Effectiveness of a midwife-led continuity of care model on birth outcomes and maternal mental health in vulnerable women: study protocol for a randomised controlled trial with an internal pilot, process evaluation and economic analysis.

INTRODUCTION: Women from social disadvantage are at greater risk of poor birth outcomes. The midwife-led continuity of care (MCC) model, which offers flexible and relational care from a small team of midwives, has demonstrated improved birth outcomes. In the general population, the impact of MCC on socially disadvantaged women and on birth outcomes is still unclear. This protocol describes a pragmatic evaluation of the MCC model in a socially disadvantaged population. METHODS AND ANALYSIS: An open-labelled individual prospective randomised controlled trial with an internal pilot, process evaluation and economic analysis, from 1 April 2022 to 31 March 2024.Women will be randomly allocated to MCC or standard care as part of usual midwifery practice. Participants and midwives will not be blinded, but researchers will be. An internal pilot will test the feasibility of this process.Participants are those randomised into MCC or standard care, who consent to participate in one of two Born in Bradford (BiB) birth cohort studies. Outcomes are taken from routinely linked health data, supplemented by additional data capture. The sample size is fixed by the capacity of MCC teams, commissioning duration and numbers recruited into the cohort. The estimated maximum fixed sample size is 1,410 pregnancies (minimum 734).Intention to treat (ITT) analysis will be undertaken to assess the impact of MCC on two independent primary outcomes. An economic evaluation will explore the impact on health resource use and a process evaluation will explore fidelity to the MCC model, and barriers/facilitators to implementation from midwives' and women's perspectives. ETHICS AND DISSEMINATION: Ethical approval has been obtained for the randomisation in midwifery practice, use of the cohort data for evaluation and for the process evaluation. Findings will be published in peer-reviewed journals, presented at conferences and translated into policy briefings. TRIAL REGISTRATION NUMBER: IsRCTNhttps://doi.org/10.1186/ISRCTN31836167.

Using light scattering to assess how phospholipid-protein interactions affect complex I functionality in liposomes.

Complex I is an essential membrane protein in respiration, oxidising NADH and reducing ubiquinone to contribute to the proton-motive force that powers ATP synthesis. Liposomes provide an attractive platform to investigate complex I in a phospholipid membrane with the native hydrophobic ubiquinone substrate and proton transport across the membrane, but without convoluting contributions from other proteins present in the native mitochondrial inner membrane. Here, we use dynamic and electrophoretic light scattering techniques (DLS and ELS) to show how physical parameters, in particular the zeta potential (ζ-potential), correlate strongly with the biochemical functionality of complex I-containing proteoliposomes. We find that cardiolipin plays a crucial role in the reconstitution and functioning of complex I and that, as a highly charged lipid, it acts as a sensitive reporter on the biochemical competence of proteoliposomes in ELS measurements. We show that the change in ζ-potential between liposomes and proteoliposomes correlates linearly with protein retention and catalytic oxidoreduction activity of complex I. These correlations are dependent on the presence of cardiolipin, but are otherwise independent of the liposome lipid composition. Moreover, changes in the ζ-potential are sensitive to the proton motive force established upon proton pumping by complex I, thereby constituting a complementary technique to established biochemical assays. ELS measurements may thus serve as a more widely useful tool to investigate membrane proteins in lipid systems, especially those that contain charged lipids.

A molecular sensitization map of European children reveals exposome- and climate-dependent sensitization profiles.

BACKGROUND: Understanding differences in sensitization profiles at the molecular allergen level is important for diagnosis, personalized treatment and prevention strategies in allergy. METHODS: Immunoglobulin E (IgE) sensitization profiles were determined in more than 2800 sera from children in nine population-based cohorts in different geographical regions of Europe; north [BAMSE (Sweden), ECA (Norway)], west/central [PIAMA (the Netherlands), BiB (the United Kingdom), GINIplus (Germany)], and south [INMA Sabadell and Gipuzkoa (Spain) and ROBBIC Rome and Bologna (Italy)] using the MeDALL-allergen chip. RESULTS: Sensitization to grass pollen allergen, Phl p 1, and to major cat allergen, Fel d 1, dominated in most European regions whereas sensitization to house dust mite allergens Der p 1, 2 and 23 varied considerably between regions and were lowest in the north. Less than half of children from Sabadell which has a hot and dry climate were sensitized to respiratory allergens, in particular house dust mite allergens as compared to Gipuzkoa nearby with a more humid climate. Peanut allergen Ara h 1 was the most frequently recognized class 1 food allergen in Northern/Western Europe, while the fruit allergens Pru p 3, Act d 1 and 2 were prominent in Southern and Western/Central Europe. Ves v 5-sensitization dominated in North and West/Central Europe. CONCLUSION: We show regional, exposome- and climate-dependent differences in molecular IgE-reactivity profiles in Northern, Western/Central and Southern Europe which may form a molecular basis for precision medicine-based approaches for treatment and prevention of allergy.

Costs of Specialist Referrals From Employer-Sponsored Integrated Health Care Clinics Are Lower Than Those From Community Providers.

BACKGROUND: There have been very few published studies of referral management among commercially insured populations and none on referral management from employer-sponsored health centers. OBJECTIVE: Describe the referral management system of an integrated employer-sponsored health care system and compare specialist referral rates and costs of specialist visits between those initiated from employer-sponsored health clinics and those initiated from community providers. DESIGN: Retrospective, comparative cohort study using multivariate analysis of medical claims comparing care initiated in employer-sponsored health clinics with propensity-matched controls having specialist referrals initiated by community providers. PATIENTS: Adult patients (≥ 18 years) eligible for employer-sponsored clinical services incurring medical claims for specialist referrals between 12/1/2018 and 12/31/2020. The study cohort was comprised of 3129 receiving more than 75% of their care in the employer-sponsored clinic matched to a cohort of 3129 patients receiving care in the community. INTERVENTION: Specialist referral management program implemented by Crossover Health employer-sponsored clinics. MAIN MEASURES: Rates and costs of specialist referrals. KEY RESULTS: The relative rate of specialist referrals was 22% lower among patients receiving care in employers-sponsored health clinics (35.1%) than among patients receiving care in the community (45%, p <0.001). The total per-user per-month cost for patients in the study cohort was $372 (SD $894), compared to $401 (SD $947) for the community cohort, a difference of $29 (p<0.001) and a relative reduction of 7.2%. The lower costs can be attributed, in part, to lower specialist care costs ($63 (SD $140) vs $76 (SD $213) (p<0.001). CONCLUSIONS: Employer-sponsored health clinics can provide effective integrated care and may be able to reduce avoidable specialist utilization. Standardized referral management and care navigation may drive lower specialist spend, when referrals are needed.

Prenatal and Postpartum Maternal Iodide Intake from Diet and Supplements, Urinary Iodine and Thyroid Hormone Concentrations in a Region of the United Kingdom with Mild-to-Moderate Iodine Deficiency.

Iodine is essential for normal thyroid function, supporting healthy fetal and child development. Iodine requirements increase in pregnancy, but many women in regions without salt iodization have insufficient intakes. We explored associations between iodide intake and urinary iodine concentration (UIC), urinary iodine/creatinine ratio (I/Cr), thyroid stimulating hormone, thyroglobulin, free triiodothyronine, free thyroxine and palpable goiter in a region of mild-to-moderate iodine insufficiency. A total of 246 pregnant women aged 18-40 in Bradford, UK, joined the Health and Iodine in Babies (Hiba) study. They provided detailed information on diet and supplement use, urine and serum samples and were assessed for goiter at around 12, 26 and 36 weeks' gestation, and 6, 18 and 30 weeks postpartum. Dietary iodide intake from food and drink was estimated using six 24 h recalls. During pregnancy, median (IQR) dietary iodide intake was 101 µg/day (54, 142), with 42% from dairy and 9% from white fish. Including supplements, intake was 143 µg/day (94, 196), with 49% < UK reference nutrient intake (140 µg/day). Women with Pakistani heritage had 129 µg/day (87, 190) median total intake. Total intake during pregnancy was associated with 4% (95% CI: 1%, 7%) higher UIC, 5% (3%, 7%) higher I/Cr, 4% (2%, 6%) lower thyroglobulin and 21% (9%, 32%) lower odds of palpable goiter per 50 µg/day. This cohort consumed less iodide in pregnancy than UK and World Health Organization dietary recommendations. UIC, I/Cr and thyroglobulin were associated with intake. Higher intake was associated with fewer goiters. Because dairy was the dominant source of iodide, women following plant-based or low-dairy diets may be at particular risk of iodine insufficiency.

Do nuclear magnetic resonance (NMR)-based metabolomics improve the prediction of pregnancy-related disorders? Findings from a UK birth cohort with independent validation.

BACKGROUND: Prediction of pregnancy-related disorders is usually done based on established and easily measured risk factors. Recent advances in metabolomics may provide earlier and more accurate prediction of women at risk of pregnancy-related disorders. METHODS: We used data collected from women in the Born in Bradford (BiB; n = 8212) and UK Pregnancies Better Eating and Activity Trial (UPBEAT; n = 859) studies to create and validate prediction models for pregnancy-related disorders. These were gestational diabetes mellitus (GDM), hypertensive disorders of pregnancy (HDP), small for gestational age (SGA), large for gestational age (LGA) and preterm birth (PTB). We used ten-fold cross-validation and penalised regression to create prediction models. We compared the predictive performance of (1) risk factors (maternal age, pregnancy smoking, body mass index (BMI), ethnicity and parity) to (2) nuclear magnetic resonance-derived metabolites (N = 156 quantified metabolites, collected at 24-28 weeks gestation) and (3) combined risk factors and metabolites. The multi-ethnic BiB cohort was used for training and testing the models, with independent validation conducted in UPBEAT, a multi-ethnic study of obese pregnant women. RESULTS: Maternal age, pregnancy smoking, BMI, ethnicity and parity were retained in the combined risk factor and metabolite models for all outcomes apart from PTB, which did not include maternal age. In addition, 147, 33, 96, 51 and 14 of the 156 metabolite traits were retained in the combined risk factor and metabolite model for GDM, HDP, SGA, LGA and PTB, respectively. These include cholesterol and triglycerides in very low-density lipoproteins (VLDL) in the models predicting GDM, HDP, SGA and LGA, and monounsaturated fatty acids (MUFA), ratios of MUFA to omega 3 fatty acids and total fatty acids, and a ratio of apolipoprotein B to apolipoprotein A-1 (APOA:APOB1) were retained predictors for GDM and LGA. In BiB, discrimination for GDM, HDP, LGA and SGA was improved in the combined risk factors and metabolites models. Risk factor area under the curve (AUC 95% confidence interval (CI)): GDM (0.69 (0.64, 0.73)), HDP (0.74 (0.70, 0.78)) and LGA (0.71 (0.66, 0.75)), and SGA (0.59 (0.56, 0.63)). Combined risk factor and metabolite models AUC 95% (CI): GDM (0.78 (0.74, 0.81)), HDP (0.76 (0.73, 0.79)) and LGA (0.75 (0.70, 0.79)), and SGA (0.66 (0.63, 0.70)). For GDM, HDP and LGA, but not SGA, calibration was good for a combined risk factor and metabolite model. Prediction of PTB was poor for all models. Independent validation in UPBEAT at 24-28 weeks and 15-18 weeks gestation confirmed similar patterns of results, but AUCs were attenuated. CONCLUSIONS: Our results suggest a combined risk factor and metabolite model improves prediction of GDM, HDP and LGA, and SGA, when compared to risk factors alone. They also highlight the difficulty of predicting PTB, with all models performing poorly.

Phase II trial of bevacizumab and sorafenib in recurrent ovarian cancer patients with or without prior-bevacizumab treatment.

OBJECTIVE: To examine whether blocking multiple points of the angiogenesis pathway by addition of sorafenib, a multi-kinase inhibitor against VEGFR2/3, Raf, c-Kit, and PDGFR, to bevacizumab would yield clinical activity in ovarian cancer (OvCa). METHODS: This phase II study tested bevacizumab plus sorafenib in two cohorts; bevacizumab-naïve and bevacizumab-exposed patients. Bevacizumab (5 mg/kg IV every 2 weeks) was given with sorafenib 200 mg bid 5 days-on/2 days-off. The primary objective was response rate using a Simon two-stage optimal design. Progression-free survival (PFS) and toxicity were the secondary endpoints. Exploratory correlative studies included plasma cytokine concentrations, tissue proteomics and dynamic contrast-enhanced-magnetic resonance imaging (DCE-MRI). RESULTS: Between March 2007 and August 2012, 54 women were enrolled, 41 bevacizumab-naive and 13 bevacizumab-prior, with median 5 (2-9) and 6 (5-9) prior systemic therapies, respectively. Nine of 35 (26%) evaluable bevacizumab-naive patients attained partial responses (PR), and 18 had stable disease (SD) ≥ 4 months. No responses were seen in the bevacizumab-prior group and 7 (54%) patients had SD ≥ 4 months, including one exceptional responder with SD of 27 months. The overall median PFS was 5.5 months (95%CI: 4.0-6.8 months). Treatment-related grade 3/4 adverse events (≥5%) included hypertension (17/54 [31%]; grade 3 in 16 patients and grade 4 in one patient) and venous thrombosis or pulmonary embolism (5/54 [9%]; grade 3 in 4 patients and grade 4 in one patient). Pretreatment low IL8 concentration was associated with PFS ≥ 4 months (p = .031). CONCLUSIONS: The bevacizumab and sorafenib combination did not meet the pre-specified primary endpoint although some clinical activity was seen in heavily-pretreated bevacizumab-naive OvCa patients with platinum-resistant disease. Anticipated class toxicities required close monitoring and dose modifications.

High rates of treatment failure for Mycoplasma genitalium among men and women attending a sexual health clinic.

BACKGROUND: Mycoplasma genitalium (Mgen) causes non-gonococcal urethritis (NGU) and is believed to cause pelvic inflammatory disease (PID). High rates of macrolide resistance are well documented globally for Mgen. In Brighton, patients with NGU and PID are tested for Mgen and test of cure (TOC) offered post-treatment. METHODS: Demographic, clinical and treatment history data were collected over a 12-month period for all Mgen-positive patients in a Brighton-based genitourinary clinic. RESULTS: There were 114 patients with Mgen. 18% (61/339) of men with NGU and 9% (15/160) of women with PID had Mgen. 62/114 (54%) returned for first test TOC 4 weeks after treatment. 27/62 (44%) had a positive TOC; 25/27 (92.6%) had received azithromycin first line (500 mg stat then 250 mg OD for 4 days), 1/27 (3.7%) had received moxifloxacin first line (400 mg OD for 14 days) and 1/27 (3.7%) had received doxycycline first line (100 mg BD for 7 days). 20/27 (74%) returned for a second TOC 4 weeks later. 5/20 (25%) patients were positive on second TOC; 3/5 (60%) had received azithromycin second line and 2/5 (40%) had received moxifloxacin second line. Patients were more likely to have a positive TOC if they were at risk of reinfection (9/27 positive TOC vs 3/35 negative TOC; p=0.02). Patients given moxifloxacin were more likely to have a negative TOC (1/27 positive TOC vs 9/35 negative TOC; p=0.03) than those who received other antibiotic regimens. CONCLUSIONS: Treatment failure rates for Mgen following azithromycin use are substantial, raising concerns regarding resistance. However, reinfection risk may contribute, suggesting a requirement for improved public awareness and clinician knowledge.

Integrating behavioral health services at employer-sponsored health clinics: A descriptive analysis.

INTRODUCTION: Approximately, 20% of adults in the United States have a behavioral health concern, resulting in $732M in direct medical spending and over 5 million lost workdays annually. Employers bear a substantial share of these costs. The objective of this study was to describe the integration of behavioral health services at employer-sponsored health clinics. METHOD: Retrospective cohort analysis of patients seen for individual behavioral health services from 1/1/2018 to 12/31/2018 in employer-sponsored clinics. RESULTS: Among the 2,954 patients cared for by a behavioral health provider, 49% met criteria for moderate or severe depression and/or anxiety. The median duration between appointment scheduling and a behavioral health triage visit was 2 days (SD = 7.2 days), and median interval to an initial psychotherapy visit was 10 days (SD = 14 days). The mean number of visits with a behavioral health provider within the initial 3 months after presenting for care was 5.3 visits (SD = 2.8 visits). During the course of treatment, anxiety (Generalized Anxiety Disorder-7 [GAD-7] scores) decreased by 31% and depression (Patient Health Questionnaire-9 [PHQ-9] scores) decreased by 24%. Patient satisfaction with their behavioral health care was excellent. DISCUSSION: Integrating behavioral health services into employer-sponsored clinics can result in timely access to psychotherapy, improvements in clinical symptoms, and excellent patient satisfaction. Employers interested in providing greater access to behavioral health care should evaluate integrating such services into onsite or near-site health clinics. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Transient Silencing of Antibiotic Resistance by Mutation Represents a Significant Potential Source of Unanticipated Therapeutic Failure.

Sporadic literature reports describe isolates of pathogenic bacteria that harbor an antibiotic resistance determinant but remain susceptible to the corresponding antibiotic as a consequence of a genetic defect. Such strains represent a source from which antibiotic resistance may reemerge to cause treatment failure in patients. Here, we report a systematic investigation into the prevalence and nature of this phenomenon, which we term silencing of antibiotic resistance by mutation (SARM). Instances of SARM were detected among 1,470 Staphylococcus aureus isolates through side-by-side comparison of antibiotic resistance genotype (as determined by whole-genome sequencing) versus phenotype (as assessed through susceptibility testing). Of the isolates analyzed, 152 (10.3%) harbored a silenced resistance gene, including 46 (3.1%) that exhibited SARM to currently deployed antistaphylococcal drugs. SARM resulted from diverse mutational events but most commonly through frameshift mutation of resistance determinants as a result of point deletion in poly(A) tracts. The majority (∼90%) of SARM strains reverted to antibiotic resistance at frequencies of ≥10-9; thus, while appearing antibiotic sensitive in the clinical microbiology laboratory, most S. aureus isolates exhibiting SARM will revert to antibiotic resistance at frequencies achievable in patients. In view of its prevalence in a major pathogen, SARM represents a significant potential threat to the therapeutic efficacy of antibiotics.IMPORTANCE Antibiotic resistance hinders the treatment of bacterial infection. To guide effective therapy, clinical microbiology laboratories routinely perform susceptibility testing to determine the antibiotic sensitivity of an infecting pathogen. This approach relies on the assumption that it can reliably distinguish bacteria capable of expressing antibiotic resistance in patients, an idea challenged by the present study. We report that the important human pathogen Staphylococcus aureus frequently carries antibiotic resistance genes that have become inactivated ("silenced") by mutation, leading strains to appear antibiotic sensitive. However, resistance can rapidly reemerge in most such cases, at frequencies readily achievable in infected patients. Silent antibiotic resistance is therefore prevalent, transient, and evades routine detection, rendering it a significant potential threat to antibacterial chemotherapy.

Early-Life Environmental Exposures and Blood Pressure in Children.

BACKGROUND: Growing evidence exists about the fetal and environmental origins of hypertension, but mainly limited to single-exposure studies. The exposome has been proposed as a more holistic approach by studying many exposures simultaneously. OBJECTIVES: This study aims to evaluate the association between a wide range of prenatal and postnatal exposures and blood pressure (BP) in children. METHODS: Systolic and diastolic BP were measured among 1,277 children from the European HELIX (Human Early-Life Exposome) cohort aged 6 to 11 years. Prenatal (n = 89) and postnatal (n = 128) exposures include air pollution, built environment, meteorology, natural spaces, traffic, noise, chemicals, and lifestyles. Two methods adjusted for confounders were applied: an exposome-wide association study considering the exposures independently, and the deletion-substitution-addition algorithm considering all the exposures simultaneously. RESULTS: Decreases in systolic BP were observed with facility density (ß change for an interquartile-range increase in exposure: -1.7 mm Hg [95% confidence interval (CI): -2.5 to -0.8 mm Hg]), maternal concentrations of polychlorinated biphenyl 118 (-1.4 mm Hg [95% CI: -2.6 to -0.2 mm Hg]) and child concentrations of dichlorodiphenyldichloroethylene (DDE: -1.6 mm Hg [95% CI: -2.4 to -0.7 mm Hg]), hexachlorobenzene (-1.5 mm Hg [95% CI: -2.4 to -0.6 mm Hg]), and mono-benzyl phthalate (-0.7 mm Hg [95% CI: -1.3 to -0.1 mm Hg]), whereas increases in systolic BP were observed with outdoor temperature during pregnancy (1.6 mm Hg [95% CI: 0.2 to 2.9 mm Hg]), high fish intake during pregnancy (2.0 mm Hg [95% CI: 0.4 to 3.5 mm Hg]), maternal cotinine concentrations (1.2 mm Hg [95% CI: -0.3 to 2.8 mm Hg]), and child perfluorooctanoate concentrations (0.9 mm Hg [95% CI: 0.1 to 1.6 mm Hg]). Decreases in diastolic BP were observed with outdoor temperature at examination (-1.4 mm Hg [95% CI: -2.3 to -0.5 mm Hg]) and child DDE concentrations (-1.1 mm Hg [95% CI: -1.9 to -0.3 mm Hg]), whereas increases in diastolic BP were observed with maternal bisphenol-A concentrations (0.7 mm Hg [95% CI: 0.1 to 1.4 mm Hg]), high fish intake during pregnancy (1.2 mm Hg [95% CI: -0.2 to 2.7 mm Hg]), and child copper concentrations (0.9 mm Hg [95% CI: 0.3 to 1.6 mm Hg]). CONCLUSIONS: This study suggests that early-life exposure to several chemicals, as well as built environment and meteorological factors, may affect BP in children.

Influence of the Urban Exposome on Birth Weight.

BACKGROUND: The exposome is defined as the totality of environmental exposures from conception onwards. It calls for providing a holistic view of environmental exposures and their effects on human health by evaluating multiple environmental exposures simultaneously during critical periods of life. OBJECTIVE: We evaluated the association of the urban exposome with birth weight. METHODS: We estimated exposure to the urban exposome, including the built environment, air pollution, road traffic noise, meteorology, natural space, and road traffic (corresponding to 24 environmental indicators and 60 exposures) for nearly 32,000 pregnant women from six European birth cohorts. To evaluate associations with either continuous birth weight or term low birth weight (TLBW) risk, we primarily relied on the Deletion-Substitution-Addition (DSA) algorithm, which is an extension of the stepwise variable selection method. Second, we used an exposure-by-exposure exposome-wide association studies (ExWAS) method accounting for multiple hypotheses testing to report associations not adjusted for coexposures. RESULTS: The most consistent statistically significant associations were observed between increasing green space exposure estimated as Normalized Difference Vegetation Index (NDVI) and increased birth weight and decreased TLBW risk. Furthermore, we observed statistically significant associations among presence of public bus line, land use Shannon's Evenness Index, and traffic density and birth weight in our DSA analysis. CONCLUSION: This investigation is the first large urban exposome study of birth weight that tests many environmental urban exposures. It confirmed previously reported associations for NDVI and generated new hypotheses for a number of built-environment exposures. https://doi.org/10.1289/EHP3971.

A prospective comparison of wide-awake local anesthesia and general anesthesia for forefoot surgery.

BACKGROUND: A recent case series suggested that surgery with wide-awake local anesthesia is tolerated well by most foot and ankle patients. However, patients were assessed retrospectively and there was no comparison group to show the relative efficacy of this approach. The present study was conducted to address these concerns. METHODS: Perioperative pain and anxiety were assessed in 40 patients receiving forefoot surgery using either wide-awake local anesthesia or general anesthesia. Ratings were collected on the day of surgery using 11-point (0-10) numerical rating scales. RESULTS: Patients in the two anesthesia groups reported no differences in preoperative pain (p=0.500) or anxiety (p=0.820). Patients who received wide-awake local anesthesia reported lower levels of postoperative pain (p<0.001) and anxiety (p<0.001) than patients who received general anesthesia. They also reported little pain (M=0.17, SD=0.32) or anxiety (M=1.33, SD=1.74) during the operation. CONCLUSIONS: Results indicate that surgery with wide-awake local anesthesia is tolerated well by most patients, and that it may have some benefit compared to surgery with general anesthesia.

Sorafenib for Advanced and Refractory Desmoid Tumors.

BACKGROUND: Desmoid tumors (also referred to as aggressive fibromatosis) are connective tissue neoplasms that can arise in any anatomical location and infiltrate the mesentery, neurovascular structures, and visceral organs. There is no standard of care. METHODS: In this double-blind, phase 3 trial, we randomly assigned 87 patients with progressive, symptomatic, or recurrent desmoid tumors to receive either sorafenib (400-mg tablet once daily) or matching placebo. Crossover to the sorafenib group was permitted for patients in the placebo group who had disease progression. The primary end point was investigator-assessed progression-free survival; rates of objective response and adverse events were also evaluated. RESULTS: With a median follow-up of 27.2 months, the 2-year progression-free survival rate was 81% (95% confidence interval [CI], 69 to 96) in the sorafenib group and 36% (95% CI, 22 to 57) in the placebo group (hazard ratio for progression or death, 0.13; 95% CI, 0.05 to 0.31; P<0.001). Before crossover, the objective response rate was 33% (95% CI, 20 to 48) in the sorafenib group and 20% (95% CI, 8 to 38) in the placebo group. The median time to an objective response among patients who had a response was 9.6 months (interquartile range, 6.6 to 16.7) in the sorafenib group and 13.3 months (interquartile range, 11.2 to 31.1) in the placebo group. The objective responses are ongoing. Among patients who received sorafenib, the most frequently reported adverse events were grade 1 or 2 events of rash (73%), fatigue (67%), hypertension (55%), and diarrhea (51%). CONCLUSIONS: Among patients with progressive, refractory, or symptomatic desmoid tumors, sorafenib significantly prolonged progression-free survival and induced durable responses. (Funded by the National Cancer Institute and others; ClinicalTrials.gov number, NCT02066181 .).

A phase I trial of escalating doses of cixutumumab (IMC-A12) and sorafenib in the treatment of advanced hepatocellular carcinoma.

PURPOSE: The insulin-like growth factor (IGF) pathway is activated in hepatocarcinogenesis. Cixutumumab is a monoclonal antibody against human insulin-like growth factor-1 receptor (IGF-1R). Given the cross-talk between the IGF and VEGF pathways, we performed a phase I study of the combination of cixutumumab and sorafenib in hepatocellular cancer (HCC). METHODS: Eligible patients with no prior systemic therapy for advanced HCC and Child-Pugh A to B7 were treated with sorafenib 400 mg BID and escalating doses of cixutumumab (2, 4, or 6 mg/kg IV weekly) in a 3 + 3 design. Dose limiting toxicity (DLT) was defined as treatment-related grade 3 or 4 non-hematologic toxicity (except for a subset of manageable toxicities) or any grade 4 hematologic toxicities. RESULTS: In 21 patients enrolled, there were 3 DLTs; grade 3 hyperglycemia, grade 3 hypophosphatemia, and grade 5 peritonitis. The maximum tolerated dose of cixutumumab was 4 mg/kg IV weekly with standard dose sorafenib. Eighteen of 21 (86%) patients had grade 3 or above toxicities attributed to treatment. One patient also experienced grade 4 colonic perforation and grade 5 peritonitis. The median number of cycles completed was 4 (0-26). Of 16 patients evaluable for response, 81% achieved stable disease. The median progression free survival was 6.0 months (95% CI 3.6-undefined) and the median overall survival was 10.5 months (95% CI 7.1-undefined). CONCLUSIONS: While the combination of cixutumumab and sorafenib had a toxicity profile similar to that of sorafenib monotherapy, it manifested limited clinical efficacy in unselected patients with HCC.

Phase 1/2 trial of temsirolimus and sorafenib in the treatment of patients with recurrent glioblastoma: North Central Cancer Treatment Group Study/Alliance N0572.

BACKGROUND: Mitogen-activated protein kinase (MAPK) activation and mammalian target of rapamycin (mTOR)-dependent signaling are hallmarks of glioblastoma. In the current study, the authors conducted a phase 1/2 study of sorafenib (an inhibitor of Raf kinase and vascular endothelial growth factor receptor 2 [VEGFR-2]) and the mTOR inhibitor temsirolimus in patients with recurrent glioblastoma. METHODS: Patients with recurrent glioblastoma who developed disease progression after surgery or radiotherapy plus temozolomide and with ≤2 prior chemotherapy regimens were eligible. The phase 1 endpoint was the maximum tolerated dose (MTD), using a cohorts-of-3 design. The 2-stage phase 2 study included separate arms for VEGF inhibitor (VEGFi)-naive patients and patients who progressed after prior VEGFi. RESULTS: The MTD was sorafenib at a dose of 200 mg twice daily and temsirolimus at a dose of 20 mg weekly. In the first 41 evaluable patients who were treated at the phase 2 dose, there were 7 who were free of disease progression at 6 months (progression-free survival at 6 months [PFS6]) in the VEGFi-naive group (17.1%); this finding met the prestudy threshold of success. In the prior VEGFi group, only 4 of the first 41 evaluable patients treated at the phase 2 dose achieved PFS6 (9.8%), and this did not meet the prestudy threshold for success. The median PFS for the 2 groups was 2.6 months and 1.9 months, respectively. The median overall survival for the 2 groups was 6.3 months and 3.9 months, respectively. At least 1 adverse event of grade ≥3 was observed in 75.5% of the VEGFi-naive patients and in 73.9% of the prior VEGFi patients. CONCLUSIONS: The limited activity of sorafenib and temsirolimus at the dose and schedule used in the current study was observed with considerable toxicity of grade ≥3. Significant dose reductions that were required in this treatment combination compared with tolerated single-agent doses may have contributed to the lack of efficacy. Cancer 2018;124:1455-63. © 2018 American Cancer Society.

Exploring the implementation of an electronic record into a maternity unit: a qualitative study using Normalisation Process Theory.

BACKGROUND: To explore the benefits, barriers and disadvantages of implementing an electronic record system (ERS). The extent that the system has become 'normalised' into routine practice was also explored. METHODS: Qualitative semi-structured interviews were conducted with 19 members of NHS staff who represented a variety of staff groups (doctors, midwives of different grades, health care assistants) and wards within a maternity unit at a NHS teaching hospital. Interviews were conducted during the first year of the phased implementation of ERS and were analysed thematically. The four mechanisms of Normalisation Process Theory (NPT) (coherence, cognitive participation, collective action and reflexive monitoring) were adapted for use within the study and provided a theoretical framework to interpret the study's findings. RESULTS: Coherence (participants' understanding of why the ERS has been implemented) was mixed - whilst those involved in ERS implementation anticipated advantages such as improved access to information; the majority were unclear why the ERS was introduced. Participants' willingness to engage with and invest time into the ERS (cognitive participation) depended on the amount of training and support they received and their willingness to change from paper to electronic records. Collective action (the extent the ERS was used) may be influenced by whether participants perceived there to be benefits associated with the system. Whilst some individuals reported benefits such as improved legibility of records, others felt benefits were yet to emerge. The parallel use of paper and the lack of integration of electronic systems within and between the trust and other healthcare organisations hindered ERS use. When appraising the ERS (reflexive monitoring) participants perceived the system to negatively impact the patient-clinician relationship, time and patient safety. CONCLUSIONS: Despite expectations that the ERS would have a number of advantages, its implementation was perceived to have a range of disadvantages and only a limited number of 'clinical benefits'. The study highlights the complexity of implementing electronic systems and the associated longevity before they can become 'embedded' into routine practice. Through the identification of barriers to the employment of electronic systems this process could be streamlined with the avoidance of any potential detriment to clinical services.

Host-microbiome interactions in human type 2 diabetes following prebiotic fibre (galacto-oligosaccharide) intake.

Aberrant microbiota composition and function have been linked to several pathologies, including type 2 diabetes. In animal models, prebiotics induce favourable changes in the intestinal microbiota, intestinal permeability (IP) and endotoxaemia, which are linked to concurrent improvement in glucose tolerance. This is the first study to investigate the link between IP, glucose tolerance and intestinal bacteria in human type 2 diabetes. In all, twenty-nine men with well-controlled type 2 diabetes were randomised to a prebiotic (galacto-oligosaccharide mixture) or placebo (maltodextrin) supplement (5·5 g/d for 12 weeks). Intestinal microbial community structure, IP, endotoxaemia, inflammatory markers and glucose tolerance were assessed at baseline and post intervention. IP was estimated by the urinary recovery of oral 51Cr-EDTA and glucose tolerance by insulin-modified intravenous glucose tolerance test. Intestinal microbial community analysis was performed by high-throughput next-generation sequencing of 16S rRNA amplicons and quantitative PCR. Prebiotic fibre supplementation had no significant effects on clinical outcomes or bacterial abundances compared with placebo; however, changes in the bacterial family Veillonellaceae correlated inversely with changes in glucose response and IL-6 levels (r -0·90, P=0·042 for both) following prebiotic intake. The absence of significant changes to the microbial community structure at a prebiotic dosage/length of supplementation shown to be effective in healthy individuals is an important finding. We propose that concurrent metformin treatment and the high heterogeneity of human type 2 diabetes may have played a significant role. The current study does not provide evidence for the role of prebiotics in the treatment of type 2 diabetes.

The impact of electronic records on patient safety: a qualitative study.

BACKGROUND: Our aim was to explore NHS staff perceptions and experiences of the impact on patient safety of introducing a maternity system. METHODS: Qualitative semi-structured interviews were conducted with 19 members of NHS staff who represented a variety of staff groups (doctors, midwives, health care assistants), staff grades (consultant and midwife grades) and wards within a maternity unit. Participants represented a single maternity unit at a NHS teaching hospital in the North of England. Interviews were conducted during the first 12 months of the system being implemented and were analysed thematically. RESULTS: Participants perceived there to be an elevated risk to patient safety during the system's implementation. The perceived risks were attributed to a range of social and technical factors. For example, poor system design and human error which resulted in an increased potential for missing information and inputting error. CONCLUSIONS: The first 12 months of introducing the maternity system was perceived to and in some cases had already caused actual risk to patient safety. Trusts throughout the NHS are facing increasing pressure to become paperless and should be aware of the  potential adverse impacts on patient safety that can occur when introducing electronic systems. Given the potential for increased risk identified, recommendations for further research and for NHS trusts introducing electronic systems are proposed.

A Phase II Study of Sorafenib Combined With Cetuximab in EGFR-Expressing, KRAS-Mutated Metastatic Colorectal Cancer.

BACKGROUND: Mutations in the KRAS gene predict for resistance to anti-epidermal growth factor receptor (EGFR) therapies, including cetuximab. Upregulation of vascular endothelial growth factor (VEGF)-A has been implicated in resistance to anti-EGFR treatment. Abrogation of the VEGF and RAS/RAF/MEK/ERK pathways has the potential to restore cetuximab sensitivity. PATIENTS AND METHODS: Adult patients with histologically documented, measurable, EGFR-expressing, KRAS-mutated metastatic colorectal cancer (mCRC) that had progressed after 5-fluorouracil-based regimens were treated with sorafenib 400 mg orally twice daily and intravenous cetuximab weekly in 28-day cycles. The primary endpoint was the response rate (complete response, partial response, and stable disease at 4 cycles). The secondary endpoints included plasma biomarker analysis of angiogenic cytokines and correlative imaging studies with dynamic contrast-enhanced magnetic resonance imaging and zirconium 89-panitumumab. RESULTS: Of the 30 patients enrolled, 26 were evaluable for response. Of the 26 patients evaluated, 4 had stable disease at 4 cycles and 1 had stable disease at 8 cycles. The median progression-free survival was 1.84 months. The common toxicities were rash, diarrhea, and liver enzyme elevations. Of the angiogenic cytokines evaluated, only the placental growth factor increased significantly with treatment (P < .0001). No pharmacodynamic parameters were associated with the treatment response. CONCLUSION: We report the results of a trial that combined cetuximab and sorafenib for the treatment of KRAS-mutated mCRC, with correlative imaging studies and pharmacodynamic angiogenic cytokine profiling as downstream markers of EGFR and VEGF receptor (VEGFR) signaling. No objective responses were observed. Additional development of biomarkers for patient selection is needed to evaluate combined EGFR and VEGFR blockade as a therapeutic option in KRAS-mutated CRC.