Plastic Food Packaging from Five Countries Contains Endocrine- and Metabolism-Disrupting Chemicals.

Plastics are complex chemical mixtures of polymers and various intentionally and nonintentionally added substances. Despite the well-established links between certain plastic chemicals (bisphenols and phthalates) and adverse health effects, the composition and toxicity of real-world mixtures of plastic chemicals are not well understood. To assess both, we analyzed the chemicals from 36 plastic food contact articles from five countries using nontarget high-resolution mass spectrometry and reporter-gene assays for four nuclear receptors that represent key components of the endocrine and metabolic system. We found that chemicals activating the pregnane X receptor (PXR), peroxisome proliferator receptor γ (PPARγ), estrogen receptor α (ERα), and inhibiting the androgen receptor (AR) are prevalent in plastic packaging. We detected up to 9936 chemical features in a single product and found that each product had a rather unique chemical fingerprint. To tackle this chemical complexity, we used stepwise partial least-squares regressions and prioritized and tentatively identified the chemical features associated with receptor activity. Our findings demonstrate that most plastic food packaging contains endocrine- and metabolism-disrupting chemicals. Since samples with fewer chemical features induce less toxicity, chemical simplification is key to producing safer plastic packaging.

Beyond the Nucleus: Plastic Chemicals Activate G Protein-Coupled Receptors.

G protein-coupled receptors (GPCRs) are central mediators of cell signaling and physiological function. Despite their biological significance, GPCRs have not been widely studied in the field of toxicology. Herein, we investigated these receptors as novel targets of plastic chemicals using a high-throughput drug screening assay with 126 human non-olfactory GPCRs. In a first-pass screen, we tested the activity of triphenol phosphate, bisphenol A, and diethyl phthalate, as well as three real-world mixtures of chemicals extracted from plastic food packaging covering all major polymer types. We found 11 GPCR-chemical interactions, of which the chemical mixtures exhibited the most robust activity at adenosine receptor 1 (ADORA1) and melatonin receptor 1 (MTNR1A). We further confirm that polyvinyl chloride and polyurethane products contain ADORA1 or MTNRA1 agonists using a confirmatory secondary screen and pharmacological knockdown experiments. Finally, an analysis of the associated gene ontology terms suggests that ADORA1 and MTNR1A activation may be linked to downstream effects on circadian and metabolic processes. This work highlights that signaling disruption caused by plastic chemicals is broader than that previously believed and demonstrates the relevance of nongenomic pathways, which have, thus far, remained unexplored.

Prevalence of neural tube defects in England prior to the mandatory fortification of non-wholemeal wheat flour with folic acid: a population-based cohort study.

OBJECTIVES: To determine the baseline trends in the total birth prevalence of neural tube defects (NTDs) in England (2000-2019) to enable the impact of folic acid fortification of non-wholemeal wheat flour to be monitored. DESIGN: Population-based, observational study using congenital anomaly (CA) registration data for England curated by the National Congenital Anomaly and Rare Disease Registration Service (NCARDRS). SETTING: Regions of England with active registration in the time period. PARTICIPANTS: Babies that were liveborn or stillborn and pregnancies that resulted in a termination of pregnancy or a late miscarriage (20-23 weeks' gestation) with an NTD. MAIN OUTCOME MEASURES: Total birth prevalence of anencephaly, spina bifida and all NTDs in England. Poisson regression analysis was used to evaluate time trends with regional register as a random effect. The progress of national registration across England was assessed. RESULTS: There were 4541 NTD pregnancies out of 3 637 842 births in England; 1982 anencephaly and 2127 spina bifida. NTD prevalence was 12.5 (95% CI 12.1 to 12.9) per 10 000 total births. NTD prevalence per 10 000 total births was significantly higher in 2015-2019 (13.6, 95% CI 12.9 to 14.4) compared with 2010-2014 (12.1, 95% CI 11.7 to 12.5). An increasing trend in NTDs overall was detected (incidence rate ratio (IRR) 1.01, 1.00 to 1.02), although further analysis determined this effect was confined to 2015-2019 (compared against 2000-2004, IRR 1.14, 1.04 to 1.24). The birth prevalence of anencephaly reflected this pattern. The prevalence of spina bifida remained relatively stable over time. CONCLUSIONS: Baseline NTD prevalence for England has been established. National and standardised CA registration is in place, facilitating the systematic and consistent monitoring of pre-fortification and post-fortification NTD trends and evaluating the impact of fortification on NTD prevalence.

Tumor Regression upon Intratumoral and Subcutaneous Dosing of the STING Agonist ALG-031048 in Mouse Efficacy Models.

Stimulator of interferon genes (STING) agonists have shown potent anti-tumor efficacy in various mouse tumor models and have the potential to overcome resistance to immune checkpoint inhibitors (ICI) by linking the innate and acquired immune systems. First-generation STING agonists are administered intratumorally; however, a systemic delivery route would greatly expand the clinical use of STING agonists. Biochemical and cell-based experiments, as well as syngeneic mouse efficacy models, were used to demonstrate the anti-tumoral activity of ALG-031048, a novel STING agonist. In vitro, ALG-031048 is highly stable in plasma and liver microsomes and is resistant to degradation via phosphodiesterases. The high stability in biological matrices translated to good cellular potency in a HEK 293 STING R232 reporter assay, efficient activation and maturation of primary human dendritic cells and monocytes, as well as long-lasting, antigen-specific anti-tumor activity in up to 90% of animals in the CT26 mouse colon carcinoma model. Significant reductions in tumor growth were observed in two syngeneic mouse tumor models following subcutaneous administration. Combinations of ALG-031048 and ICIs further enhanced the in vivo anti-tumor activity. This initial demonstration of anti-tumor activity after systemic administration of ALG-031048 warrants further investigation, while the combination of systemically administered ALG-031048 with ICIs offers an attractive approach to overcome key limitations of ICIs in the clinic.

Fatigue in Hematopoietic Cell Transplantation Survivors: Correlates, Care Team Communication, and Patient-Identified Mitigation Strategies.

With improved survival after hematopoietic cell transplantation (HCT), the number of individuals at risk for persistent or late effects is increasing. The importance of optimizing HCT survivor health and well-being is mounting. Fatigue is a common post-transplantation symptom that impairs quality of life, yet it remains poorly understood and inadequately addressed. Multiple challenges to addressing fatigue exist, including its multidimensional presentation, multiple (often concomitant) causes, patient-clinician communication barriers, and few highly effective, evidence-based interventions that can be readily implemented. To address these challenges, we sought to better describe the impact and potential causes of fatigue in the post-transplantation setting, fatigue-related communication with clinicians, and the most effective patient-identified mitigation strategies (PIMS) for fatigue. A total of 1703 adult HCT recipients from a single center completed a survey including the Medical Outcomes Survey Short Form-36 (SF-36), PROMIS Fatigue, and other fatigue-related items between July 2017-June 2018. The survey was offered to recipients at their post-transplantation anniversary occurring during this interval. Two independent raters categorized free-text responses about fatigue PIMS. PROMIS Fatigue scores were dichotomized into low (≤55) or high (>55). Associations between high fatigue and participant characteristics and health outcomes were evaluated using the Fisher exact test for categorical variables and the Student 2-sample t test for continuous variables. Among the 1660 respondents with evaluable fatigue scores, 67% underwent allogeneic HCT. The majority of these (n = 1588; 96%) had a malignancy, with hematologic malignancy the most common diagnostic category (n = 1555; 94%). The median time post-transplantation was 11 years (interquartile range, 4 to 20 years). PROMIS item responses indicate that 44% of patients were at least somewhat fatigued and 37% were at least somewhat bothered by it. The mean fatigue score was 50.2 ± 11; 591 patients (36%) had high fatigue, which was associated with worse SF-36 scores across all domains (General Health, Physical Functioning, Emotional Well-being/Mental Health, Social Functioning, Role Limitation due to Physical Health, Role Limitation due to Emotional Health, Vitality [eg, energy], and Bodily Pain). High fatigue also was associated with self-reported chronic graft-versus-host disease, anxiety, depression and sleep problems. Diagnosis of plasma cell disorder and receipt of an autologous transplant were associated with high fatigue (P = .001). Among the 553 individuals who received an autologous transplant, 226 (41%) had multiple myeloma. Compared with the autologous transplant recipients without myeloma group, those with multiple myeloma were significantly more likely to have high fatigue (109 of 226 [48%] versus 118 of 325 [36%]; P < .01). Twenty percent of the patients with high fatigue did not discuss it with their care team. Among the 89 different reasons provided for not discussing it, the most common was "thought they already knew the answer" (n = 21). The 370 survivors with high fatigue who identified at least 1 most effective PIMS generated a total of 639 PIMS. Although the PIMS for fatigue spanned a wide array of strategies, most PIMS were related to sleep/rest (n = 192; 30%) or exercise (n = 139; 22%). Although fatigue is associated with worse HCT survivor-reported outcomes, it is only sometimes discussed with care teams. Survivors identify specific strategies that are most effective. Given its prevalence and impact, clinicians should promote communication about fatigue, treat underlying causes, and recommend sleep/rest and exercise, recognizing that individualized approaches also may be beneficial.

Adaptation of the Day100 Talk communication intervention for Spanish-speaking families of children with cancer.

The Day100 Talk (Day100) bridges communication gaps between parents and clinicians early in pediatric cancer care through an interprofessional family conference facilitated by structured tools. We aimed to understand communication challenges and facilitators and to adapt Day100 for Spanish-speaking parents. We interviewed Spanish-speaking parents with limited English proficiency, Spanish-English medical interpreters, and clinicians to gather communication experiences and adapt Day100. Results showed that communication difficulties were precipitated by linguistic and cultural differences, nonvisual technologies, and limited spontaneous communication. Interpreters enhanced communication as linguistic and cultural brokers. Nonverbal cues also facilitated communication. Participants offered recommendations to adapt Day100 for future study.

Detection rates of a national fetal anomaly screening programme: A national cohort study.

OBJECTIVE: To measure condition-specific detection rates for 14 physical conditions screened for by the NHS fetal anomaly screening programme (FASP) fetal anomaly (FA) ultrasound scan. DESIGN: Retrospective audit of 12 694 diagnoses across a 3-year national cohort. SETTING: All English NHS and crown-dependency hospital trusts providing maternity services. POPULATION: Pregnancies booked for maternity services with an expected date of delivery between 1 April 2017 and 31 March 2020 and at least one diagnosis of a condition screened for by FASP. METHODS: Active multi-source ascertainment, linkage, audit and validation of clinical information to identify the subset of diagnoses meeting the condition-specific positivity threshold for the FA scan. MAIN OUTCOME MEASURE: The accuracy of the FA scan compared with diagnostic reference standards. RESULTS: FA scan detection rates were: anencephaly 96.3% (95% confidence interval [CI] 81.7-99.3%), atrioventricular septal defect: 69.2% (95% CI 65.8-72.4%), bilateral renal agenesis: 98.7% (95% CI 95.4-99.6%), cleft lip: 89.5% (95% CI 87.8-90.9%), congenital diaphragmatic hernia: 60.8% (95% CI 56.5-65%), Edwards syndrome: 73.8% (95% CI 67.5-79.3%), exomphalos: 59.4% (95% CI 49.4-68.7%), gastroschisis: 88.6% (95% CI 79-94.1%), hypoplastic left heart syndrome: 92.7% (95% CI 90-94.8%), lethal skeletal dysplasia: 93.2% (95% CI 88.6-96%), Patau syndrome: 82.3% (95% CI 72.4-89.1%), spina bifida: 93.8% (95% CI 91.8-95.3%), tetralogy of Fallot: 75.4% (95% CI 72.1-78.4%) and transposition of the great arteries: 84.9% (95% CI 81.7-87.5%). CONCLUSIONS: The performance of the FA scan is above the expectations set in 2010 for most conditions. For the remaining conditions, the majority of fetuses and babies affected are detected before the FA scan.

Feasibility and acceptability of the "Day 100 Talk": An interdisciplinary communication intervention during the first six months of childhood cancer treatment.

BACKGROUND: Communication gaps arise early in the childhood cancer trajectory and may persist. The authors conducted a pilot study of the feasibility and acceptability of a communication intervention, the Day 100 Talk (D100). D100 involves an interprofessional family conference during initial months of treatment between oncologists, psychosocial clinicians, and parents, facilitated by a 3-part conversation tool. METHODS: The authors enrolled English-speaking parents of children with nonrelapsed, nonprogressive cancer who were receiving continuity care from enrolled pediatric oncologists and psychosocial clinicians at a single site. The a priori feasibility threshold was 60% parent completion of the D100 intervention. Surveys from parents and professionals and debrief interviews with professionals assessed D100 acceptability. RESULTS: Thirty-seven parents (77%) and 38 oncology professionals (67%) enrolled. Twenty of 33 evaluable parents (61%) participated in a D100 family conference. Most commonly, parents did not complete the D100 intervention because of scheduling difficulties related to clinical team constraints. All 17 parents who completed a post-D100 survey agreed or strongly agreed that D100 participation was helpful. In debrief interviews, professionals identified D100 benefits, namely, stepping back to the big picture and getting on the same page, and barriers related to logistical challenges and professionals' anticipatory dread. CONCLUSIONS: The D100 intervention pilot demonstrates high acceptability among parents of children with cancer. Despite meeting the prespecified feasibility threshold, findings highlight important barriers to D100 dissemination, namely, perceived burdens on professionals. Potential strategies to reduce burden may include using virtual visit platforms, incorporating D100 elements across multiple visits, or prioritizing intervention delivery to parents with the greatest need for enhanced communication.

Optimizing pharmacologic thromboprophylaxis use in pediatric orthopedic surgical patients through implementation of a perioperative venous thromboembolism risk screening tool.

BACKGROUND: Although rare, venous thromboembolic events (VTE) are a significant challenge in pediatric orthopedic surgical patients (POSP). A VTE thromboprophylaxis screening tool was developed and implemented in POSPs at the IWK Health Centre since October 2016. OBJECTIVES: This retrospective cohort study was designed to evaluate and assess the impact of the VTE thromboprophylaxis screening tool in terms of use of thromboprophylaxis in POSP. METHODS: Using the tool, POSPs were screened and were categorized into risk groups. Patient groups were compared and spearman correlation analysis was performed to show the strength of association between risk factors and thromboprophylaxis. Retrospective screening of pre-algorithm patients who received thromboprophylaxis was done to further assess the screening tool. RESULTS: After the implementation of the VTE thromboprophylaxis screening tool in POSPs, there was a 47.9% reduction in the use of thromboprophylaxis (P = 0.046) as compared with before. Neither VTE nor significant bleeding complications occurred before or after screening tool implementation. Compliance with the screening tool was excellent (100% of patients in the high-risk category received thromboprophylaxis). High-risk patients were more likely to have body mass index  > 30 (35.7%), limited/altered mobility (57.1%), and to be undergoing a complicated/repeat surgery (64.3%). CONCLUSIONS: The present study demonstrates successful implementation of a VTE thromboprophylaxis screening tool that resulted in significant reduction in use of thromboprophylaxis in POSPs with no increase in VTE or change in bleeding complications.

The Impact of Specialty Palliative Care in Pediatric Oncology: A Systematic Review.

CONTEXT: Children with cancer and their families have complex needs related to symptoms, decision-making, care planning, and psychosocial impact extending across the illness trajectory, which for some includes end of life. Whether specialty pediatric palliative care (SPPC) is associated with improved outcomes for children with cancer and their families is unknown. OBJECTIVE: We conducted a systematic review following PRISMA guidelines to investigate outcomes associated with SPPC in pediatric oncology with a focus on intervention delivery, collaboration, and alignment with National Quality Forum domains. METHODS: We searched PubMed, Embase, Scopus, Web of Science, and CINAHL databases from inception until April 2020 and reviewed references manually. Eligible articles were published in English, involved pediatric patients aged 0-18 years with cancer, and contained original data regarding patient and family illness and end-of-life experiences, including symptom management, communication, decision-making, quality of life, satisfaction, and healthcare utilization. RESULTS: We screened 6682 article abstracts and 82 full-text articles; 32 studies met inclusion criteria, representing 15,635 unique children with cancer and 342 parents. Generally, children with cancer who received SPPC had improved symptom burden, pain control, and quality of life with decreased intensive procedures, increased completion of advance care planning and resuscitation status documentation, and fewer end-of-life intensive care stays with higher likelihood of dying at home. Family impact included satisfaction with SPPC and perception of improved communication. CONCLUSION: SPPC may improve illness experiences for children with cancer and their families. Multisite studies utilizing comparative effectiveness approaches and validated metrics may support further advancement of the field.

Regulation of gene transcription by thyroid hormone receptor ß agonists in clinical development for the treatment of non-alcoholic steatohepatitis (NASH).

Thyroid hormones are important modulators of metabolic activity in mammals and alter cholesterol and fatty acid levels through activation of the nuclear thyroid hormone receptor (THR). Currently, there are several THRß agonists in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH) that have demonstrated the potential to reduce liver fat and restore liver function. In this study, we tested three THRß-agonism-based NASH treatment candidates, GC-1 (sobetirome), MGL-3196 (resmetirom), and VK2809, and compared their selectivity for THRß and their ability to modulate the expression of genes specific to cholesterol and fatty acid biosynthesis and metabolism in vitro using human hepatic cells and in vivo using a rat model. Treatment with GC-1 upregulated the transcription of CPT1A in the human hepatocyte-derived Huh-7 cell line with a dose-response comparable to that of the native THR ligand, triiodothyronine (T3). VK2809A (active parent of VK2809), MGL-3196, and VK2809 were approximately 30-fold, 1,000-fold, and 2,000-fold less potent than T3, respectively. Additionally, these relative potencies were confirmed by quantification of other direct gene targets of THR, namely, ANGPTL4 and DIO1. In primary human hepatocytes, potencies were conserved for every compound except for VK2809, which showed significantly increased potency that was comparable to that of its active counterpart, VK2809A. In high-fat diet fed rats, a single dose of T3 significantly reduced total cholesterol levels and concurrently increased liver Dio1 and Me1 RNA expression. MGL-3196 treatment resulted in concentration-dependent decreases in total and low-density lipoprotein cholesterol with corresponding increases in liver gene expression, but the compound was significantly less potent than T3. In conclusion, we have implemented a strategy to rank the efficacy of THRß agonists by quantifying changes in the transcription of genes that lead to metabolic alterations, an effect that is directly downstream of THR binding and activation.

Precision Antifungal Treatment Significantly Extends Voice Prosthesis Lifespan in Patients Following Total Laryngectomy.

Indwelling silicone valves called voice prostheses (VPs) are the gold standard for speech rehabilitation in patients with laryngeal cancer following total laryngectomy. Reported VP lifespans amongst these patients are highly variable but when devices fail patients experience loss of voice and an increase risk of chest infection. Early failure of VP is a current clinical concern that is associated with regular hospital visits, reduced quality of life and associated medical cost. Poly-microbial biofilms comprised of both bacterial and fungal microorganisms readily colonize VPs and are linked to loss of device performance and its early failure in addition to providing a reservoir for potential infection. Our detailed analysis of poly-microbial biofilm composition on 159 early failing VPs from 48 total laryngectomy patients confirmed Candida albicans as the predominant fungal species and Staphylococcus aureus as the most common bacterial colonizer within our patient cohort. Using a combination of microbiological analysis, patient data and a high-throughput antifungal test assay mimicking in vivo conditions we established an evidence based precision antifungal treatment approach to VP management. Our approach has allowed us to implement a personalized VP management pathway, which increases device in situ lifespan by an average of 270%. Our study represents a significant step forward in both our understanding of the cause of VP failure and a new effective treatment pathway that offers tangible benefit to patients.

Development of a perioperative venous thromboembolism prophylaxis algorithm for pediatric orthopedic surgical patients.

Venous thromboembolism (VTE) has been recognized as a rare but potentially serious complication in pediatric orthopedic patients. However, standardized guidelines for screening and management of at-risk patients do not exist. The aim of the study was to develop a VTE prophylaxis screening tool for postoperative orthopedic patients after conducting an institutional needs assessment survey. A needs assessment survey was conducted after institutional ethics board approval. Development of perioperative VTE prophylaxis algorithm for pediatric orthopedic surgical patients was planned after thorough literature review, consultation with national and international experts as well as using a modified nominal and consensus development conference (serial meetings) method for reaching a consensus. NAS as well as discussion with stakeholders indicated support for development of perioperative VTE prophylaxis algorithm for orthopedic patients. Using above methods, a VTE prophylaxis algorithm was developed and implemented at IWK Health Center. The present study involved development of a perioperative VTE prophylaxis algorithm for pediatric orthopedic surgical patients that could be easily and rapidly administered as a point of care assessment tool.

A novel herpesvirus associated with chronic superficial keratitis and proliferative conjunctivitis in a great horned owl (Bubo virginianus).

An adult great-horned owl (Bubo virginianus; GHOW) presented with a history of recurrent corneal ulceration of the right eye (OD). Findings included ulcerative superficial keratitis, proliferative conjunctivitis, and iris pigmentary changes. The ulcer was initially nonresponsive to medical therapy, but showed rapid and appropriate healing following diamond burr debridement. Proliferative conjunctivitis markedly improved following topical antiviral therapy with cidofovir 1%, interferon alpha 2B ophthalmic solutions, and oral l-lysine. Histopathologic evaluation of a conjunctival biopsy revealed epithelial features suspicious for viral cytopathic changes and intranuclear structures suspicious for viral inclusions, suggestive of a possible viral-induced papillomatous conjunctivitis. A novel alphaherpesvirus, referred to as Strigid Herpesvirus 1 (StrHV1), was identified using PCR and gene sequencing. This case represents a new clinical manifestation of a previously unreported herpesvirus in the GHOW. Identification of the herpes virus was critical to administration of appropriate therapy and resolution of the conjunctivitis, and corneal epithelial debridement promoted resolution of the chronic corneal epithelial defect.

Practice variation in the use of tests in UK primary care: a retrospective analysis of 16 million tests performed over 3.3 million patient years in 2015/16.

BACKGROUND: The UK's National Health Service (NHS) is currently subject to unprecedented financial strain. The identification of unnecessary healthcare resource use has been suggested to reduce spending. However, there is little very research quantifying wasteful test use, despite the £3 billion annual expenditure. Geographical variation has been suggested as one metric in which to quantify inappropriate use. We set out to identify tests ordered from UK primary care that are subject to the greatest between-practice variation in their use. METHODS: We used data from 444 general practices within the Clinical Practice Research Datalink to calculate a coefficient of variation (CoV) for the ordering of 44 specific tests from UK general practices. The coefficient of variation was calculated after adjusting for differences between practice populations. We also determined the tests that had both a higher-than-average CoV and a higher-than-average rate of use. RESULTS: In total, 16,496,218 tests were ordered for 4,078,091 patients over 3,311,050 person-years from April 1, 2015, to March 31, 2016. The tests subject to the greatest variation were drug monitoring 158% (95%CI 153 to 163%), urine microalbumin (52% (95%CI 49.9 to 53.2%)), pelvic CT (51% (95%CI 50 to 53%)) and Pap smear (49% (95%CI 48 to 51%). Seven tests were classified as high variability and high rate (clotting, vitamin D, urine albumin, prostate-specific antigen (PSA), bone profile, urine MCS and C-reactive protein (CRP)). CONCLUSIONS: There are wide variations in the use of common tests, which is unlikely to be explained by clinical indications. Since £3 billion annually are spent on tests, this represents considerable variation in the use of resources and inefficient management in the NHS. Our results can be of value to policy makers, researchers, patients and clinicians as the NHS strives towards identifying overuse and underuse of tests.

Factors associated with consultation rates in general practice in England, 2013-2014: a cross-sectional study.

BACKGROUND: Workload in general practice has risen during the last decade, but the factors associated with this increase are unclear. AIM: To examine factors associated with consultation rates in general practice. DESIGN AND SETTING: A cross-sectional study examining a sample of 304 937 patients registered at 316 English practices between 2013 and 2014, drawn from the Clinical Practice Research Datalink. METHOD: Age, sex, ethnicity, smoking status, and deprivation measures were linked with practice-level data on staffing, rurality, training practice status, and Quality and Outcomes Framework performance. Multilevel analyses of patient consultation rates were conducted. RESULTS: Consultations were grouped into three types: all (GP or nurse), GP, and nurse. Non-smokers consulted less than current smokers (all: rate ratio [RR] = 0.88, 95% CI = 0.87 to 0.89; GP: RR = 0.88, 95% CI = 0.87 to 0.89; nurse: RR = 0.91, 95% CI = 0.90 to 0.92). Consultation rates were higher for those in the most deprived quintile compared with the least deprived quintile (all: RR = 1.18, 95% CI = 1.16 to 1.19; GP: RR = 1.17, 95% CI = 1.15 to 1.19; nurse: RR = 1.13, 95% CI = 1.11 to 1.15). For all three consultation types, consultation rates increased with age and female sex, and varied by ethnicity. Rates in practices with >8 and ≤19 full-time equivalent (FTE) GPs were higher compared with those with ≤2 FTE GPs (all: RR = 1.26, 95% CI = 1.06 to 1.49; GP: RR = 1.36, 95% CI = 1.19 to 1.56). CONCLUSION: The analyses show consistent trends in factors related to consultation rates in general practice across three types of consultation. These data can be used to inform the development of more sophisticated staffing models, and resource allocation formulae.

Patient-level and practice-level factors associated with consultation duration: a cross-sectional analysis of over one million consultations in English primary care.

OBJECTIVES: Consultation duration has previously been shown to be associated with patient, practitioner and practice characteristics. However, previous studies were conducted outside the UK, considered only small numbers of general practitioner (GP) consultations or focused primarily on practitioner-level characteristics. We aimed to determine the patient-level and practice-level factors associated with duration of GP and nurse consultations in UK primary care. DESIGN AND SETTING: Cross-sectional data were obtained from English general practices contributing to the Clinical Practice Research Datalink (CPRD) linked to data on patient deprivation and practice staffing, rurality and Quality and Outcomes Framework (QOF) achievement. PARTICIPANTS: 218 304 patients, from 316 English general practices, consulting from 1 April 2013 to 31 March 2014. ANALYSIS: Multilevel mixed-effects models described the association between consultation duration and patient-level and practice-level factors (patient age, gender, smoking status, ethnic group, deprivation and practice rurality, number of full-time equivalent GPs/nurses, list size, consultation rate, quintile of overall QOF achievement and training status). RESULTS: Mean duration of face-to-face GP consultations was 9.24 min and 5.32 min for telephone consultations. Nurse face-to-face and telephone consultations lasted 9.70 and 5.73 min on average, respectively. Longer GP consultation duration was associated with female patient gender, practice training status and older patient age. Shorter duration was associated with higher deprivation and consultation rate. Longer nurse consultation duration was associated with male patient gender, older patient age and ever smoking; and shorter duration with higher consultation rate. Observed differences in duration were small (eg, GP consultations with female patients compared with male patients were 8 s longer on average). CONCLUSIONS: Small observed differences in consultation duration indicate that patients are treated similarly regardless of background. Increased consultation duration may be beneficial for older or comorbid patients, but the benefits and costs of increased consultation duration require further study.

Immunoreactivity of Canine Liposarcoma to Muscle and Brown Adipose Antigens.

Liposarcoma, rhabdomyosarcoma, and hibernoma share some overlapping histologic and immunohistochemical features. Although immunohistochemistry (IHC) is commonly used in the diagnosis of these neoplasms, expression of muscle markers has been reported in human liposarcoma and canine hibernoma in addition to rhabdomyosarcoma. Thus, these neoplasms are a diagnostic challenge but important to distinguish because of differences in prognosis and treatment. Rhabdomyosarcoma and liposarcoma are both malignant, but rhabdomyosarcoma has a higher potential for metastasis. In contrast, hibernomas are benign with low risk of recurrence. This study investigated expression of the muscle markers desmin, myogenin, and α-smooth muscle actin (α-SMA) and the brown fat marker uncoupling protein 1 (UCP1) in 25 cases of canine liposarcoma using IHC. Oil red O histochemistry was performed to confirm the presence of lipid and the diagnosis of liposarcoma in cases that were not well-differentiated. The 25 cases included 15 well-differentiated, 5 pleomorphic, 3 myxoid, and 2 dedifferentiated subtypes of liposarcoma. By IHC, 23 of 25 expressed UCP1, 7 of 25 expressed α-SMA, 7 of 25 expressed desmin, and 3 of 25 expressed myogenin with no clear relationship of antigen expression and tumor subtype. These findings clarify the immunohistochemical profile of canine liposarcoma and suggest overlap in the expression of several muscle antigens and UCP1 between liposarcoma, hibernoma, and rhabdomyosarcoma.

Body-mass index and risk of advanced chronic kidney disease: Prospective analyses from a primary care cohort of 1.4 million adults in England.

BACKGROUND: It is uncertain whether being overweight, but not obese, is associated with advanced chronic kidney disease (CKD) and how the size and shape of associations between body-mass index (BMI) and advanced CKD differs among different types of people. METHODS: We used Clinical Practice Research Datalink records (2000-2014) with linkage to English secondary care and mortality data to identify a prospective cohort with at least one BMI measure. Cox models adjusted for age, sex, smoking and social deprivation and subgroup analyses by diabetes, hypertension and prior cardiovascular disease assessed relationships between BMI and CKD stages 4-5 and end-stage renal disease (ESRD). FINDINGS: 1,405,016 adults aged 20-79 with mean BMI 27.4kg/m2 (SD 5.6) were followed for 7.5 years. Compared to a BMI of 20 to <25kg/m2, higher BMI was associated with a progressively increased risk of CKD stages 4-5 (hazard ratio 1.34, 95% CI 1.30-1.38 for BMI 25 to <30kg/m2; 1.94, 1.87-2.01 for BMI 30 to <35kg/m2; and 3.10, 2.95-3.25 for BMI ≥35kg/m2). The association between BMI and ESRD was shallower and reversed at low BMI. Current smoking, prior diabetes, hypertension or cardiovascular disease all increased risk of CKD, but the relative strength and shape of BMI-CKD associations, which were generally log-linear above a BMI of 25kg/m2, were similar among those with and without these risk factors. There was direct evidence that being overweight was associated with increased risk of CKD stages 4-5 in these subgroups. Assuming causality, since 2000 an estimated 39% (36-42%) of advanced CKD in women and 26% (22-30%) in men aged 40-79 resulted from being overweight or obese. CONCLUSIONS: This study provides direct evidence that being overweight increases risk of advanced CKD, that being obese substantially increases such risk, and that this remains true for those with and without diabetes, hypertension or cardiovascular disease. Strategies to reduce weight among those who are overweight, as well as those who are obese may reduce CKD risk, with each unit reduction in BMI yielding similar relative reductions in risk.

Biochemical Effect of Resistance Mutations against Synergistic Inhibitors of RSV RNA Polymerase.

ALS-8112 is the parent molecule of ALS-8176, a first-in-class nucleoside analog prodrug effective in the clinic against respiratory syncytial virus (RSV) infection. The antiviral activity of ALS-8112 is mediated by its 5'-triphosphate metabolite (ALS-8112-TP, or 2'F-4'ClCH2-cytidine triphosphate) inhibiting the RNA polymerase activity of the RSV L-P protein complex through RNA chain termination. Four amino acid mutations in the RNA-dependent RNA polymerase (RdRp) domain of L (QUAD: M628L, A789V, L795I, and I796V) confer in vitro resistance to ALS-8112-TP by increasing its discrimination relative to natural CTP. In this study, we show that the QUAD mutations specifically recognize the ClCH2 group of ALS-8112-TP. Among the four mutations, A789V conferred the greatest resistance phenotype, which was consistent with its putative position in the active site of the RdRp domain. AZ-27, a non-nucleoside inhibitor of RSV, also inhibited the RdRp activity, with decreased inhibition potency in the presence of the Y1631H mutation. The QUAD mutations had no effect on the antiviral activity of AZ-27, and the Y1631H mutation did not significantly increase the discrimination of ALS-8112-TP. Combining ALS-8112 with AZ-27 in vitro resulted in significant synergistic inhibition of RSV replication. Overall, this is the first mechanistic study showing a lack of cross-resistance between mutations selected by different classes of RSV polymerase inhibitors acting in synergy, opening the door to future potential combination therapies targeting different regions of the L protein.