behavior, weight perception, and child weight status in a diverse sample of young children. Methods Cross-sectional analysis of 2-year-old children in Greenlight, a cluster randomized trial to prevent childhood obesity. The exposure was food insecurity, defined as a positive response to a validated screen. Outcomes were parent feeding behaviors/beliefs measured by the Child Feeding Questionnaire and child weight status. t tests and linear regression were used to assess associations between food insecurity and each outcome. We adjusted for child sex, race/ethnicity, parent education, employment, site, number of children in the home, and Special Supplemental Nutrition Program for Women, Infants, and Children status. Results Five hundred three households (37%) were food insecure. After adjusting for covariates, parents from insecure households reported more pressuring feeding behaviors (mean factor score 3.2 compared to food secure parents mean factor score 2.9, P = .01) and were more worried about their child becoming overweight (mean factor score 2.3 vs 2.0; P = .02). No differences were observed in monitoring or restrictive feeding behaviors. After adjusting for covariates, there was no difference in weight status or prevalence of overweight/obesity of children or parents based on household food insecurity status. Conclusions Parents from food insecure households reported more pressuring feeding behaviors. This finding underscores the need to address food insecurity and potentially prevent harmful effects on child feeding. Parents in food insecure households might benefit from linkage with resources and education to develop healthier feeding behaviors.

Granular cell tumors (GCT) are highly vascularized and adherent to adjacent structures, and so, complete resection represents a challenge. Adjuvant therapy decisions for residual GCTs currently relies on individual clinician decisions due to a paucity of systematic literature data. We present a comprehensive analysis about the impact of adjuvant therapy in reported cases of patients with incomplete GCT resection. One database (PubMed) and crossed references were queried for GCT with incomplete resection or biopsy from 1962 to 2020. Literature review was performed according to the PRISMA guidelines. Also, two patients with residual GCT from our institutions are added to the analysis. Data regarding clinical presentation, surgical approach, use of adjuvant therapy, Ki-67 labeling, and follow up assessments were extracted and analyzed from selected publications. Thirty-three studies met the predetermined inclusion criteria and 53 patients were selected (including our two reported cases). The median of age was 49 [IQR, 39–60 years], with a slight male predominance (1.2:1). Among the surgical procedures, seven (13%) were biopsies alone. Adjuvant therapy was used in 18 patients (radiotherapy, 94.5%; chemotherapy, 5.5%) but there is no statistical correlation with adjuvant therapy and the progression of the remnant tumor (p = 0.33). Our institutions’ patients did not receive adjuvant therapy and did not show tumor progression on MRI. Our systematic literature review suggests there is a limited role for chemo and/or radiotherapy in the management of incomplete GCT resection. It may be reasonable recommending close clinical follow up in patients with incomplete resection.

BACKGROUND: Food insecurity (FI) is dynamic for families and adversely affects infant and maternal health. However, few studies have examined the longitudinal impact of FI on infant and maternal health. OBJECTIVES: We aimed to examine the relation between food insecurity in the first year of life and infant and maternal health outcomes. We hypothesized FI would be associated with poorer infant and maternal health outcomes. METHODS: We conducted a retrospective cohort study of 364 infants 12–15 months and their caregivers receiving care at a single primary care clinic. The exposure of interest was food insecurity measured during well-child checks using a validated 2-item screening tool. The primary outcome was infant weight-for-length z score. Secondary outcomes included infant log-transformed ferritin, infant hemoglobin, infant lead concentrations, and maternal depression, assessed by the Edinburgh Postnatal Depression Scale. Unadjusted and adjusted effects were estimated using generalized mixed linear models, and the linear effect of visit time was tested using likelihood ratios. RESULTS: In adjusted models, no overall association between FI and infant weight-for-length z score was observed; however, FI male infants had lower weight-for-length z scores than female infants (P = 0.05). FI infants had 14% lower log ferritin concentrations per month of exposure to FI. FI was positively associated with maternal depression (IRR 5.01 [95% CI 2.21–11.3]). CONCLUSIONS: Food insecurity can have longitudinal and demographically-varied associations with infant and maternal outcomes that warrant further exploration.

Invasive Aspergillosis (IA), typically caused by the fungusAspergillus fumigatus, is a leading cause of morbidity and mortality in immunocompromised patients. IA remains a significant burden in haematology patients, despite improvements in the diagnosis and treatment ofAspergillusinfection. Diagnosing IA is challenging, requiring multiple factors to classify patients into possible, probable and proven IA cohorts. Given the low incidence of IA, using negative results as exclusion criteria is optimal. However, frequent false positives and severe IA mortality rates in haematology patients have led to the empirical use of toxic, drug-interactive and often ineffective anti-fungal therapeutics. Improvements in IA diagnosis are needed to reduce unnecessary anti-fungal therapy. Early IA diagnosis is vital for positive patient outcomes; therefore, a pre-emptive approach is required. In this study, we examined the sequence and expression of four C-type Lectin-like receptors (Dectin-1, Dectin-2, Mincle, Mcl) from 42 haematology patients and investigated each patient’s anti-Aspergillusimmune response (IL-6, TNF). Correlation analysis revealed novel IA disease risk factors which we used to develop a pre-emptive patient stratification protocol to identify haematopoietic stem cell transplant patients at high and low risk of developing IA. This stratification protocol has the potential to enhance the identification of high-risk patients whilst reducing unnecessary treatment, minimizing the development of anti-fungal resistance, and prioritising primary disease treatment for low-risk patients.

Purpose of Review To understand recent literature that examines associations between food insecurity and cardiometabolic conditions and risk factors. We included original research, systematic reviews, and meta-analyses on the topic of food insecurity and cardiometabolic risk published from January 1, 2017, to December 31, 2020. Editorials, perspectives, and case reports were excluded. After the initial search, 3 reviewers selected studies for inclusion based on relevance and methods. Ultimately, fifty studies were included. Recent Findings We included 35 studies of adults (20 cross-sectional observational studies, 5 longitudinal observational studies, 5 interventional studies, and 5 meta-analyses/reviews). In adults, food insecurity is associated with greater prevalence of overweight/obesity (especially for women). It is also associated with hypertension, diabetes (including worse glycemic control and more diabetes complications), coronary heart disease, congestive heart failure, stroke, and chronic kidney disease. We included 15 studies of children (11 cross-sectional observational studies and 4 longitudinal observational studies). In children, findings were more nuanced, and in particular, many studies did not find an association between food insecurity and overweight/obesity. However, authors noted that these conditions may not have had time to develop. With notable exceptions, many studies were cross-sectional, and there were few interventions. Summary There is a robust association between food insecurity and cardiometabolic conditions and risk factors in adults, but the picture is less clear in children. Overt cardiometabolic clinical conditions develop more rarely in children, but childhood experiences may set a trajectory for worse health later in life. Detailed life course epidemiologic studies are needed to better understand this relationship. Future interventions should examine how to reduce the prevalence of food insecurity, and how best to improve health for those who experience food insecurity.

We explored caregivers’ experiences with food insecurity screening in a primary care setting and the impact of resources provided. English- and Spanish-speaking food insecure caregivers of children aged 1 to 5 years were recruited. In-depth individual semistructured interviews were conducted (n = 17) eliciting caregivers’ experiences with food insecurity, clinic screening, and resources provided. Interviews were audio-recorded and transcribed verbatim. Interviews were double-coded and thematic analysis was used to identify themes and subthemes. All caregivers described multiple and repeat experiences with food insecurity. Food insecurity screening was acceptable, but families were not always connected with resources. Caregivers described WIC (Women, Infants, and Children) as the most commonly used program to address food insecurity and infrequently utilized other food insecurity resources. Screening for food insecurity in primary care was generally well accepted by this sample of food insecure caregivers. Future studies are needed to determine how to improve connecting resources with families most in need.

Objective Food insecurity is associated with childhood obesity possibly mediated through caregiver feeding practices and beliefs. We examined if caregiver feeding practices differed by household food security status in a diverse sample of infants. We hypothesized that feeding practices differ based on food security status. Patients and methods Included in the baseline cross-sectional analysis of data from a randomized controlled trial to prevent obesity were 842 caregivers of 2-month-old infants presenting for well-child care at 4 academic institutions. Food insecurity exposure was based on an affirmative answer to 1 of 2 items in a 2-item validated questionnaire. Chi-square tests examined the association between parent feeding practices and food security status. Logistic regression adjusted for covariates. Differences in caregiver feeding practices by food security status and race/ethnicity were explored with an interaction term (food security status x race/ethnicity). Results Forty-three percent of families screened as food insecure. In adjusted logistic regression, parents from food-insecure households were more likely to endorse that “the best way to make an infant stop crying is to feed him or her” (adjusted odds ratio [aOR], 1.72; 95% confidence interval [CI], 1.28–2.29) and “when my baby cries, I immediately feed him or her” (aOR, 1.40; 95% CI, 1.06–1.83). Food-insecure caregivers less frequently endorsed paying attention to their baby when he or she is full or hungry (OR, 0.57; 95% CI, 0.34–0.96). Racial/ethnic differences in beliefs and behaviors were observed by food security status. Conclusions During early infancy, feeding practices differed among caregivers by household food security status. Further research is needed to examine whether these practices are associated with increased risk of obesity and obesity-related morbidity.

We aimed to determine how COVID-19 affected the number and type of pediatric primary care visits in April 2020, compared to April 2019, and which characteristics were associated with obtaining care in 2020. We performed a retrospective chart review of patients receiving care in April 2019 and April 2020 from four large, academic institutions across two states. The subjects were included if they were aged 0–18 years and were seen in a pediatric clinic in April 2019 or April 2020. We extracted the number of visits, visit type, and visit diagnosis; and the patient characteristics, including age, race/ethnicity, and insurance status. Logistic regression analysis identified characteristics associated with obtaining care in April 2020. We included 120,230 visits. Participants were 50% white and half had Medicaid. In 2020 there were significantly fewer visits for both well and acute visits with 42,670 visits in 2020 compared to 77,560 in 2019; 6616 were telehealth visits in 2020. Visits for chronic conditions were significantly decreased in 2020. Attending a visit in 2020 was more likely if the participant was black or Hispanic, younger, attending an acute visit, or had private insurance. During the COVID-19 pandemic, pediatric primary care decreased substantially for both well visits and follow-up of chronic conditions.

Optimization of a series of aryl urea RAF inhibitors led to the identification of type II pan-RAF inhibitor GNE-0749 (

Background\ud Type 2 diabetes affects Indigenous and non-European populations disproportionately, including in New Zealand, where long-term temporal trends in cause-specific clinical outcomes between Māori, Pacific, and European people remain unclear. We aimed to compare the rates of mortality and hospital admission between Māori, Pacific, and European patients with type 2 diabetes in Auckland, New Zealand, over a period of 24 years.\ud Methods\ud In this retrospective, population-based, longitudinal cohort study, we identified a cohort of patients (aged 35–84 years) with type 2 diabetes enrolled between Jan 1, 1994, and July 31, 2018, to the primary care audit programme, the Diabetes Care Support Service (DCSS) in Auckland, New Zealand. Patients with type 1 diabetes, prediabetes, and gestational diabetes were excluded. We linked data from the DCSS with national death registration, hospital admission, pharmaceutical claim, and socioeconomic status databases. Patients were followed up until death or July 31, 2018 (date of last enrolment to the DCSS). Incident clinical events (all-cause mortality, cardiovascular mortality, cancer mortality, cardiovascular hospital admission, cancer hospital admission, and end-stage renal disease hospital admission) were identified. Event rates were stratified by ethnic group, age group, sex, socioeconomic status, and time period (

Synopsis Philosophical truths are hidden in Lewis Carroll’s nonsense poems, such as “The hunting of the snark.” When the poem is used as a scientific allegory, a snark stands for the pursuit of scientific truth, while a boojum is a spurious discovery. In the study of female biology, boojums have been the result of the use of cultural stereotypes to frame hypotheses and methodologies. Although female reproduction is key for the continuation of sexually reproducing species, not only have females been understudied in many regards, but also data have commonly been interpreted in the context of now-outdated social mores. Spurious discoveries, boojums, are the result. In this article, we highlight specific gaps in our knowledge of female reproductive biology and provide a jumping-off point for future research. We discuss the promise of emerging methodologies (e.g., micro-CT scanning, high-throughput sequencing, proteomics, big-data analysis, CRISPR-Cas9, and viral vector technology) that can yield insights into previously cryptic processes and features. For example, in mice, deoxyribonucleic acid sequencing via chromatin immunoprecipitation followed by sequencing is already unveiling how epigenetics lead to sex differences in brain development. Similarly, new explorations, including microbiome research, are rapidly debunking dogmas such as the notion of the “sterile womb.” Finally, we highlight how understanding female reproductive biology is well suited to the National Science Foundation’s big idea, “Predicting Rules of Life.” Studies of female reproductive biology will enable scholars to (1) traverse levels of biological organization from reproductive proteins at the molecular level, through anatomical details of the ovum and female reproductive tract, into physiological aspects of whole-organism performance, leading to behaviors associated with mating and maternal care, and eventually reaching population structure and ecology; (2) discover generalizable rules such as the co-evolution of maternal-offspring phenotypes in gestation and lactation; and (3) predict the impacts of changes to reproductive timing when the reliability of environmental cues becomes unpredictable. Studies in these key areas relative to female reproduction are sure to further our understanding across a range of diverse taxa.

Importance People with type 2 diabetes have greater risk for some site-specific cancers, and risks of cancers differ among racial and ethnic groups in the general population of Aotearoa New Zealand. The extent of ethnic disparities in cancer risks among people with type 2 diabetes in New Zealand is unclear.\ud \ud Objective To compare the risks of 21 common adult cancers among Māori, Pasifika, and New Zealand European individuals with type 2 diabetes in New Zealand from 1994 to 2018.\ud \ud Design, Setting, and Participants This population-based, matched cohort study used data from the primary care audit program in Auckland, New Zealand, linked with national cancer, death, and hospitalization registration databases, collected from January 1, 1994, to July 31, 2018, with follow-up data obtained through December 31, 2019. Using a tapered matching method to balance potential confounders (sociodemographic characteristics, lifestyle, anthropometric and clinical measurements, treatments [antidiabetes, antihypertensive, lipid-lowering, and anticoagulant], period effects, and recorded duration of diabetes), comparative cohorts were formed between New Zealand European and Māori and New Zealand European and Pasifika individuals aged 18 years or older with type 2 diabetes. Sex-specific matched cohorts were formed for sex-specific cancers.\ud \ud Exposures Māori, Pasifika, and New Zealand European (reference group) ethnicity.\ud \ud Main Outcomes and Measures The incidence rates of 21 common cancers recorded in nationally linked databases between 1994 and 2018 were the main outcomes. Weighted Cox proportional hazards regression was used to assess ethnic differences in risk of each cancer.\ud \ud Results A total of 33 524 adults were included: 15 469 New Zealand European (mean [SD] age, 61.6 [13.2] years; 8522 [55.1%] male), 6656 Māori (mean [SD] age, 51.2 [12.4] years; 3345 [50.3%] female), and 11 399 Pasifika (mean [SD] age, 52.8 [12.7] years; 5994 [52.6%] female) individuals. In the matched New Zealand European and Māori cohort (New Zealand European: 8361 individuals; mean [SD] age, 58.9 [12.9] years; 4595 [55.0%] male; Māori: 5039 individuals; mean [SD] age, 51.4 [12.3] years; 2542 [50.5%] male), significant differences between New Zealand European and Māori individuals were identified in the risk for 7 cancers. Compared with New Zealand European individuals, the hazard ratios (HRs) among Māori individuals were 15.36 (95% CI, 4.50-52.34) for thyroid cancer, 7.94 (95% CI, 1.57-40.24) for gallbladder cancer, 4.81 (95% CI, 1.08-21.42) for cervical cancer (females only), 1.97 (95% CI, 1.30-2.99) for lung cancer, 1.81 (95% CI, 1.08-3.03) for liver cancer, 0.56 (95% CI, 0.35-0.90) for colon cancer, and 0.11 (95% CI, 0.04-0.27) for malignant melanoma. In the matched New Zealand European and Pasifika cohort (New Zealand European: 9340 individuals; mean [SD] age, 60.6 [13.1] years; 4885 [52.3%] male; Pasifika: 8828 individuals; mean [SD] age, 53.1 [12.6] years; 4612 [52.2%] female), significant differences between New Zealand European and Pasifika individuals were identified for 6 cancers. Compared with New Zealand European individuals, HRs among Pasifika individuals were 25.10 (95% CI, 3.14-200.63) for gallbladder cancer, 4.47 (95% CI, 1.25-16.03) for thyroid cancer, 0.48 (95% CI, 0.30-0.78) for colon cancer, 0.21 (95% CI, 0.09-0.48) for rectal cancer, 0.21 (95% CI, 0.07-0.65) for malignant melanoma, and 0.01 (95% CI, 0.01-0.10) for bladder cancer.\ud \ud Conclusions and Relevance In this cohort study, differences in the risk of 21 common cancers were found between New Zealand European, Māori, and Pasifika groups of adults with type 2 diabetes in New Zealand from 1994 to 2018. Research into the mechanisms underlying these differences as well as additional screening strategies (eg, for thyroid and gallbladder cancers) appear to be warranted.

Risk for smoking increases in a summative manner corresponding to the number of co-occurring vulnerabilities present (cumulative vulnerability). We examined whether cumulative vulnerabilities moderate response to reduced nicotine content cigarettes in a secondary analysis of results from 775 participants in three 12-week randomized clinical trials examining research cigarettes varying in nicotine content (0.4, 2.4, 15.8 mg nicotine/g tobacco). Participants were categorized as having 0-1, 2-3, or ≥ 4 cumulative vulnerabilities. Vulnerabilities included: rural residence, current substance use disorder, current affective disorder, low educational attainment, poverty, unemployment, physical disability. The primary outcome was total cigarettes per day (CPD) during Week 12; secondary outcomes included CPD across weeks, toxin exposure, dependence severity, craving/withdrawal (17 dependent measures). Results were analyzed using repeated measures analysis of covariance and growth-curve modeling. Total CPD during Week 12 increased as cumulative-vulnerability increased (P = 0.004), and decreased as nicotine content decreased (P 0.001), with no significant interaction of cumulative vulnerability and dose (P = 0.67). Effects on other outcomes generally followed that same pattern. The only exception across the other outcomes was on Questionnaire-on-Smoking-Urges Factor-2 ratings for usual-brand cigarettes where cumulative vulnerability, dose, and time interacted (P = 0.007), with craving at the 0.4 and 2.4 mg/g doses decreasing over time, but inconsistently across vulnerability categories. Overall, we saw little evidence that cumulative vulnerabilities moderate response to reduced nicotine content cigarettes suggesting that a policy reducing nicotine content in cigarettes to minimally addictive levels could benefit even highly vulnerable smokers including those residing in rural or other regions with overrepresentation of co-occurring vulnerabilities. Clinicaltrials.gov identifiers: NCT02232737, NCT02250664, NCT02250534.

A novel three-component, two-step, one-pot nucleophilic aromatic substitution (SNAr)–intramolecular cyclization–Suzuki coupling reaction was developed for the synthesis of benzo[h][1,6]naphthyridin-2(1H)-ones (Torins). On the basis of the new efficiently convergent synthetic route, a library of Torin analogs was synthesized. The antimalarial activities of these compounds were evaluated against asexual parasites using a growth inhibition assay and gametocytes using a viability assay.

To describe changes in the racial and ethnic diversity of the membership of a national academic health professional organization, the Academic Pediatric Association (APA) from 2009 to 2018.Administrative data from the APA was used for the study. Our sample was limited to dues-paying members of the APA with complete profile information. Data on race/ethnicity was collected by self-report and categorized as White, Hispanic, Black, Asian, or other. Gender was obtained by self-report (male/female). Membership type included physician, non-physician, or trainee and was provided by self-report. Age was calculated by subtracting the dues year from the year of birth. Descriptive statistics were used. Log-linear models were used to describe changes in membership race/ethnicity and expressed as relative risk.Three thousand one hundred and ninety-six unique individuals were included. Enrollment in the APA increased from 1429 in 2009 to 1803 in 2018. Females represented 68% of the sample. Six percent of the sample identified as Black, 5% as Hispanic, 12% as Asian, and 74% as White. Using log-linear models, the proportion of members identifying as Black increased from 4% to 6% (P.001), Asian 8% to 13% (P.001) and Hispanic increased 4% to 5% (P = .17).The APA has increased the representation of underrepresented racial and ethnic minorities in medicine within its membership. The APA and other academic pediatric professional organizations, can build on these current trends by continuing to invest in programming focused on increasing racial/ethnic minority groups underrepresented in medicine.

OBJECTIVES:To describe temporal trends in car seat tolerance screening (CSTS) failure within a large hospital system (2014–2018).METHODS:We conducted a retrospective cohort study using electronic medical record data for infants who underwent a CSTS. Our primary outcome measure was the CSTS failure rate. Covariates included year, CSTS location (well nursery or NICU), gestational age (GA), race, sex, birth weight, CSTS date, and age at CSTS. Associations of covariates with CSTS failure were examined by using χ2 tests, t tests, analysis of variance, and Wilcoxon rank tests. Multivariable logistic regression was used to determine the adjusted odds of CSTS failure.RESULTS:Of 4849 infants tested, the failure rate was 8.1% (n = 394). Most CSTS occurred in the well nursery (79.5%) and involved late preterm (55.2%) or term infants (23.7%). In bivariate analyses, year, unit location, higher birth weight, younger chronological age at testing, and higher GA were positively associated with CSTS failure (P < .05). After stratification by CSTS location, the CSTS failure rate rose in the well nursery but remained stable in the NICU, and use of screening rose among term infants. In the adjusted model, year, GA, and corrected gestational age at CSTS were associated with failure. Each subsequent year was associated with a 19% increase in odds of CSTS failure (P < .001).CONCLUSIONS:We found a higher rate of CSTS failure in the well nursery compared with the NICU, and the difference in failure rates increased over time. Improved understanding of infants at the highest risk of CSTS failure could impact routine screening guidelines.

Background The diet quality of adults living in the United States has improved overtime. We aim to determine whether diet quality among adults with diabetes mellitus has changed over time, and to examine trends in socioeconomic disparities in diet quality. Methods Repeated cross-sectional analysis of eight National Health and Nutrition Examination Survey (NHANES) cycles (1999–2000 through 2013–2014). We included 5882 adult participants (age 20 or older) with diabetes mellitus (type 1 or 2) who completed 24-h dietary recalls. Diet quality was measured by the Healthy Eating Index 2010 (HEI) score (range 0–100, higher scores indicate better diet quality). We tested whether there were differences in diet quality across education, income, and food security categories, and whether any differences changed over time, using weighted linear regression models accounting for the complex survey design and adjusted for age, gender, and race/ethnicity. Results Twenty nine percent of US adults with diabetes had less than a high school diploma, 17% had income

Childhood hypertension can result in adverse outcomes during adulthood; identifying and treating primary and secondary childhood hypertension may reduce such risks.To update the evidence on screening and treatment of hypertension in childhood and adolescence for the US Preventive Services Task Force.PubMed, Cochrane Library, International Pharmaceutical Abstracts, EMBASE, and trial registries through September 3, 2019; bibliographies from retrieved articles, experts, and surveillance of the literature through October 6, 2020.Fair- or good-quality English-language studies evaluating diagnostic accuracy of blood pressure screening; cohort studies assessing the association of hypertension in childhood and adolescence with blood pressure or other intermediate outcomes in adulthood; randomized clinical trials (RCTs) or meta-analyses of pharmacological and lifestyle interventions.Two reviewers independently assessed titles/abstracts and full-text articles, extracted data, and assessed study quality; the evidence was synthesized qualitatively.Sensitivity, specificity, and measures of association between childhood and adulthood blood pressure; reduction of childhood blood pressure; adverse effects of treatments.Forty-two studies from 43 publications were included (N12 400). No studies evaluated the benefits or harms of screening and the effect of treating childhood hypertension on outcomes in adulthood. One study reported a sensitivity of 0.82 and a specificity of 0.70 for 2 office-based blood pressure measurements. Twenty observational studies suggested a significant association between childhood hypertension and abnormal blood pressure in adulthood (odds ratios, 1.1-4.5; risk ratios, 1.45-3.60; hazard ratios, 2.8-3.2). Thirteen placebo-controlled RCTs and 1 meta-analysis assessed reductions in systolic (SBP) and diastolic blood pressure from pharmacological treatments. Pooled reductions of SBP were -4.38 mm Hg (95% CI, -7.27 to -2.16) for angiotensin-converting enzyme inhibitors and -3.07 mm Hg (95% CI, -4.99 to -1.44) for angiotensin receptor blockers. Candesartan reduced SBP by -6.56 mm Hg (P .001; n = 240). β-Blockers, calcium channel blockers, and mineralocorticoid receptor antagonists did not achieve significant reductions over 2 to 4 weeks. SBP was significantly reduced by exercise over 8 months (-4.9 mm Hg, P ≤ .05; n = 69), by dietary approaches to stop hypertension over 3 months (-2.2 mm Hg, P .01; n = 57), and by a combination of drug treatment and lifestyle interventions over 6 months (-7.6 mm Hg; P .001; n = 95). Low-salt diet did not achieve reductions of blood pressure.Observational studies indicate an association between hypertension in childhood and hypertension in adulthood. However, the evidence is inconclusive whether the diagnostic accuracy of blood pressure measurements is adequate for screening asymptomatic children and adolescents in primary care.

Several data sources exist for estimating U.S. smoking prevalence among pregnant women, yet each differs in ways that have the potential to impact the estimates. In the present study we used the Population Assessment of Tobacco and Health (PATH), the National Survey on Drug use and Health (NSDUH), and the Pregnancy Risk Assessment Monitoring System (PRAMS), three common data sources, to evaluate the following questions about estimating U.S. smoking prevalence among pregnant women: To what extent are estimates impacted by differences in whether the samples include younger (< 18 years) or older (> 44 years) women, represent smoking in any trimester or only the 3(rd), and use data from nationally representative or more selected national samples. Among the factors examined, inclusion of younger or older women does not appear to meaningfully alter prevalence estimates. Focusing on only the third trimester likely underestimates smoking prevalence, while the influence of basing estimates on selected national subgroups of women (i.e., only women who delivered live born infants) rather than nationally representative surveys has little discernible influence. Going forward, this research area would benefit from greater consistency in explicitly discussing the sampling methods used and how these various methods may have influenced the estimates reported.

The incidence of urinary stone disease (USD) has increased four-fold in 50 years. Oxalate, which is degraded exclusively by gut bacteria, is an important constituent in 80% of urinary stones. We quantified the effects of antibiotics and a high fat/high sugar (HFHS) diet on the microbial metabolism of oxalate in the gut. High and low oxalate-degrading mouse models were developed by administering fecal transplants from either the wild mammalian rodent Neotoma albigula or Swiss-Webster mice to Swiss-Webster mice, which produces a microbiota with or without the bacteria necessary for persistent oxalate metabolism, respectively. Antibiotics led to an acute loss of both transplant bacteria and associated oxalate metabolism. Transplant bacteria exhibited some recovery over time but oxalate metabolism did not. In contrast, a HFHS diet led to an acute loss of function coupled with a gradual loss of transplant bacteria, indicative of a shift in overall microbial metabolism. Thus, the effects of oral antibiotics on the microbiome form and function were greater than the effects of diet. Results indicate that both antibiotics and diet strongly influence microbial oxalate metabolism.

Highlights • IL-12 and IL-23 have established roles during anti-fungal immunity. • IL-27 promotes regulatory effector responses during fungal infections. • IL-35 drives T cell differentiation to produce anti-inflammatory responses. • Increasing evidence for IL-12 family cytokines in maintaining anti-fungal immune homeostasis., Invasive fungal infections cause approximately 1.5 million deaths per year worldwide and are a growing threat to human health. Current anti-fungal therapies are often insufficient, therefore studies into host-pathogen interactions are critical for the development of novel therapies to improve mortality rates. Myeloid cells, such as macrophages and dendritic cells, express pattern recognition receptor (PRRs), which are important for fungal recognition. Engagement of these PRRs by fungal pathogens induces multiple cytokines, which in turn activate T effector responses. Interleukin (IL)-12 family members (IL-12p70, IL-23, IL-27 and IL-35) link innate immunity with the development of adaptive immunity and are also important for regulating T cell responses. IL-12 and IL-23 have established roles during anti-fungal immunity, whereas emerging roles for IL-27 and IL-35 have recently been reported. Here, we discuss the IL-12 family, focusing on IL-27 and IL-35 during anti-fungal immune responses to pathogens such as Candida and Aspergillus.

Sperm storage, the extended maintenance of viable sperm, probably occurs in most internally fertilizing animals. Because it temporally separates mating from conception, sperm storage can be adaptive in ecologically diverse habitats and affect life histories, mating systems, cryptic female choice, sperm competition, and sexual conflict. Sperm storage can result from different selective forces acting on females and/or males, sometimes resulting in coevolution. The various criteria often used to determine the presence of sperm storage in any given taxon can result from the action of any one or all of these selective forces. Here we discuss the criteria used to study sperm storage and how we can use these to better understand the evolution of diversity in sperm-storage adaptations.

Since the discovery of Toll, in the fruit fly Drosophila melanogaster, as the first described pattern recognition receptor (PRR) in 1996, many families of these receptors have been discovered and characterized. PRRs play critically important roles in pathogen recognition to initiate innate immune responses that ultimately link to the generation of adaptive immunity. Activation of PRRs leads to the induction of immune and inflammatory genes, including proinflammatory cytokines and chemokines. It is increasingly clear that many PRRs are linked to a range of inflammatory, infectious, immune, and chronic degenerative diseases. Several drugs to modulate PRR activity are already in clinical trials and many more are likely to appear in the near future. Here, we review the different families of mammalian PRRs, the ligands they recognize, the mechanisms of activation, their role in disease, and the potential of targeting these proteins to develop the anti-inflammatory therapeutics of the future.

Background This study focuses on health-related plant use among speakers of the critically endangered Naukan language (Inuit-Yupik-Unangan family) in the Russian Far East. The Naukan people were forced, in 1958, under Soviet consolidation, to move from their original settlement on Cape Dezhnev, leading to significant changes in spiritual worldview, subsistence, social structure, and language proficiency in the years that followed. Here, we focus on changes that elders report in their edible, medicinal, and spiritual uses of local plant species since their childhood. Methods The authors worked from 2014 to 2016 in the villages of Lavrentiya, Lorino, and Uelen, in the Chukotskiy district of the Chukotka autonomous region, directly adjacent to the Bering Strait. We conducted structured interviews, using an oral history approach, along with participant observation and collection of voucher specimens from the local arctic tundra. Those with Naukan names and uses represent 42 species in 25 families. Results Participants reported a decrease of 13% in the number of edible species that people currently harvest, from what they recall harvesting in their youth. On the other hand, the number of local species considered to be medicinal has actually increased by 225%. Current and past Naukan medicinal practices diverge in some notable ways from those of neighboring societies on the Alaskan side of the Bering Strait. Most of the spiritual significance of local plants species is remembered by only a few elders. Conclusions Naukan elders explained the large increase in use of medicinal plants by noting that their original concept of medicine emphasized prevention and that illnesses were often assigned a spiritual rather than physical cause. Increased integration with ethnic Russians after moving from Naukan led to the adoption not only of new plant uses, but also of an entirely different, more naturalistic way of viewing illness and treatment.

The adoption of sustainable land management strategies and practices that respond to current climate and human pressures requires both assessment tools that can lead to better informed decision-making and effective knowledge-exchange mechanisms that facilitate new learning and behavior change. We propose a learning-centered participatory approach that links land management assessment and knowledge exchange and integrates science-based data and stakeholder perspectives on both biophysical and socio-economic attributes. We outline a structured procedure for a transparent assessment of land management alternatives, tailored to dryland management, that is based on (1) principles of constructivism and social learning, (2) the participation of stakeholders throughout the whole assessment process, from design to implementation, and (3) the combination of site-specific indicators, identified by local stakeholders as relevant to their particular objectives and context conditions, and science-based indicators that represent ecosystem services of drylands worldwide. The proposed procedure follows a pattern of eliciting, challenging, and self-reviewing stakeholder perspectives that aims to facilitate learning. The difference between the initial baseline perspectives and the final self-reviewed stakeholder perspectives is used as a proxy of learning. We illustrate the potential of this methodology by its application to the assessment of land uses in a Mediterranean fire-prone area in East Spain. The approach may be applied to a variety of socio-ecological systems and decision-making and governance scales. The PRACTICE protocol was developed in the framework of the project PRACTICE: Prevention and Restoration Actions to Combat Desertification. An integrated Assessment, funded by the European Commission (GA226818). This research was also funded by the European project CASCADE (GA283068), and the Marie Skłodowska-Curie Actions Fellowship of the European Union (GA 629677) “S4S, Science for Society Solutions”, awarded to B.J.O.

Neighborhood design affects lifestyle physical activity, and ultimately human wellbeing. There are, however, a limited number of studies that examine neighborhood design types. In this research, we examine four types of neighborhood designs: traditional development, suburban development, enclosed community, and cluster housing development, and assess their level of walkability and their effects on physical activity and wellbeing. We examine significant associations through a questionnaire (n = 486) distributed in Tucson, Arizona using the Walkability Model. Among the tested neighborhood design types, traditional development showed significant associations and the highest value for walkability, as well as for each of the two types of walking (recreation and transportation) representing physical activity. Suburban development showed significant associations and the highest mean values for mental health and wellbeing. Cluster housing showed significant associations and the highest mean value for social interactions with neighbors and for perceived safety from crime. Enclosed community did not obtain the highest means for any wellbeing benefit. The Walkability Model proved useful in identifying the walkability categories associated with physical activity and perceived crime. For example, the experience category was strongly and inversely associated with perceived crime. This study provides empirical evidence of the importance of including vegetation, particularly trees, throughout neighborhoods in order to increase physical activity and wellbeing. Likewise, the results suggest that regular maintenance is an important strategy to improve mental health and overall wellbeing in cities.

Global positioning system (GPS) watches have been introduced commercially, converting frequent measurements of time, location, speed (pace), and elevation into energy expenditure (EE) estimates. The purpose of this study was to compare EE estimates of 4 different GPS watches (Forerunner, Suunto, Polar, Adeo), at various walking speeds, with EE estimate from a triaxial accelerometer (RT3), which was used as a reference measure in this study. Sixteen healthy young adults completed the study. Participants wore 4 different GPS watches and an RT3 accelerometer and walked at 6-minute intervals on an outdoor track at 3 speeds (3, 5, and 7 km/hr). The statistical significance of differences in EE between the 3 watches was assessed using linear contrasts of the coefficients from the overall model. Reliability across trials for a given device was assessed using intraclass correlation coefficients as estimated in the mixed model. The GPS watches demonstrated lower reliability (intraclass correlation coefficient) across trials when compared with the RT3, particularly at the higher speed, 7 km/hr. Three GPS watches (Forerunner, Polar, and Suunto) significantly and consistently underestimated EE compared with the reference EE given by the RT3 accelerometer (average mean difference: Garmin, -50.5%; Polar, -41.7%; and Suunto, -41.7%; all p < 0.001). Results suggested that caution should be exercised when using commercial GPS watches to estimate EE in athletes during field-based testing and training.

LAB/NTAL/Lat2 is a transmembrane adaptor protein closely related to LAT. It is expressed in various myeloid and lymphoid cells, many of which also express LAT. Phosphorylation of LAB occurs following engagement of various ITAM- and non-ITAM-linked receptors and can play positive and negative roles following receptor engagement. LAT binds PLCγ directly, resulting in efficient Ca2+ flux and degranulation. However, LAB does not contain a PLCγ-binding motif and only binds PLCγ indirectly, possibly via Grb2, thereby resulting in suboptimal signaling. As LAT can signal more efficiently than LAB, competition between the 2 for space/substrates in the lipid rafts can attenuate signaling. This competition model requires coexpression of LAT; however, LAB is repressive, even in cells lacking substantial LAT expression such as macrophages and mature B cells. The reported interaction between LAB and the ubiquitin E3-ligase c-Cbl suggests 1 possible mechanism for LAT-independent inhibition by LAB, but such a model requires further investigation. Given the wide-reaching expression pattern of LAB, LAB has the ability to modulate signaling in virtually every type of leukocyte. Regardless of its ultimate mode of action, the potent regulatory capability of LAB proves this protein to be a complex adaptor that warrants continued, substantial scrutiny by biochemists and immunologists alike.

Although production of cytokines by TLR is essential for viral and bacterial clearance, overproduction can be detrimental, thus controlling these responses is essential. CD33-related sialic acid binding Ig-like lectin receptors (Siglecs) have been implicated in the control of leukocyte responses. In this study, we report that murine Siglec-E is induced by TLRs in a MyD88-specific manner, is tyrosine phosphorylated following LPS stimulation, and negatively regulates TLR responses. Specifically, we demonstrate the Siglec-E expression inhibits TLR-induced NF-κB and more importantly, the induction of the antiviral cytokines IFN-β and RANTES. Siglec-E mediates its inhibitory effects on TIR domain containing adaptor inducing IFN-β (TRIF)-dependent cytokine production via recruitment of the serine/threonine phosphatase SHP2 and subsequent inhibition of TBK1 activity as evidenced by enhanced TBK1 phosphorylation in cells following knockdown of Siglec-E expression. Taken together, our results demonstrate a novel role for Siglec-E in controlling the antiviral response to TLRs and thus helping to maintain a healthy cytokine balance following infection.

In sexually reproducing organisms, the genetic interests of individuals are not perfectly aligned. Conflicts among family members are prevalent since interactions involve the transfer of limited resources between interdependent players. Intrafamilial conflict has traditionally been considered along three major axes: between the sexes, between parents and offspring, and between siblings. In these interactions, conflict is expected over traits in which the resulting phenotypic value is determined by multiple family members who have only partially overlapping fitness optima. We focus on four major categories of animal reproductive mode (broadcast spawning, egg laying, live bearing, and live bearing with matrotrophy) and identify the shared phenotypes or traits over which conflict is expected, and then review the empirical literature for evidence of their occurrence. Major transitions among reproductive mode, such as a shift from external to internal fertilization, an increase in egg-retention time, modifications of embryos and mothers for nutrient transfer, the evolution of postnatal parental care, and increased interaction with the kin network, mark key shifts that both change and expand the arenas in which conflict is played out.

CD33 is a member of the sialic acid–binding immunoglobulin-like lectin (Siglec) family of inhibitory receptors and a therapeutic target for acute myeloid leukemia (AML). CD33 contains a cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM), which can recruit SHP-1 and SHP-2. How CD33 expression is regulated is unclear. Suppressor of cytokine signaling 3 (SOCS3) is expressed in response to cytokines, LPS, and other PAMPs, and competes with SHP-1/2 binding to ITIMs of cytokine receptors, thereby inhibiting signaling. In this study, using peptide pull-down experiments, we found that SOCS3 can specifically bind to the phosphorylated ITIM of CD33. Additionally, following cross-linking SOCS3 can recruit the ECS E3 ligase resulting in accelerated proteasomal degradation of both CD33 and SOCS3. Our data suggest that the tyrosine motifs in CD33 are not important for internalization, while they are required for degradation. Moreover, SOCS3 inhibited the CD33-induced block on cytokine-induced proliferation. This is the first receptor shown to be degraded by SOCS3 and where SOCS3 and its target protein are degraded concomitantly. Our findings clearly suggest that during an inflammatory response, the inhibitory receptor CD33 is lost by this mechanism. Moreover, this has important clinical implications as tumors expressing SOCS3 may be refractory to α-CD33 therapy.

Objectives To evaluate systematically the effectiveness of the primary healthcare system in Australia in preventing the development of advanced diabetes complications. Methods Diabetes patients (n = 4632) who had received their first laser photocoagulation treatment in 2000 were compared with a random sample of diabetes patients who had never received this treatment (n = 4632). Patterns of health care utilization were compared over a 7-year period (1993–1999) using the Australian Medicare database. Results There were significant differences in levels of healthcare utilization: cases were less likely to attend a general practitioner, from odds ratio (OR) = 0.21 (P

Initiation of T-lymphocyte-mediated immune responses involves two cellular processes: entry into the cell cycle (G(0)-->G(1)) for clonal proliferation and coordinated changes in surface and secreted molecules that mediate effector functions. However, a point during G(0)-->G(1) beyond which T cells are committed to enter the cell cycle has not been defined. We define here a G(0)-->G(1) commitment point that occurs 3 to 5 h after CD3 and CD28 stimulation of human CD4 or CD8 T cells. Transition through this point requires cdk6/4-cyclin D, since inhibition with TAT-p16(INK4A) during the first 3 to 5 h prevents cell cycle entry and maintains both naive and memory T cells in G(0). Transition through the G(0)-->G(1) commitment point is also necessary for T cells to increase in size, i.e., to enter the cellular growth cycle. However, transition through this point is not required for the induction of effector functions. These can be initiated while cells are maintained in G(0) with TAT-p16(INK4A). We have termed this quiescent, activated state G(0(A)). Our data provide proof of the principle that entry of T cells into the cell cycle and cellular growth cycles are coupled at the G(0)-->G(1) commitment point but that these processes can be uncoupled from the early expression of molecules of effector functions.

Primary hematopoietic cells are relatively refractory to DNA transfection methodologies. This is particularly so when they are quiescent or terminally differentiated and no longer able to divide. However, whole proteins can be introduced into such cells by protein transduction. We have modified the protein transduction domain (PTD) from the HIV-TAT protein used by other investigators. Using green fluorescent protein (GFP) as a reporter, we show that this new sequence allows more efficient transduction of recombinant fusion protein into a variety of hematopoietic cells tested compared with the native HIV TAT domain. This is true for peripheral blood CD34+ cells, dendritic cells, granulocytes, monocytes and lymphocytes all of which are quiescent or terminally differentiated. Furthermore, we were able to transduce myeloblasts from patients with acute myeloid leukemia (AML). In all cell types tested transduction efficiency was almost 100%. Transduction is maximal 15-30 s after addition of PTD or TAT-GFP fusion proteins as tested on quiescent T lymphocytes. This method will allow us to study of the effects of a variety of gene products in cell types that were previously resistant to gene transfection studies.

Continuous subcutaneous insulin infusion (CSII) is an effective method of intensive therapy for patients with type 1 diabetes; however, most studies have not examined long-term glycemic control. We evaluated the long-term efficacy of CSII in a cohort of adult patients with type 1 diabetes.This was a retrospective observational study of 200 patients with type 1 diabetes who initiated CSII at a single outpatient clinic in Kingston, ON, Canada between January 1998 and December 2012. Data were collected from 3 months prior to and up to 15 years after initiation of CSII and included glycated hemoglobin (HbA1c) level and demographic factors potentially associated with glycemic control.Mean age and duration of diabetes at CSII initiation were 35.4 years and 22.4 years, respectively. Mean duration of CSII at the time of analysis was 6 years. Mean HbA1c at initiation of CSII was 8.7% and decreased to a nadir of 7.5% 6 months post-initiation (SD = 1.0) (P0.001). This increased over time (range, 7.8-8.2%) but remained lower than the pre-CSII HbA1c (P0.001). Shorter duration of diabetes prior to CSII initiation, history of missed appointments, mental illness, and active smoking were predictors of higher HbA1c on CSII. Pre-CSII HbA1c predicted long-term HbA1c on CSII.The data demonstrate that in a clinic setting, patients on CSII maintain lower HbA1c values over a 1-10-year period compared with pre-CSII values. Poor pre-CSII HbA1c, history of missed appointments, mental illness, and active smoking are predictors of those less likely to achieve an HbA1c target of ≤ 7.0%.

Recognition of microbial components via innate receptors including the C-type lectin receptor Dectin-1, together with the inflammatory environment, programs dendritic cells (DCs) to orchestrate the magnitude and type of adaptive immune responses. The exposure to β-glucan, a known Dectin-1 agonist and component of fungi, yeasts, and certain immune support supplements, activates DCs to induce T helper (Th)17 cells that are essential against fungal pathogens and extracellular bacteria but may trigger inflammatory pathology or autoimmune diseases. However, the exact mechanisms of DC programming by β-glucan have not yet been fully elucidated. Using a gene expression/perturbation approach, we demonstrate that in human DCs β-glucan transcriptionally activates via an interleukin (IL)-1- and inflammasome-mediated positive feedback late-induced genes that bridge innate and adaptive immunity. We report that in addition to its known ability to directly prime T cells toward the Th17 lineage, IL-1 by promoting the transcriptional cofactor inhibitor of κB-ζ (IκB-ζ) also programs β-glucan-exposed DCs to express cell adhesion and migration mediators, antimicrobial molecules, and Th17-polarizing factors. Interferon (IFN)-γ interferes with the IL-1/IκB-ζ axis in β-glucan-activated DCs and promotes T cell-mediated immune responses with increased release of IFN-γ and IL-22, and diminished production of IL-17. Thus, our results identify IL-1 and IFN-γ as regulators of DC programming by β-glucan. These molecular networks provide new insights into the regulation of the Th17 response as well as new targets for the modulation of immune responses to β-glucan-containing microorganisms.

Pyloric stenosis is sometimes associated with hemodynamic instability and postoperative apnea. In this multicenter study we examined the hemodynamic response and recovery profile of remifentanil and compared it with that of halothane in infants undergoing pyloromyotomy. After atropine, propofol, and succinylcholine administration and tracheal intubation, patients were randomized (2:1 ratio) to receive either remifentanil with nitrous oxide and oxygen or halothane with nitrous oxide and oxygen as the maintenance anesthetic. Pre- and postoperative pneumograms were done and evaluated by an observer blinded to the study. Intraoperative hemodynamic data and postanesthesia care unit (PACU) discharge times, PACU recovery scores, pain medications, and adverse events (vomiting, bradycardia, dysrhythmia, and hypoxemia) were recorded by the study's research nurse. There were no significant differences in patient age or weight between the two groups. There were no significant differences in hemodynamic values between the two groups at the various intraoperative stress points. The extubation times, PACU discharge times, pain medications, and adverse events were similar for both groups. No patient anesthetized with remifentanil who had a normal preoperative pneumogram had an abnormal postoperative pneumogram, whereas three patients with a normal preoperative pneumogram who were anesthetized with halothane had abnormal pneumograms after.The use of ultra-short-acting opioids may be an appropriate technique for infants less than 2 mo old when tracheal extubation after surgery is anticipated.

A retrospective ecological study was undertaken to identify social and environmental factors associated with increased incidence of meningococcal disease in university halls of residence. A standardized questionnaire was sent to UK universities and colleges of higher education outside London, for distribution to halls containing at least 50 students. Incidence rate ratios of invasive meningococcal disease were obtained for a range of social and environmental variables. Multi-variable Poisson regression analysis identified 3 factors as having a strong association: a high proportion of first year undergraduate residents (P = 0·0008), decreasing smokiness of the hall bar (P < 0·0001), and opening of hall bar before 1990 (P = 0·0001). The inverse relationship between disease incidence and smokiness of bars was an unexpected finding, and may be due to confounding factors. Universities should continue to promote awareness of meningococcal disease, encourage vaccination of first year students against serogroup C disease, and where appropriate, take measures to reduce overcrowding.