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Lisa M Einhorn,1 Padmaja Krishnan,2 Cassandra Poirier,3 Pablo Ingelmo4– 7 1Department of Anesthesiology, Division of Pediatrics, Duke University School of Medicine, Durham, NC, USA; 2Campbell University School of Osteopathic Medicine, Lillington, NC, USA; 3Department of Anesthesiology, University of British Columbia, Kelowna, BC, Canada; 4Edwards Family Interdisciplinary Center for Complex Pain, Montreal Children’s Hospital, McGill University Health Center, Montreal, QC, Canada; 5Research Institute, McGill University Health Center, Montreal, QC, Canada; 6Department of Anesthesia, McGill University, Montreal, QC, Canada; 7Alan Edwards Center for Research in Pain, Montreal, QC, CanadaCorrespondence: Lisa M Einhorn, Department of Anesthesiology, Division of Pediatrics, DUMC 3094, Durham, NC, 27710, USA, Tel +1 919 681-4487, Email Lisa.einhorn@duke.eduAbstract: Chronic postsurgical pain (CPSP) affects a significant proportion of children and adolescents after major surgery and is a detriment to both short- and long-term recovery outcomes. While clinical characteristics and psychosocial risk factors for developing CPSP in children and adults are well established in the literature, there has been little progress on the prevention and management of CPSP after pediatric surgery. Limited evidence to support current pharmacologic approaches suggests a fundamentally new paradigm must be considered by clinicians to both conceptualize and address this adverse complication. This narrative review provides a comprehensive evaluation of both the known and emerging mechanisms that support our current understanding of CPSP. Additionally, we discuss the importance of optimizing perioperative analgesic strategies to mitigate CPSP based on individual patient risks. We highlight the importance of postoperative pain trajectories to identify those most at risk for developing CPSP, the early referral to multi-disciplinary pain clinics for comprehensive evaluation and treatment of CPSP, and additional work needed to differentiate CPSP characteristics from other chronic pain syndromes in children. Finally, we recognize ongoing challenges associated with the universal implementation of available knowledge about pediatric CPSP into practically useful care plans for clinicians.Keywords: chronic postsurgical pain, pediatrics, perioperative care, pain management, secondary pain

Abstract. Introduction:. Mu opioid receptor gene (OPRM1) variant rs1799971 introduces a CpG site, which may influence DNA methylation (DNAm) and opioid/pain outcomes. Objectives:. In this nested analysis, we investigated both OPRM1 A118G genotype and promoter/immediate downstream blood DNAm sequencing data for associations with opioid effects and chronic postsurgical pain (CPSP) in a surgical cohort. Methods:. Prospectively recruited opioid naïve patients undergoing Nuss procedure or spinal fusion with rs1799971 genotypes (Illumina arrays), DNAm (next generation enzymatic methylation sequencing at Chr6:154,039,209-154,039,803) and outcomes—opioid analgesia (integrated opioid use + pain over postoperative days 0 and 1 normalized to surgery type), safety—respiratory depression (RD) in high opioid use groups, and CPSP (Numerical Rating Scale >3/10 2-12 months postsurgery)—were included. Linear and logistic regression were performed to test genetic and epigenetic associations, adjusted for sociodemographics, cell types, and analgesics. Results:. In this cohort (N = 112; 15.3 ± 2.0 years, 50% female, 83% White, 55% had CPSP, 13% had RD), DNAm at Chr6:154039216-154039217 was associated with CPSP (odds ratio [OR], 1.26; 95% confidence interval [CI], 1.00-1.57; P = 0.03), Chr6:154039661-154039662 with acute integrated pain (β = −20.9, 95% CI, −40.70 to −1.10, P = 0.04), Chr6:154039520-154039521 (OR, 1.49; 95% CI, 1.09-2.03; P = 0.01), and Chr6:154039571-154039572 (OR, 1.47; 95% CI, 1.08-2.01; P = 0.02) with RD. Significant CpG sites were located in Repressed Polycomb chromatin states. Genotype was not associated with DNAm or outcomes. Conclusion:. Our analyses support OPRM1 DNAm as predictors of acute and chronic pain/opioid outcomes in children after painful surgery. Study limitations included absent GG genotype, low sequencing coverage, and lack of correction for multiple testing.

Introduction Even with recent treatment advances, type 2 diabetes (T2D) remains poorly controlled for many patients, despite the best efforts to adhere to therapies and lifestyle modifications. Although estimates vary, studies indicate that in >10% of individuals with difficult-to-control T2D, hypercortisolism may be an underlying contributing cause. To better understand the prevalence of hypercortisolism and the impact of its treatment on T2D and associated comorbidities, we describe the two-part Hypercortisolism in Patients with Difficult to Control Type 2 Diabetes Despite Receiving Standard-of-Care Therapies: Prevalence and Treatment with Korlym® (Mifepristone) (CATALYST) trial.Methods and analysis In part 1, approximately 1000 participants with difficult-to-control T2D (haemoglobin A1c (HbA1c) 7.5%–11.5% despite multiple therapies) are screened with a 1 mg dexamethasone suppression test (DST). Those with post-DST cortisol >1.8 µg/dL and dexamethasone level ≥140 ng/dL are identified to have hypercortisolism (part 1 primary endpoint), have morning adrenocorticotropic hormone (ACTH) and dehydroepiandrosterone sulfate (DHEAS) measured and undergo a non-contrast adrenal CT scan. Those requiring evaluation for elevated ACTH are referred for care outside the study; those with ACTH and DHEAS in the range may advance to part 2, a randomised, double-blind, placebo-controlled trial to evaluate the impact of treating hypercortisolism with the competitive glucocorticoid receptor antagonist mifepristone (Korlym®). Participants are randomised 2:1 to mifepristone or placebo for 24 weeks, stratified by the presence/absence of an abnormal adrenal CT scan. Mifepristone is dosed at 300 mg once daily for 4 weeks, then 600 mg daily based on tolerability and clinical improvement, with an option to increase to 900 mg. The primary endpoint of part 2 assesses changes in HbA1c in participants with hypercortisolism with or without abnormal adrenal CT scan. Secondary endpoints include changes in antidiabetes medications, cortisol-related comorbidities and quality of life.Ethics and dissemination The study has been approved by Cleveland Clinic IRB (Cleveland, Ohio, USA) and Advarra IRB (Columbia, Maryland, USA). Findings will be presented at scientific meetings and published in peer-reviewed journals.Trial registration number NCT05772169.

Abstract Background The American College of Medical Genetics and Genomics (ACMG) recently published new tier-based carrier screening recommendations. While many pan-ethnic genetic disorders are well established, some genes carry pathogenic founder variants (PFVs) that are unique to specific ethnic groups. We aimed to demonstrate a community data-driven approach to creating a pan-ethnic carrier screening panel that meets the ACMG recommendations. Methods Exome sequencing data from 3061 Israeli individuals were analyzed. Machine learning determined ancestries. Frequencies of candidate pathogenic/likely pathogenic (P/LP) variants based on ClinVar and Franklin were calculated for each subpopulation based on the Franklin community platform and compared with existing screening panels. Candidate PFVs were manually curated through community members and the literature. Results The samples were automatically assigned to 13 ancestries. The largest number of samples was classified as Ashkenazi Jewish (n = 1011), followed by Muslim Arabs (n = 613). We detected one tier-2 and seven tier-3 variants that were not included in existing carrier screening panels for Ashkenazi Jewish or Muslim Arab ancestries. Five of these P/LP variants were supported by evidence from the Franklin community. Twenty additional variants were detected that are potentially pathogenic tier-2 or tier-3. Conclusions The community data-driven and sharing approaches facilitate generating inclusive and equitable ethnically based carrier screening panels. This approach identified new PFVs missing from currently available panels and highlighted variants that may require reclassification.

Abstract Objectives Tonsillectomy is a common pediatric surgery, and pain is an important consideration in recovery. Due to the opioid epidemic, individual states, medical societies, and institutions have all taken steps to limit postoperative opioids, yet few studies have examined the effect of these interventions on pediatric otolaryngology practices. The primary aim of this study was to characterize opioid prescribing practices following North Carolina state opioid legislation and targeted institutional changes. Methods This single center retrospective cohort study included 1552 pediatric tonsillectomy patient records from 2014 to 2021. The primary outcome was number of oxycodone doses per prescription. This outcome was assessed over three time periods: (1) Before 2018 North Carolina opioid legislation. (2) Following legislation, before institutional changes. (3) After institutional opioid‐specific protocols. Results The mean (± standard deviation) number of doses per prescription in Periods 1, 2, and 3 was: 58 ± 53, range 4–493; 28 ± 36, range 3–488; and 23 ± 17, range 1–139, respectively. In the adjusted model, Periods 2 and 3 had lower doses by −41% (95% CI −49%, −32%) and −40% (95% CI −55%, −19%) compared to Period 1. After 2018 North Carolina legislation, dosage decreased by −9% (95% CI −13%, −5%) per year. Despite interventions, ongoing variability in prescription regimens remained in all periods. Conclusion Legislative and institution specific opioid interventions was associated with a 40% decrease in oxycodone doses per prescription following pediatric tonsillectomy. While variability in opioid practices decreased post‐interventions, it was not eliminated. Level of evidence 3

IntroductionThis study examines the changes in childhood self-reported health and wellbeing between 2014 and 2022.MethodsAn annual survey delivered by HAPPEN-Wales, in collaboration with 500 primary schools, captured self-reported data on physical health, dietary habits, mental health, and overall wellbeing for children aged 8–11 years.ResultsThe findings reveal a decline in physical health between 2014 and 2022, as evidenced by reduced abilities in swimming and cycling. For example, 68% of children (95%CI: 67%–69%) reported being able to swim 25m in 2022, compared to 85% (95% CI: 83%–87%) in 2018. Additionally, unhealthy eating habits, such as decreased fruit and vegetable consumption and increased consumption of sugary snacks, have become more prevalent. Mental health issues, including emotional and behavioural difficulties, have also increased, with emotional difficulties affecting 13%–15% of children in 2017–2018 and now impacting 29% of children in 2021–2022. Moreover, indicators of wellbeing, autonomy, and competence have declined.DiscussionImportantly, this trend of declining health and wellbeing predates the onset of the Covid-19 pandemic, suggesting that it is not solely attributed to the pandemic’s effects. The health of primary school children has been on a declining trajectory since 2018/2019 and has continued to decline through the COVID recovery period. The study suggests that these trends are unlikely to improve without targeted intervention and policy focus.

BackgroundHypertension is a leading cause of cardiovascular and kidney disease in the United States, yet blood pressure (BP) control at a population level is poor and worsening. Systematic home BP monitoring (HBPM) programs can lower BP, but programs supporting HBPM are not routinely used. The MyBP program deploys automated bidirectional text messaging for HBPM and disease self-management support. ObjectiveWe aim to produce a qualitative analysis of input from providers and staff regarding implementation of an innovative HBPM program in primary care practices. MethodsSemistructured interviews (average length 31 minutes) were conducted with physicians (n=11), nurses, and medical assistants (n=6) from primary care settings. The interview assessed multiple constructs in the Consolidated Framework for Implementation Research domains of intervention characteristics, outer setting, inner setting, and characteristics of individuals. Interviews were transcribed verbatim and analyzed using inductive coding to organize meaningful excerpts and identify salient themes, followed by mapping to the updated Consolidated Framework for Implementation Research constructs. ResultsHealth care providers reported that MyBP has good ease of use and was likely to engage patients in managing their high BP. They also felt that it would directly support systematic BP monitoring and habit formation in the convenience of the patient’s home. This could increase health literacy and generate concrete feedback to raise the day-to-day salience of BP control. Providers expressed concern that the cost of BP devices remains an encumbrance. Some patients were felt to have overriding social or emotional barriers, or lack the needed technical skills to interact with the program, use good measurement technique, and input readings accurately. With respect to effects on their medical practice, providers felt MyBP would improve the accuracy and frequency of HBPM data, and thereby improve diagnosis and treatment management. The program may positively affect the patient-provider relationship by increasing rapport and bidirectional accountability. Providers appreciated receiving aggregated HBPM data to increase their own efficiency but also expressed concern about timely routing of incoming HBPM reports, lack of true integration with the electronic health record, and the need for a dedicated and trained staff member. ConclusionsIn this qualitative analysis, health care providers perceived strong relative advantages of using MyBP to support patients. The identified barriers suggest the need for corrective implementation strategies to support providers in adopting the program into routine primary care practice, such as integration into the workflow and provider education. Trial RegistrationClinicalTrials.gov NCT03650166; https://tinyurl.com/bduwn6r4

Abstract Purpose Deficits in speech understanding constitute one of the most severe consequences of hearing loss. Here we investigate the clinical and genetic risk factors for symmetric deterioration of speech recognition thresholds (SRT) among cancer survivors treated with cisplatin. Methods SRT was measured using spondaic words and calculating the mean of measurements for both ears with symmetric SRT values. For clinical associations, SRT‐based hearing disability (SHD) was defined as SRT≥15 dB hearing loss and clinical variables were derived from the study dataset. Genotyped blood samples were used for GWAS with rank‐based inverse normal transformed SRT values as the response variable. Age was used as a covariate in association analyses. Results SHD was inversely associated with self‐reported health (p = 0.004). Current smoking (p = 0.002), years of smoking (p = 0.02), BMI (p

O câncer de testículo é uma doença rara, sendo identificados 5000 casos novos por ano nos Estados Unidos. Apesar de representar somente 1% de todos os tumores masculinos, o câncer de testículo tem sido matéria de constante atenção por vários fatores.

Since 72% of rare diseases are genetic in origin and mostly paediatrics, genetic newborn screening represents a diagnostic "window of opportunity". Therefore, many gNBS initiatives started in different European countries. Screen4Care is a research project, which resulted of a joint effort between the European Union Commission and the European Federation of Pharmaceutical Industries and Associations. It focuses on genetic newborn screening and artificial intelligence-based tools which will be applied to a large European population of about 25.000 infants. The neonatal screening strategy will be based on targeted sequencing, while whole genome sequencing will be offered to all enrolled infants who may show early symptoms but have resulted negative at the targeted sequencing-based newborn screening. We will leverage artificial intelligence-based algorithms to identify patients using Electronic Health Records (EHR) and to build a repository "symptom checkers" for patients and healthcare providers. S4C will design an equitable, ethical, and sustainable framework for genetic newborn screening and new digital tools, corroborated by a large workout where legal, ethical, and social complexities will be addressed with the intent of making the framework highly and flexibly translatable into the diverse European health systems.

Abstract Purpose Cisplatin is a critical component of first‐line chemotherapy for several cancers, but causes peripheral sensory neuropathy, hearing loss, and tinnitus. We aimed to identify comorbidities for cisplatin‐induced neurotoxicities among large numbers of similarly treated patients without the confounding effect of cranial radiotherapy. Methods Utilizing linear and logistic regression analyses on 1680 well‐characterized cisplatin‐treated testicular cancer survivors, we analyzed associations of hearing loss, tinnitus, and peripheral neuropathy with nongenetic comorbidities. Genome‐wide association studies and gene‐based analyses were performed on each phenotype. Results Hearing loss, tinnitus, and peripheral neuropathy, accounting for age and cisplatin dose, were interdependent. Survivors with these neurotoxicities experienced more hypertension and poorer self‐reported health. In addition, hearing loss was positively associated with BMIs at clinical evaluation and nonwork‐related noise exposure (>5 h/week). Tinnitus was positively associated with tobacco use, hypercholesterolemia, and noise exposure. We observed positive associations between peripheral neuropathy and persistent vertigo, tobacco use, and excess alcohol consumption. Hearing loss and TXNRD1, which plays a key role in redox regulation, showed borderline significance (p = 4.2 × 10−6) in gene‐based analysis. rs62283056 in WFS1 previously found to be significantly associated with hearing loss (n = 511), was marginally significant in an independent replication cohort (p = 0.06; n = 606). Gene‐based analyses identified significant associations between tinnitus and WNT8A (p = 2.5 × 10−6), encoding a signaling protein important in germ cell tumors. Conclusions Genetics variants in TXNRD1 and WNT8A are notable risk factors for hearing loss and tinnitus, respectively. Future studies should investigate these genes and if replicated, identify their potential impact on preventive strategies.

Abstract Background No comparison of a single hypervascular tumor entity in terms of major complications in different spinal regions has been performed. We aimed to evaluate post-embolic and post-operative outcomes in anatomic regions with renal cell carcinoma (RCC) metastases to the spine. Methods We retrospectively evaluated data from patients with confirmed, embolized, and surgically treated RCC spine metastases at a single-spine center between 2010 and 2020. Patients were divided into thoracic (TSM) and lumbar (LSM) spine metastasis groups. Results Seventeen patients had TSM and 14 had LSM. In all cases, embolization was performed preoperatively. The ΔHb value did not differ between the two groups pre- and postoperatively (p=0.3934). There was no significant difference in intraoperative blood loss between both groups either within 1 day or 2 days after embolization. Neurological deficits occurred in eight patients after embolization or surgery, with no significant difference between TSM (n=5) and LSM (n=3). Conclusions Embolization is the standard procedure for the preoperative treatment of hypervascular spinal metastases, possible up to 48 h before surgery, without the risk of higher intraoperative blood loss. Regardless of intraoperative complications, major complications can occur up to several hours after embolization. We recommend surgery the day after embolization to reliably detect neurologic complications from this procedure.

Abstract The genomic effects of circulating glucocorticoids are particularly relevant in cortico-limbic structures, which express a high concentration of steroid hormone receptors. To date, no studies have investigated genomic differences in hippocampal subregions, namely the dorsal (dHPC) and ventral (vHPC) hippocampus, in preclinical models treated with exogenous glucocorticoids. Chronic oral corticosterone (CORT) in mouse is a pharmacological approach that disrupts the activity of the hypothalamic-pituitary-adrenal axis, increases affective behavior, and induces genomic changes after stress in the HPC of wildtype (WT) mice and mice heterozygous for the gene coding for brain-derived neurotrophic factor Val66Met (hMet), a variant associated with genetic susceptibility to stress. Using RNA-sequencing, we investigated the genomic signatures of oral CORT in the dHPC and vHPC of WT and hMet male and female mice, and examined sex and genotype differences in response to oral CORT. Males under CORT showed lower glycemia and increased anxiety- and depression-like behavior compared to females that showed instead opposite affective behavior in response to CORT. Rank–rank-hypergeometric overlap (RRHO) was used to identify genes from a continuous gradient of significancy that were concordant across groups. RRHO showed that CORT-induced differentially expressed genes (DEGs) in WT mice and hMet mice converged in the dHPC of males and females, while in the vHPC, DEGs converged in males and diverged in females. The vHPC showed a higher number of DEGs compared to the dHPC and exhibited sex differences related to glucocorticoid receptor (GR)-binding genes and epigenetic modifiers. Methyl-DNA-immunoprecipitation in the vHPC revealed differential methylation of the exons 1C and 1F of the GR gene (Nr3c1) in hMet females. Together, we report behavioral and endocrinological sex differences in response to CORT, as well as epigenetic signatures that i) differ in the dHPC and vHPC,ii) are distinct in males and females, and iii) implicate differential methylation of Nr3c1 selectively in hMet females.

Abstract Background The use of alcohol and illicit drugs during adolescence can lead to serious short- and long-term health related consequences. Despite a global trend of decreased substance use, in particular alcohol, among adolescents, evidence suggests excessive use of substances by young people in socioeconomically affluent areas. To prevent substance use-related harm, we need in-depth knowledge about the reasons for substance use in this group and how they perceive various prevention interventions. The aim of the current study was to explore motives for using or abstaining from using substances among students in affluent areas as well as their attitudes to, and suggestions for, substance use prevention. Methods Twenty high school students (age 15–19 years) in a Swedish affluent municipality were recruited through purposive sampling to take part in semi-structured interviews. Qualitative content analysis of transcribed interviews was performed. Results The most prominent motive for substance use appears to be a desire to feel a part of the social milieu and to have high social status within the peer group. Motives for abstaining included academic ambitions, activities requiring sobriety and parental influence. Students reported universal information-based prevention to be irrelevant and hesitation to use selective prevention interventions due to fear of being reported to authorities. Suggested universal prevention concerned reliable information from credible sources, stricter substance control measures for those providing substances, parental involvement, and social leisure activities without substance use. Suggested selective prevention included guaranteed confidentiality and non-judging encounters when seeking help. Conclusions Future research on substance use prevention targeting students in affluent areas should take into account the social milieu and with advantage pay attention to students’ suggestions on credible prevention information, stricter control measures for substance providers, parental involvement, substance-free leisure, and confidential ways to seek help with a non-judging approach from adults.

The COVID-19 pandemic has posed significant burden across different industrial sectors. Generally, an increase in psychological stress experiences has been reported, while the stress and coping responses of specific, potentially burdened populations have received less attention thus far. Thus, the present study investigated relations between individual (i.e., extraversion, neuroticism, conscientiousness) and organizational (i.e., organizational commitment and study satisfaction) factors, indicators of psychological health (i.e., loneliness, life satisfaction, COVID-19-related stress), and possible mediating effects of four broad coping dimensions (active coping, avoidant coping, social support, positive cognitive restructuring) in a specific sample of soldier students who engage in a double-role being military affiliates and students of non-military subjects. To this end, we assessed data of soldier students at two measurement points (N = 106 at t1 and N = 63 at t2) shortly after the second national lockdown in Germany (20. May 2021 to 11. July 2021) during the COVID-19 pandemic. Personality traits showed expected associations with indicators of psychological health, i.e., positive relations between neuroticism and social loneliness, between extraversion and COVID-19 stress, and negative relations between neuroticism and life satisfaction. Remarkably, organizational variables showed effects above and beyond personality traits on loneliness and life satisfaction. Neither individual, nor organizational factors could predict change in psychological health over time. We found evidence for mediation effects through active coping, avoidant coping, and the use of social support, but not through positive cognitive restructuring. Findings highlight the relative importance of organizational factors besides personality traits for psychological health in a military student sample, holding important implications for designing efficient support systems in the military.

At Krabstadt Education Center, we take admissions very seriously, since our broadened participation reaches out to admit not only humans, but also fauna, flora, and fungi. In the KEC admissions game, you play as the admissions officer. You have the responsibility to target and admit eligible students by selecting matching word pairs and rejecting/deleting others. Your choice will have a direct impact on the appearance of the school building. There is a diversity quota that you need to reach, in order to be the most perfectly diverse school in the Arctic circle.

Abstract Background Due to the unspecific symptoms of spondylodiscitis (SpD), an early radiological examination is necessary. However, controversially discussed is the need for magnetic resonance imaging of the entire spine to exclude multisegmental infections and to determine the required surgical interventions. The aims of this study were to assess the incidence of multilevel non-contiguous pyogenic SpD and compare comorbidities, pain symptoms, and subsequent surgical strategies between unifocal (uSpD) and multifocal (mSpD) SpD. Methods We retrospectively evaluated the data of patients with confirmed, surgically treated, pyogenic SpD who had received a total spine MRI in a single spine center between 2016 and 2018. MRI findings were classified according to Pola-classification and demographics, duration of clinical symptoms (pain and neurology) and Charlson Comorbidity-Index (CCI) results were compared between uSpD und mSpD groups. Surgical therapy was evaluated in patients with mSpD. Results uSpD was detected by MRI in 69 of 79 patients (87%). Of these, mSpD was detected in 10 patients (13%) with 21 infected segments (cervical and/ or thoracic and/ or lumbar region). Age and CCI were similar between uSpD and mSpD and 24 of all SpD regions were clinically unapparent. All patients with uSpD were treated operatively. In seven patients with mSpD, all infected levels of the spine were treated surgically in a one-stage procedure; one patient had a two-stage procedure and one patient had surgery at the lumbar spine, and an additional infected segment of the upper thoracic spine was treated conservatively. One patient died before a planned two-stage procedure was performed. Conclusions Due to mSpD being found in approximately 13% of SpD cases, and considering the risk of overlooking an mSpD case, MRI imaging of the total spine is recommended. The detection of multiple infection levels can have an impact on the therapeutic strategy chosen.

Abstract Background Less attention has been given to younger adults’ psycho-oncology care needs than to children and older adults with cancer. The aim was to explore how care following end-of-treatment was perceived by women treated for different gynecologic cancer diagnoses during younger adulthood. Methods A sample of 207 women diagnosed with gynecologic cancer 2008 to 2016, aged 19–39 at time of diagnosis answered one open-ended question regarding important aspects of care after end-of-treatment. The written responses were analyzed with manifest content analysis and presented in relation to the women’s diagnoses, i.e., cervical (n = 130), ovarian (n = 57), and other gynecologic cancer diagnoses (n = 20). Results The analysis resulted in three categories: Unmet long-term supportive care needs, Satisfying long-term supportive care, and Health care organizational difficulties. Over half of the women (66.7%) described unmet care needs. The corresponding figures were 80.7, 63.1 and 50% for women diagnosed with ovarian, cervical and other gynecologic cancer diagnoses, respectively. Satisfying supportive care were described by approximately one quarter of the women (26.1%). Among women diagnosed with ovarian cancer 14% described satisfying supportive care. The corresponding figures were 26.9 and 30% for women diagnosed with cervical cancer and other gynecological diagnoses, respectively. Approximately one quarter of the women, irrespectively of diagnosis, described aspects related to health care organizational difficulties (28%). Conclusions The results highlight the importance of good quality care linked to the diagnosis and based on an understanding of the woman’s need, desire and expectation of support after end-of-treatment.

Abstract Metamitron is a relatively new postbloom thinning compound for pome fruits that inhibits the photosystem II (PS II) pathway of photosynthesis. Reduced assimilation of carbohydrate by metamitron action may lead to a carbohydrate deficit that promotes fruit abscission. We have evaluated the thinning efficacy of metamitron rate and, to a limited extent, application timing for ‘Bartlett’ pear in five separate trials over 3 years (2015–17) in northern Oregon. Comparisons were made to a nontreated control and, depending on the trial, a commercial standard thinning compound [benzyladenine (6-BA) or abscisic acid (ABA)]. Application timings ranged between 7- and 16-mm fruit diameter depending on the trial. Metamitron markedly inhibited photosynthesis (PN), typically for a duration of 2 to 3 weeks, although longer persistence was observed in two trials. Generally, PN was reduced linearly with increasing metamitron rate, but the effect varied by rate and year and may have been enhanced by high temperatures. Metamitron effectively thinned in four of five trials whereby pear fruit set was negatively and linearly related to rate. Rates of 200 to 300 ppm were efficacious and produced target crop loads. In only one trial, increasing concentrations (600 ppm) led to greater thinning. Metamitron significantly thinned ‘Bartlett’ pears when applied between 10 and 13 mm. In contrast, early application timing (≈7 mm) had little effect on fruit abscission. Fruit size increased with decreasing crop load and thus was significantly improved by metamitron. Interaction between biological and environmental factors likely contributed to year-to-year variability in efficacy.

Stress and mental ill-health carry considerable costs for both individuals and organizations. Although interventions targeting compassion and self-compassion have been shown to reduce stress and benefit mental health, related research in organizational settings is limited. We investigated the effects of a 6-week psychological intervention utilizing compassion training on stress, mental health, and self-compassion. Forty-nine employees of two organizations were randomly assigned to either the intervention (n = 25) or a physical exercise control condition (n = 24). Multilevel growth models showed that stress (p = 0.04) and mental ill-health (p = 0.02) decreased over 3 months in both groups (pre-intervention to follow-up: Cohen’s d = −0.46 and d = 0.33, respectively), while self-compassion only increased in the intervention group (p = 0.03, between group d = 0.53). There were no significant effects on life satisfaction in any of the groups (p > 0.53). The findings show promising results regarding the ability of compassion training within organizations to decrease stress and mental ill-health and increase self-compassion.

The profitability of modern apple orchard plantings depends largely on how rapidly the costs of planting are returned. Tree establishment and growth in the formative years are often can be limited by transplant shock associated with bare-root trees. In this experiment, we examined the effect of two planting systems, air-pruning containers, and field-grown liners, on above- and below-ground growth and development during the first year in the nursery. M9 ‘Nic 29’ bench grafts for three apple cultivars of different vigor classes, ‘Fuji’ (high vigor), ‘Gala’ (moderate vigor), and ‘Honeycrisp’ (low vigor). We hypothesized that air root-pruning containers would alter rooting distribution compared to field-grown liners by increasing fine root production, and this, in turn, would result in improved resource allocation and greater biomass partitioned to above-ground organs. Bench grafts were divided evenly between a field-grown liner bed (for bare root production) and an air-pruning container system. Air-pruning containers produced trees with significantly more root tips and greater total root length per tree than field-grown liners. Importantly, air-pruning containers resulted in a marked and significant increase in roots < 0.4 mm in diameter; however, field-grown liners produced trees had significantly more roots with diameters > 1.5 mm and, thus, significantly greater root dry matter content (DMC). Above-ground parameters (scion length, DMC of wood and leaves, and individual leaf area and DMC) were significantly increased for plants in air-pruning containers. Generally, the growth benefits from air-pruning containers were less pronounced in ‘Gala’ compared to ‘Honeycrisp’ or ‘Fuji’. The percentage of total DMC partitioned to the canopies of air-pruning containerized trees was significantly greater than field-grown liners.

ObjectiveBenevolence is an emerging concept in motivation theory and research as well as in on pro-social behavior, which has stimulated increasing interest in studying factors that impair or facilitate benevolence and effects thereof. This exploratory study examines the associations between benevolence, stress, mental health, self-compassion, and satisfaction with life in two workplace samples.MethodsIn the first study n = 522 (38% = female, median age = 42) participants answered questionnaires regarding self-reported stress symptoms (i.e., emotional exhaustion), depressive symptoms and benevolence. In the second study n = 49 (female = 96%) participants answered questionnaires regarding perceived stress, self-compassion, anxiety, depression symptoms, and benevolence.ResultsIn study 1, measures of emotional exhaustion (r = −0.295) and depression (r = −0.190) were significantly negatively correlated with benevolence. In study 2, benevolence was significantly negatively correlated with stress (r = −0.392) and depression (r = −0.310), whereas self-compassion (0.401) was significantly positively correlated with benevolence. While correlations were in expected directions, benevolence was not significantly associated with Satisfaction with Life (r = 0.148) or anxiety (r = −0.199) in study 2.ConclusionSelf-assessed benevolence is associated with levels of perceived stress, exhaustion, depression, and self-compassion. Future studies are warranted on how benevolence is related to stress and mental ill health such as depression and anxiety, and if benevolence can be trained in order to decrease stress and mental ill health such as depression and anxiety in workplace settings.

Abstract We analyze SO(N) and SU(N) gauge theories with scalars in adjoint and fundamental representations, coupled to renormalisable, classically scale invariant gravity. In the specific case of SO(11), we show that the quantum field theory can be can be asymptotically free in all couplings (hence ultra-violet complete). For a region of parameter space, Dimensional Transmutation occurs, with the adjoint vacuum expectation value breaking SO(11) → SU(6) ⊗ U(1) and producing a Low Energy Effective Theory having Einstein-Hilbert gravity. We verify that certain minima are locally stable and lie within the catchment basin of the ultraviolet fixed points.

Advances in precision agriculture technologies provide opportunities to improve the efficiency of agricultural production systems, especially for high-value specialty crops such as fresh apples (Malus domestica). We distributed an online survey to apple growers in Washington, New York, and Michigan to elicit stakeholder perceptions of precision agriculture technologies. Findings from this study demonstrated that growers are willing to adopt precision agriculture technologies when they receive results from applied research projects and are engaged with active extension programs. The availability of customized services and purchasing and rental options may minimize the effects of the economies of size that create barriers to adopting increasing access to technologies. Finally, respondents deemed collaborative efforts between industry and academic institutions crucial for adapting the innovation to better address the needs of growers.

Background Detecting significant coronary artery disease (CAD) in the general population is complex and relies on combined assessment of traditional CAD risk factors and noninvasive testing. We hypothesized that a CAD‐specific heart rate variability (HRV) algorithm can be used to improve detection of subclinical or early ischemia in patients without known CAD. Methods and Results Between 2014 and 2018 we prospectively enrolled 1043 patients with low to intermediate pretest probability for CAD who were screened for myocardial ischemia in tertiary medical centers in the United States and Israel. Patients underwent 1‐hour Holter testing, with immediate HRV analysis using the HeartTrends DyDx algorithm, followed by exercise stress echocardiography (n=612) or exercise myocardial perfusion imaging (n=431). The threshold for low HRV was identified using receiver operating characteristic analysis based on sensitivity and specificity. The primary end point was the presence of myocardial ischemia detected by exercise stress echocardiography or exercise myocardial perfusion imaging. The mean age of patients was 61 years and 38% were women. Myocardial ischemia was detected in 66 (6.3%) patients. After adjustment for CAD risk factors and exercise stress testing results, low HRV was independently associated with a significant 2‐fold increased likelihood for myocardial ischemia (odds ratio, 2.00; 95% CI, 1.41–2.89 [P=0.01]). Adding HRV to traditional CAD risk factors significantly improved the pretest probability for myocardial ischemia. Conclusions Our data from a large prospective international clinical study show that short‐term HRV testing can be used as a novel digital‐health modality for enhanced risk assessment in low‐ to intermediate‐risk individuals without known CAD. Clinical Trial Registration URL: http://www.ClinicalTrials.gov. Unique identifiers: NCT01657006, NCT02201017).

Abstract Allergies need not only affect humans; this multifactorial and complex disease can also affect animals. Comparative allergology investigates the many similarities between the pathogenesis, clinics, diagnosis, and therapy of the disorders in humans and pet animals. In contrast to human allergy research, the veterinary field lacks access to a central database, which means there are no cohort studies published. This limits not only the research on breed and regional differences in allergies, but also further studies on the impact of gender in allergies of domestic animals. Moreover, domestic cats, dogs and male horses are castrated in most cases, which neutralises any effects of sexual hormones. In this review article a few interesting findings regarding gender aspects in companion animals were extracted from current literature. In summary, there is a lack of data on gender effects on allergies in cats, dogs or horses.

Receptor for Activated protein C kinase 1 (RACK1) is a scaffold protein that has been found in association with several signaling complexes, and with the 40S subunit of the ribosome. Using the model organism Drosophila melanogaster, we recently showed that RACK1 is required at the ribosome for internal ribosome entry site (IRES)-mediated translation of viruses. Here, we report a proteomic characterization of the interactome of RACK1 in Drosophila S2 cells. We carried out Label-Free quantitation using both Data-Dependent and Data-Independent Acquisition (DDA and DIA, respectively) and observed a significant advantage for the Sequential Window Acquisition of all THeoretical fragment-ion spectra (SWATH) method, both in terms of identification of interactants and quantification of low abundance proteins. These data represent the first SWATH spectral library available for Drosophila and will be a useful resource for the community. A total of 52 interacting proteins were identified, including several molecules involved in translation such as structural components of the ribosome, factors regulating translation initiation or elongation, and RNA binding proteins. Among these 52 proteins, 15 were identified as partners by the SWATH strategy only. Interestingly, these 15 proteins are significantly enriched for the functions translation and nucleic acid binding. This enrichment reflects the engagement of RACK1 at the ribosome and highlights the added value of SWATH analysis. A functional screen did not reveal any protein sharing the interesting properties of RACK1, which is required for IRES-dependent translation and not essential for cell viability. Intriguingly however, 10 of the RACK1 partners identified restrict replication of Cricket paralysis virus (CrPV), an IRES-containing virus.

Abstract Background Exposure to the house dust mite Dermatophagoides pteronyssinus (D.p.) increases the risk for developing allergic diseases in humans and their best friends, the dogs. Here, we explored whether this allergenic mite via its enzymes may impact the cutaneous extracellular matrix (ECM), which critically determines epithelial barrier integrity both structurally and functionally. Methods Two extracts obtained from either dust-purified or cultured D.p. bodies were used in the present study. To assess the potential impact of D.p. on protein components of the ECM, proteolytic activity of the D.p. extracts were determined by casein and gelatin gel zymography, and their N-acetyl-β-hexosaminidase activity determined colorimetrically. In addition, IgE-dependent and innate degranulation potential of D.p. was examined in canine MPT-1 mast cells and neurite outgrowth assay using rat pheochromocytoma PC-12 cells. Results In gel zymography, both extracts digested the substrates casein and gelatin in a dose-dependent manner, especially at alkaline pH, and effective in a wide range of temperatures (30 °C−42 °C). In particular, a 25-kDa band corresponding to Der p 1, the major D.p. allergen for humans, was found enzymatically active in both casein and gelatin gels regardless of the presence of metal ions and of alkaline conditions. Besides protease activity, N-acetyl-β-hexosaminidase activity was detected in both extracts, suggesting that D.p. affects the cutaneous ECM through deteriorating both proteins and glycosaminoglycans. While both D.p. extracts induced IgE-dependent mast cell degranulation, much less innate effects on mast- and neuronal cells were observed. Conclusions Our data highlight that D.p. is a robust source of several distinct enzymes with protease- and N-acetyl-β-hexosaminidase activities. In alkaline milieu they can degrade components of the ECM. Therefore, D.p. may contribute to epithelial barrier disruption especially when the skin surface pH is elevated.

Abstract There are five well-known zero modes among the fluctuations of the metric of de Sitter (dS) spacetime. For Euclidean signature, they can be associated with certain spherical harmonics on the S 4 sphere, viz., the vector representation 5 of the global SO(5) isometry. They appear, for example, in the perturbative calculation of the on-shell effective action of dS space, as well as in models containing matter fields. These modes are shown to be associated with collective modes of S 4 corresponding to certain coherent fluctuations. When dS space is embedded in flat five dimensions E 5, they may be seen as a legacy of translation of the center of the S 4 sphere. Rigid translations of the S 4-sphere on E 5 leave the classical action invariant but are unobservable displacements from the point of view of gravitational dynamics on S 4. Thus, unlike similar moduli, the center of the sphere is not promoted to a dynamical degree of freedom. As a result, these zero modes do not signify the possibility of physically realizable fluctuations or flat directions for the metric of dS space. They are not associated with Killing vectors on S 4 but can be identified with certain non-isometric, conformal Killing forms that locally correspond to a rescaling of the volume element dV 4. We frame much of our discussion in the context of renormalizable gravity, but, to the extent that they only depend upon the global symmetry of the background, the conclusions should apply equally to the corresponding zero modes found in Einstein gravity. Although their existence has only been demonstrated at one-loop, we expect that these zero modes will be present to all orders in perturbation theory. They will occur for Lorentzian signature as well, so long as the hyperboloid H 4 is locally stable, but there remain certain infrared issues that need to be clarified. We conjecture that they will appear in any gravitational theory having dS background as a locally stable solution of the effective action, regardless of whether additional matter is included.

Abstract: The objective of this work was to evaluate the fruiting and vegetative growth of 'Starkrimson' pear in response to the application of prohexadione calcium (P-Ca). P-Ca (250 mg L-1) was sprayed to scaffold limbs and to whole trees in commercial orchards. A randomized complete block design was used to minimize declivity effects. Vegetative growth (length and number of shoots, increment in limb and trunk cross-sectional area, number of nodes, and internode length), production (fruit number, yield, yield efficiency, and fruit size), and return bloom were evaluated from 2010 to 2013. P-Ca efficiently controlled shoot growth in all growing seasons, when applied early in the season, due to the reduction in internode length. Production was not negatively affected by the application of P-Ca in all years and at both sites, and fruit size and return bloom were not reduced. Fruit quality attributes were also little affected by P-Ca, except for total soluble solids content, which was lower than that of the control. This shows that P-Ca is efficient to manage tree vigor in high-density 'Starkrimson' pear orchards.

Early life experiences program brain structure and function and contribute to behavioral endophenotypes in adulthood. Epigenetic control of gene expression by those experiences affect discrete brain regions involved in mood, cognitive function and regulation of hypothalamic-pituitary-adrenal (HPA) axis. In rodents, acute restraint stress increases the expression of the repressive histone H3 lysine 9 tri-methylation (H3K9me3) in hippocampal fields, including the CA3 pyramidal neurons. These CA3 neurons are crucially involved in cognitive function and mood regulation as well as activation of glucocorticoid (CORT) secretion. CA3 neurons also exhibit structural and functional changes after early-life stress (ELS) as well as after chronic stress in adulthood. Using a protocol of chronic ELS induced by limited bedding and nesting material followed by acute-swim stress (AS) in adulthood, we show that mice with a history of ELS display a blunted CORT response to AS, despite exhibiting activation of immediate early genes after stress similar to that found in control mice. We find that ELS induced persistently increased expression of the repressive H3K9me3 histone mark in the CA3 subfield at baseline that was subsequently decreased following AS. In contrast, AS induced a transient increase of this mark in control mice. Using translating ribosome affinity purification (TRAP) method to isolate CA3 translating mRNAs, we found that expression of genes of the epigenetic gene family, GABA/glutamate family, and glucocorticoid receptors binding genes were decreased transiently in control mice by AS and showed a persistent reduction in ELS mice. In most cases, AS in ELS mice did not induce gene expression changes. A stringent filtering of genes affected by AS in control and ELS mice revealed a noteworthy decrease in gene expression change in ELS mice compared to control. Only 18 genes were selectively regulated by AS in ELS mice and encompassed pathways such as circadian rhythm, inflammatory response, opioid receptors, and more genes included in the glucocorticoid receptor binding family. Thus, ELS programs a restricted translational response to stress in stress-sensitive CA3 neurons leading to persistent changes in gene expression, some of which mimic the transient effects of AS in control mice, while leaving in operation the immediate early gene response to AS.

Background: In recent years, much has been written about how to present a compelling business case. But, if just one critical piece of information is overlooked, it can lead to the wrong decision being taken. This article aims to minimise the risk. It stems from research conducted into how the business case can be used more effectively to improve the success rate of information technology (IT) or information technology or business (ITB) projects. The business case, usually a document, indicates whether the investment in money and resources is justified, prior to or at any time during the project. ‘Effective use’ involves using certain business case processes throughout the ITB project’s lifetime. Here, the life cycle refers only to the IT component of the project. The lifetime is longer, extending from initial proposal until all benefits have been realised. However, it is found that the processes are not easy to adhere to, a probable cause being the lack of relevant information. Objectives: The aim of this study was to determine what information is needed to drive the business case processes before, during and after the IT deliverables are produced. Method: The information types are derived from a structured review of literature related to the business case. Results: Details of the information types to create the business case are presented and related back to the business case content elements. Further information types that only arise during planning and subsequent tracking of the business case are also presented. Conclusion: For sound project governance, underpinned by effective use of the business case, it is essential to know what information needs to be gathered throughout the project’s lifetime. While knowing the processes and their relevant information is essential, further research is needed into the organisational factors that either facilitate, or inhibit such information gathering.

European pears (Pyrus communis L.) require a range of cold-temperature exposure to induce ethylene biosynthesis and fruit ripening. Physiological and hormonal responses to cold temperature storage in pear have been well characterized, but the molecular underpinnings of these phenomena remain unclear. An established low-temperature conditioning model was used to induce ripening of 'D'Anjou' and 'Bartlett' pear cultivars and quantify the expression of key genes representing ripening-related metabolic pathways in comparison to non-conditioned fruit. Physiological indicators of pear ripening were recorded, and fruit peel tissue sampled in parallel, during the cold-conditioning and ripening time-course experiment to correlate gene expression to ontogeny. Two complementary approaches, Nonparametric Multi-Dimensional Scaling and efficiency-corrected 2-(ΔΔCt), were used to identify genes exhibiting the most variability in expression. Interestingly, the enhanced alternative oxidase (AOX) transcript abundance at the pre-climacteric stage in 'Bartlett' and 'D'Anjou' at the peak of the conditioning treatments suggests that AOX may play a key and a novel role in the achievement of ripening competency. There were indications that cold-sensing and signaling elements from ABA and auxin pathways modulate the S1-S2 ethylene transition in European pears, and that the S1-S2 ethylene biosynthesis transition is more pronounced in 'Bartlett' as compared to 'D'Anjou' pear. This information has implications in preventing post-harvest losses of this important crop.

Background: Insects have become increasingly interesting as alternative nutrient sources for feeding humans and animals, most reasonably in processed form. Initially, some safety aspects — among them allergenicity — need to be addressed. Objective: To reveal the cross-reactivity of shrimp-, mite- and flies-allergic patients to different edible insects, and further to assess the efficacy of food processing in reducing the recognition of insect proteins by patients' IgE and in skin prick testing of shrimp-allergic patients. Methods: IgE from patients allergic to crustaceans, house dust mite or flies was evaluated for cross-recognition of proteins in house cricket Acheta domesticus (AD), desert locust Schistocerca gregaria (SG) and Yellow mealworm Tenebrio molitor (TM). Changes in IgE-binding and SPT-reactivity to processed insect extracts were determined for migratory locust (Locusta migratoria, LM), after different extraction methods, enzymatic hydrolysis, and thermal processing were applied. Results: IgE from patients with crustacean-allergy shows cross-recognition of AD, SG and stable flies; house dust mite allergics' IgE binds to AD and SG; and the flies-allergic patient recognized cricket, desert locust and migratory locust. Cross-reactivity and allergenicity in SPT to LM can be deleted by conventional processing steps, such as hydrolysis with different enzymes or heat treatment, during the preparation of protein concentrates. Conclusion: The results show that crustacean-, HDM- and stable flies-allergic patients cross-recognize desert locust and house cricket proteins, and crustacean-allergic patients also flies proteins. Furthermore, this study shows that appropriate food processing methods can reduce the risk of cross-reactivity and allergenicity of edible insects. Keywords: Allergenicity, Cross-recognition, Edible insects, Enzymatic hydrolysis, Food allergy, Immunoreactivity, Thermal processing

Smooth muscle contraction is controlled by the regulated activity of the myosin heavy chain ATPase (Myh11). Myh11 mutations have diverse effects in the cardiovascular, digestive and genitourinary systems in humans and animal models. We previously reported a recessive missense mutation, meltdown (mlt), which converts a highly conserved tryptophan to arginine (W512R) in the rigid relay loop of zebrafish Myh11. The mlt mutation disrupts myosin regulation and non-autonomously induces invasive expansion of the intestinal epithelium. Here, we report two newly identified missense mutations in the switch-1 (S237Y) and coil-coiled (L1287M) domains of Myh11 that fail to complement mlt. Cell invasion was not detected in either homozygous mutant but could be induced by oxidative stress and activation of oncogenic signaling pathways. The smooth muscle defect imparted by the mlt and S237Y mutations also delayed intestinal transit, and altered vascular function, as measured by blood flow in the dorsal aorta. The cell-invasion phenotype induced by the three myh11 mutants correlated with the degree of myosin deregulation. These findings suggest that the vertebrate intestinal epithelium is tuned to the physical state of the surrounding stroma, which, in turn, governs its response to physiologic and pathologic stimuli. Genetic variants that alter the regulation of smooth muscle myosin might be risk factors for diseases affecting the intestine, vasculature, and other tissues that contain smooth muscle or contractile cells that express smooth muscle proteins, particularly in the setting of redox stress.

Background . Polish society is characterized with low physical activity. Medical University students, as future doctors, should not only understand the importance of physical activity, but also do all they can to actively propagate it. Objectives. The aim of conducted research was to assess the level of physical activity among students of the final study year of Medical and Dentistry Faculties of Wroclaw Medical University. Material and methods . Study group included 211 people. In term of age and gender students of both faculties were a homogenous group. The study was conducted in summer term of 2011/2012 academic year, auditory method, ensuring anonymity. The study tool was International Questioner of Physical Activity (IPAQ) – long form. Based on MET s values the authors distinguished three levels of total physical activity – intense, moderate and low. Results . The level of students’ physical activity is comparable between the faculties with slightly higher values for students of Dentistry Faculty. Distributions of three levels of physical activity were similar between the faculties. Conclusions. The present study showed a need of health promotion in contests of physical activity among students of both faculties. The lowest activity of them (both male and female) is in the domain of work-related, during academic year. It creates a need for modifications of the study curriculum by adding additional sport classes and promoting attitudes of undertaking physical activity during other than study related activities.

Background Patients who have had an acute coronary syndrome (ACS) are at increased risk of recurrent cardiovascular events; however, paradoxically, high‐risk patients who may derive the greatest benefit from guideline‐recommended therapies are often undertreated. The aim of our study was to examine the management, clinical outcomes, and temporal trends of patients after ACS stratified by the Thrombolysis in Myocardial Infarction (TIMI) risk score for secondary prevention, a recently validated clinical tool that incorporates 9 clinical risk factors. Methods and Results Included were patients with ACS enrolled in the biennial Acute Coronary Syndrome Israeli Surveys (ACSIS) between 2008 and 2016. Patients were stratified by the TIMI risk score for secondary prevention to low (score 0–1), intermediate (2), or high (≥3) risk. Clinical outcomes included 30‐day major adverse cardiac events (death, myocardial infarction, stroke, unstable angina, stent thrombosis, urgent revascularization) and 1‐year mortality. Of 6827 ACS patients enrolled, 35% were low risk, 27% were intermediate risk, and 38% were high risk. Compared with the other risk groups, high‐risk patients were older, were more commonly female, and had more renal dysfunction and heart failure (P

BackgroundAlthough guidelines and performance measures exist for patients with diabetes mellitus, achievement of these metrics is not well known. The Diabetes Collaborative Registry® (DCR) was formed to understand the quality of diabetes mellitus care across the primary and specialty care continuum in the United States. Methods and ResultsWe assessed the frequency of achievement of 7 diabetes mellitus–related quality metrics and variability across the Diabetes Collaborative Registry® sites. Among 574 972 patients with diabetes mellitus from 259 US practices, median (interquartile range) achievement of the quality metrics across the practices was the following: (1) glycemic control: 19% (5–47); (2) blood pressure control: 80% (67–88); (3) angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers in patients with coronary artery disease: 62% (51–69); (4) nephropathy screening: 62% (53–71); (5) eye examination: 0.7% (0.0–79); (6) foot examination: 0.0% (0.0–2.3); and (7) tobacco screening/cessation counseling: 86% (80–94). In hierarchical, modified Poisson regression models, there was substantial variability in meeting these metrics across sites, particularly with documentation of glycemic control and eye and foot examinations. There was also notable variation across specialties, with endocrinology practices performing better on glycemic control and diabetes mellitus foot examinations and cardiology practices succeeding more in blood pressure control and use of angiotensin‐converting enzyme inhibitors/angiotensin II receptor blockers. ConclusionsThe Diabetes Collaborative Registry® was established to document and improve the quality of outpatient diabetes mellitus care. While target achievement of some metrics of cardiovascular risk modification was high, achievement of others was suboptimal and highly variable. This may be attributable to fragmentation of care, lack of ownership among various specialists concerning certain domains of care, incomplete documentation, true gaps in care, or a combination of these factors.

BackgroundFew data are available regarding the optimal management of ST‐elevation myocardial infarction patients with clinically defined spontaneous reperfusion (SR). We report on the characteristics and outcomes of patients with SR in the primary percutaneous coronary intervention era, and assess whether immediate reperfusion can be deferred. Methods and ResultsData were drawn from a prospective nationwide survey, ACSIS (Acute Coronary Syndrome Israeli Survey). Definition of SR was predefined as both (1) ≥70% reduction in ST‐segment elevation on consecutive ECGs and (2) ≥70% resolution of pain. Of 2361 consecutive ST‐elevation–acute coronary syndrome patients in Killip class 1, 405 (17%) were not treated with primary reperfusion therapy because of SR. Intervention in SR patients was performed a median of 26 hours after admission. These patients were compared with the 1956 ST‐elevation myocardial infarction patients who underwent primary reperfusion with a median door‐to‐balloon of 66 minutes (interquartile range 38–106). Baseline characteristics were similar except for slightly higher incidence of renal dysfunction and prior angina pectoris in SR patients. Time from symptom onset to medical contact was significantly greater in SR patients. Patients with SR had significantly less in‐hospital heart failure (4% versus 11%) and cardiogenic shock (0% versus 2%) (P

Background Exposure to the house dust mite Dermatophagoides pteronyssinus (D.p.) increases the risk for developing allergic diseases in humans and their best friends, the dogs. Here, we explored whether this allergenic mite via its enzymes may impact the cutaneous extracellular matrix (ECM), which critically determines epithelial barrier integrity both structurally and functionally.Methods Two extracts obtained from either dust-purified or cultured D.p. bodies were used in the present study. To assess the potential impact of D.p. on protein components of the ECM, proteolytic activity of the D.p. extracts were determined by casein and gelatin gel zymography, and their N-acetyl-β-hexosaminidase activity determined colorimetrically. In addition, IgE-dependent and innate degranulation potential of D.p. was examined in canine MPT-1 mast cells and neurite outgrowth assay using rat pheochromocytoma PC-12 cells.Results In gel zymography, both extracts digested the substrates casein and gelatin in a dose-dependent manner, especially at alkaline pH, and effective in a wide range of temperatures (30 °C−42 °C). In particular, a 25-kDa band corresponding to Der p 1, the major D.p. allergen for humans, was found enzymatically active in both casein and gelatin gels regardless of the presence of metal ions and of alkaline conditions. Besides protease activity, N-acetyl-β-hexosaminidase activity was detected in both extracts, suggesting that D.p. affects the cutaneous ECM through deteriorating both proteins and glycosaminoglycans. While both D.p. extracts induced IgE-dependent mast cell degranulation, much less innate effects on mast- and neuronal cells were observed.Conclusions Our data highlight that D.p. is a robust source of several distinct enzymes with protease- and N-acetyl-β-hexosaminidase activities. In alkaline milieu they can degrade components of the ECM. Therefore, D.p. may contribute to epithelial barrier disruption especially when the skin surface pH is elevated. Keywords: Dermatophagoides pteronyssinus, Allergens, Epithelial barrier, Extracellular matrix, Proteases, N-acetyl-β-hexosaminidase

Allergies need not only affect humans; this multifactorial and complex disease can also affect animals. Comparative allergology investigates the many similarities between the pathogenesis, clinics, diagnosis, and therapy of the disorders in humans and pet animals. In contrast to human allergy research, the veterinary field lacks access to a central database, which means there are no cohort studies published. This limits not only the research on breed and regional differences in allergies, but also further studies on the impact of gender in allergies of domestic animals. Moreover, domestic cats, dogs and male horses are castrated in most cases, which neutralises any effects of sexual hormones. In this review article a few interesting findings regarding gender aspects in companion animals were extracted from current literature. In summary, there is a lack of data on gender effects on allergies in cats, dogs or horses. Keywords: Atopic dermatitis, Canine, Cat, Dog, Gender, Horse, Pet

Thinning is a critical but challenging practice in apple production, especially for organic producers. The objective of this experiment was to determine if exclusion netting, used to manage insect pests and stress, could reduce fruit set and thinning requirements of ‘Gala’ and ‘Honeycrisp’ apple trees in Michigan and Washington, U.S.A., respectively. Nets were closed around whole canopies at different timings based on a predetermined percentage of open flowers. In 2017 and 2018, netted trees set a full commercial crop regardless of percentage of open bloom at the time of netting, including prebloom enclosures. Fruit set and yield of netted ‘Honeycrisp’ trees were significantly lower than non-netted, nonthinned controls but similar to non-netted hand-thinned controls. ‘Gala’ fruit set and yield did not differ among treatments. Exclusion netting markedly reduced the number of mature seeds and increased the number of nonfertilized seeds in both cultivars. Pollinator exclusion to ‘Gala’ in a frost year increased parthenocarpic fruit set two-fold compared to non-netted trees. Fruit size, shape, and quality attributes of ‘Gala’ were were similar among treatments, but ‘Honeycrisp’ fruit were significantly smaller than hand-thinned, non-netted controls. Netting may constitute an alternative, viable strategy to manage fruit set but requires testing on different cultivars.

Explicitly incorporating individual vehicle acceleration into a traffic simulation model is not a trivial task, and typically results in a considerable increase in model complexity. For this reason, alternative implicit techniques have been introduced in the literature to compensate for the delay times associated with acceleration. In this paper, the claim is investigated that these implicit modelling techniques adequately account for the time delays due to vehicle acceleration; the modelling techniques are implemented in a simulated environment, and compared with models in which vehicle acceleration has been incorporated explicitly for a number of traffic network topologies and traffic densities. It is found that considerable discrepancies may result between the two approaches.

We report a novel technology for the rapid healing of large osseous and chondral defects, based upon the genetic modification of autologous skeletal muscle and fat grafts. These tissues were selected because they not only possess mesenchymal progenitor cells and scaffolding properties, but also can be biopsied, genetically modified and returned to the patient in a single operative session. First generation adenovirus vector carrying cDNA encoding human bone morphogenetic protein-2 (Ad.BMP-2) was used for gene transfer to biopsies of muscle and fat. To assess bone healing, the genetically modified (“gene activated”) tissues were implanted into 5mm-long critical size, mid-diaphyseal, stabilized defects in the femora of Fischer rats. Unlike control defects, those receiving gene-activated muscle underwent rapid healing, with evidence of radiologic bridging as early as 10 days after implantation and restoration of full mechanical strength by 8 weeks. Histologic analysis suggests that the grafts rapidly differentiated into cartilage, followed by efficient endochondral ossification. Fluorescence in situ hybridization detection of Y-chromosomes following the transfer of male donor muscle into female rats demonstrated that at least some of the osteoblasts of the healed bone were derived from donor muscle. Gene activated fat also healed critical sized defects, but less quickly than muscle and with more variability. Anti-adenovirus antibodies were not detected. Pilot studies in a rabbit osteochondral defect model demonstrated the promise of this technology for healing cartilage defects. Further development of these methods should provide ways to heal bone and cartilage more expeditiously, and at lower cost, than is presently possible.

We report a novel technology for the rapid healing of large osseous and chondral defects, based upon the genetic modification of autologous skeletal muscle and fat grafts. These tissues were selected because they not only possess mesenchymal progenitor cells and scaffolding properties, but also can be biopsied, genetically modified and returned to the patient in a single operative session. First generation adenovirus vector carrying cDNA encoding human bone morphogenetic protein-2 (Ad.BMP-2) was used for gene transfer to biopsies of muscle and fat. To assess bone healing, the genetically modified (“gene activated”) tissues were implanted into 5mm-long critical size, mid-diaphyseal, stabilized defects in the femora of Fischer rats. Unlike control defects, those receiving gene-activated muscle underwent rapid healing, with evidence of radiologic bridging as early as 10 days after implantation and restoration of full mechanical strength by 8 weeks. Histologic analysis suggests that the grafts rapidly differentiated into cartilage, followed by efficient endochondral ossification. Fluorescence in situ hybridization detection of Y-chromosomes following the transfer of male donor muscle into female rats demonstrated that at least some of the osteoblasts of the healed bone were derived from donor muscle. Gene activated fat also healed critical sized defects, but less quickly than muscle and with more variability. Anti-adenovirus antibodies were not detected. Pilot studies in a rabbit osteochondral defect model demonstrated the promise of this technology for healing cartilage defects. Further development of these methods should provide ways to heal bone and cartilage more expeditiously, and at lower cost, than is presently possible.

The legal problems encountered by same-sex spouses in Israeli law are more complicated than those encountered in other democratic, developed countries. This stems from the fact that under Israeli law many areas of family law, first and foremost marriage and divorce, are governed by religious law, which is opposed to the legal recognition of such relationships. It is also not possible for such couples to establish a registered partnership in Israel, since partnerships can only be established for commercial purposes. A spectrum of family unions has nonetheless developed, gaining state recognition in various respects, mostly owing to the liberal approach of the Israel Supreme Court. Yet, it would appear that only legislation will be able resolve the outstanding problems. In its absence, a legal status is not conferred upon same-sex family unions and as such they are regarded as purely contractual arrangements. Other subject-matters in this article include: the extent of recognition granted to such family unions established abroad, by marriage or registered partnership; spouses’ rights and obligations regarding maintenance obligations and property relations; child adoption in Israel, especially if the child is unrelated to the spouses; parenthood if one spouse is the biological mother and the other a surrogate; the extent of recognition of foreign adoption orders; the dissolution of such family unions and succession.