Plus Sutures for preventing surgical site infection: a systematic review of clinical outcomes with economic and environmental models.

BACKGROUND: Surgical site infections (SSIs) represent ~ 20% of all hospital-acquired infections in surgical patients and are associated with prolonged hospital stay, admission to intensive care, and mortality. We conducted a systematic review with economic and environmental models to assess whether triclosan-coated sutures (Plus Sutures) provide benefits over non-coated sutures in the reduction of SSI risk. METHODS: Searches were conducted in fifteen databases. A total of 1,991 records were retrieved. Following deduplication and screening by two independent reviewers, 31 randomized controlled trials in adults and children were included in the review. Similarity of the studies was assessed by narrative review and confirmed by quantitative assessment. A fixed effects meta-analysis of SSI incidence model including all groups of patients estimated a risk ratio of 0.71 (95% confidence interval: 0.64 to 0.79) indicating those in the Plus Sutures group had a 29% reduction in the risk of developing an SSI compared with those in the control group (p < 0.001). Safety outcomes were analysed qualitatively. RESULTS: The economic model estimated the use of Plus Sutures to result in average cost savings of £13.63 per patient. Plus Sutures remained cost-saving in all subgroup analyses with cost-savings ranging between £11 (clean wounds) and £140 (non-clean wounds). The environmental impact of SSI is substantial, and the model suggests that the introduction of Plus Sutures could result in potential environmental benefits. CONCLUSIONS: The evidence suggests that Plus Sutures are associated with a reduced incidence of SSI across all surgery types alongside cost savings when compared with standard sutures.

Latency of late preterm steroid administration to delivery and risk of neonatal hypoglycemia.

BACKGROUND: Late preterm antenatal corticosteroid administration has been associated with an increased risk of neonatal hypoglycemia. The mechanism is thought to be secondary to transient fetal hyperinsulinemia, which may be more likely if delivery occurs during peak antenatal corticosteroid levels. OBJECTIVE: This study aimed to investigate whether there is a latency interval between antenatal corticosteroid administration and delivery that places neonates at the greatest risk of hypoglycemia. STUDY DESIGN: This was a retrospective matched cohort study of pregnant women who received antenatal corticosteroid vs unexposed women between 34 0/7 and 36 6/7 weeks of gestation from 2016 to 2019. Unexposed women were those who did not receive antenatal corticosteroid matched according to gestational age at delivery, diabetes mellitus status, and maternal body mass index from 2010 to 2015. Latency periods from initial steroid administration to delivery were defined in grouped intervals until ≥72 hours. The primary outcome was neonatal hypoglycemia, defined as a neonatal glucose level of <40 mg/dL within 24 hours of life. Poisson regression was used to generate an adjusted relative risk of hypoglycemia for each latency period adjusting for confounders. RESULTS: A total of 812 women were included in the analysis (406 exposed and 406 unexposed). Women who received antenatal corticosteroids were more likely to be nulliparous (P=.009); moreover, the women were well matched on pregnancy complications and baseline demographics. Neonatal hypoglycemia was more frequently identified in women receiving antenatal corticosteroids than in women not receiving antenatal corticosteroids (42% vs 26%; P<.001). Severe hypoglycemia, defined as a glucose level of <20 mg/dL, was significantly more common in patients receiving antenatal corticosteroids than in patients not receiving antenatal corticosteroids (8.4% vs 2.7%; P<.001). Latency time intervals of 12 to 71 hours from antenatal corticosteroid administration were significantly associated with neonatal hypoglycemia in exposed women compared with unexposed women after adjustment; within this time frame, the highest risk was 24 to 47 hours after antenatal corticosteroid administration (adjusted relative risk, 2.09; 95% confidence interval, 1.29-3.38). CONCLUSION: In the late preterm period, the risk of neonatal hypoglycemia is the greatest in the latency period of 12 to 71 hours between steroid administration and delivery. Neonates exposed to antenatal corticosteroids were more likely to experience severe hypoglycemia within 24 hours of life than unexposed neonates.

Dexamethasone Alters Tracheal Aspirate T-Cell Cytokine Production in Ventilated Preterm Infants.

Postnatal corticosteroids improve respiratory status and facilitate respiratory support weaning in preterm infants with bronchopulmonary dysplasia (BPD). Older literature describes characteristic cytokine profiles in tracheal aspirates (TA) of BPD patients which are altered with corticosteroids. Corticosteroids also influence peripheral blood T-cell presence. However, little is known regarding TA T-cell phenotype and cytokine production before or after exogenous corticosteroids. We hypothesized that postnatal dexamethasone alters the TA T-cell cytokine profiles of preterm infants. TA samples were collected from 14 infants born from 23 0/7 to 28 6/7 weeks who were mechanically ventilated for at least 14 days. Samples were collected up to 72 h before a ten-day dexamethasone course and again 1 to 3 calendar days after dexamethasone initiation. The primary outcome was change in T cell populations present in TA and their intracellular cytokine profile after dexamethasone treatment, ascertained via flow cytometry. Following dexamethasone treatment, there were significant decreases in respiratory severity score (RSS), percent CD4+IL-6+ cells, CD8+IL-6+ cells, CXCR3+IL-6+ cells, and CXCR3+IL-2+ cells and total intracellular IFN-γ in TA. RSS significantly correlated with TA percent CD4+IL-6+ cells. To our knowledge, this is the first study demonstrating that dexamethasone reduced T-cell IL-6 and this reduction was associated with improved RSS in pre-term infants with evolving BPD.

Faecal immunochemical testing and blood tests for prioritization of urgent colorectal cancer referrals in symptomatic patients: a 2-year evaluation.

BACKGROUND: A novel pathway incorporating faecal immunochemical testing (FIT) for rapid colorectal cancer diagnosis (RCCD) was introduced in 2017. This paper reports on the service evaluation after 2 years of pathway implementation. METHODS: The RCCD protocol was based on FIT, blood results and symptoms to stratify adult patients in primary care. Two-week-wait (2WW) investigation was indicated for patients with rectal bleeding, rectal mass and faecal haemoglobin (fHb) level of 10 µg Hb/g faeces or above or 4 µg Hb/g faeces or more in the presence of anaemia, low ferritin or thrombocytosis, in all other symptom groups. Patients with 100 µg Hb/g faeces or above had expedited investigation . A retrospective audit of colorectal cancer detected between 2017 and 2019 was conducted, fHb thresholds were reviewed and critically assessed for cancer diagnoses. RESULTS: In 2 years, 14788 FIT tests were dispatched with 13361 (90.4 per cent) completed returns. Overall, fHb was less than 4 µg Hb/g faeces in 9208 results (68.9 per cent), 4-9.9 µg Hb/g in 1583 (11.8 per cent), 10-99.9 µg Hb/g in 1850 (13.8 per cent) and 100 µg Hb/g faeces or above in 720 (5.4 per cent). During follow-up (median 10.4 months), 227 colorectal cancers were diagnosed. The cancer detection rate was 0.1 per cent in patients with fHb below 4 µg Hb/g faeces, 0.6 per cent in those with fHb 4-9.9 µg Hb/g faeces, 3.3 per cent for fHb 10-99.9 µg Hb/g faeces and 20.7 per cent for fHb 100 µg Hb/g faeces or above. The detection rate in the cohort with 10-19.9 µg Hb/g faeces was 1.4 per cent, below the National Institute for Health and Care Excellence threshold for urgent referral. The colorectal cancer rate in patients with fHb below 20 µg Hb/g faeces was less than 0.3 per cent. CONCLUSION: Use of FIT to "rule out" urgent referral from primary care misses a small number of cases. The threshold for referral may be adjusted with blood results to improve stratification .

Pseudomonas aeruginosa infection in augmented care: the molecular ecology and transmission dynamics in four large UK hospitals.

BACKGROUND: Pseudomonas aeruginosa is a common opportunistic pathogen and molecular typing in outbreaks has linked patient acquisition to contaminated hospital water systems. AIM: To elucidate the role of P. aeruginosa transmission rates in non-outbreak augmented care settings in the UK. METHODS: Over a 16-week period, all water outlets in augmented care units of four hospitals were sampled for P. aeruginosa and clinical isolates were collected. Outlet and clinical P. aeruginosa isolates underwent whole-genome sequencing (WGS), which with epidemiological data identified acquisition from water as definite (level 1), probable (level 2), possible (level 3), and no evidence (level 4). FINDINGS: Outlets were positive in each hospital on all three occasions: W (16%), X (2.5%), Y (0.9%) and Z (2%); and there were 51 persistently positive outlets in total. WGS identified likely transmission (at levels 1, 2 and 3) from outlets to patients in three hospitals for P. aeruginosa positive patients: W (63%), X (54.5%) and Z (26%). According to the criteria (intimate epidemiological link and no phylogenetic distance), approximately 5% of patients in the study 'definitely' acquired their P. aeruginosa from their water outlets in the intensive care unit. This study found extensive evidence of transmission from the outlet to the patients particularly in the newest hospital (W), which had the highest rate of positive outlets. CONCLUSIONS: The overall findings suggest that water outlets are the most likely source of P. aeruginosa nosocomial infections in some settings, and that widespread introduction of control measures would have a substantial impact on infections.

Evaluating the impact of a pharmacist-led prescribing feedback intervention on prescribing errors in a hospital setting.

BACKGROUND: Prescribing errors are prevalent in hospital settings with provision of feedback recommended to support prescribing of doctors. Feedback on prescribing has been described as feasible and valued but limited by doctors, with pharmacists described as credible facilitators of prescribing feedback. Evidence supporting prescribing feedback has been limited to date. A formalised programme of pharmacist-led prescribing error feedback was designed and implemented to support prescribers. OBJECTIVE: To evaluate the impact of a prescribing feedback intervention on prescribing error rates and frequency of prescribing error severity and type. METHOD: Prospective prescribing audits were undertaken across sixteen hospital wards in a UK teaching hospital over a five day period with 36 prescribers in the intervention group and 41 in the control group. The intervention group received pharmacist-led, individualised constructive feedback on their prescribing, whilst the control group continued with existing practice. Prescribing was re-audited after three months. Prescribing errors were classified by type and severity and data were analysed using relevant statistical tests. RESULTS: A total of 5191 prescribed medications were audited at baseline and 5122 post-intervention. There was a mean prescribing error rate of 25.0% (SD 16.8, 95% CI 19.3 to 30.7) at baseline and 6.7% (SD 9.0, 95% CI 3.7 to 9.8) post-intervention for the intervention group, and 19.7% (SD 14.5, 95% CI 15.2 to 24.3) at baseline and 25.1% (SD 17.0, 95% CI 19.8 to 30.6) post-intervention for the control group with a significant overall change in prescribing error rates between groups of 23.7% (SD 3.5, 95% CI, -30.6 to -16.8), t(75) = -6.9, p < 0.05. The frequency of each error type and severity rating was reduced in the intervention group, whilst the error frequency of some error types and severity increased in the control group. CONCLUSION: Pharmacist-led prescribing feedback has the potential to reduce prescribing errors and improve prescribing outcomes and patient safety.

Containing a measles outbreak in Minnesota, 2017: methods and challenges.

AIMS: We report on a measles outbreak largely occurring in Minnesota's under-vaccinated Somali community in the spring of 2017. The outbreak was already into its third generation when the first two cases were confirmed, and rapid public health actions were needed. The aim of our response was to quickly end transmission and contain the outbreak. METHODS: The state public health department performed laboratory testing on suspect cases and activated an Incident Command staffed by subject matter experts that was operational within 2 h of case confirmation. Epidemiologic interviews identified exposures in settings where risk of transmission was high, that is, healthcare, childcare, and school settings. Vaccination status of exposed persons was assessed, and postexposure prophylaxis (PEP) was offered, if applicable. Exposed persons who did not receive PEP were excluded from childcare centers or schools for 21 days. An accelerated statewide measles, mumps, and rubella (MMR) recommendation was made for Somali Minnesota children and children in affected outbreak counties. Partnerships with the Somali Minnesota community were deepened, building off outreach work done with the community since 2008. RESULTS: Public health identified 75 measles cases from 30 March to 25 August 2017: 43% were female, 81% Somali Minnesotan, 91% unvaccinated, and 28% hospitalized. The median age of cases was 2 years (range: 3 months-57 years). Most transmission (78%) occurred in childcare centers and households. A secondary attack rate of 91% was calculated for unvaccinated household contacts. Over 51,000 doses of MMR were administered during the outbreak above expected baseline. At least 8490 individuals were exposed to measles; 155 individuals received PEP; and over 500 persons were excluded from childcare and school. State and key public health partners spent an estimated $2.3 million on response. CONCLUSION: This outbreak demonstrates the necessity of immediate, targeted disease control actions and strong public health, healthcare, and community partnerships to end a measles outbreak.

Impact of Lymphadenectomy on Survival After Unimodality Transthoracic Esophagectomy for Adenocarcinoma of Esophagus.

BACKGROUND: Debate remains regarding the extent of lymphadenectomy required with esophagectomy. In patients who receive neoadjuvant treatment, this may address lymph node metastases. However, patients with early disease and those with comorbidities may not receive neoadjuvant treatment. The aim of this study is to determine the impact of lymph node yield and location on prognosis in patients undergoing esophagectomy without neoadjuvant treatment. PATIENTS AND METHODS: Data from consecutive patients with potentially curable adenocarcinoma of the esophagus or gastroesophageal junction were reviewed. Patients were treated with transthoracic esophagectomy and two-field lymphadenectomy. Outcomes according to lymph node yield were determined. The prognosis of carrying out less radical lymphadenectomy was calculated according to three groups: exclusion of proximal thoracic nodes (group 1), minimal abdominal lymphadenectomy (group 2), and minimal abdominal and thoracic lymphadenectomy (group 3). RESULTS: 357 patients were included. Median survival was 78 months [confidence interval (CI) 53-103 months]. Absolute lymph node retrieval was not related to survival (p = 0.920). An estimated additional 4 (2-6) cancer-related deaths was projected if group 1 nodes were omitted, 15 (11-19) additional deaths if group 2 nodes were omitted, and 4 (2-6) deaths if group 3 nodes were omitted. Minimal lymphadenectomy (groups 1, 2, and 3) was projected to lead to 19 (15-23) additional cancer-related deaths. CONCLUSIONS: Extensive lymphadenectomy allows accurate staging. In patients who do not receive neoadjuvant treatment, it may confer a survival benefit. The number of lymph nodes retrieved may not be a good surrogate for extent of lymphadenectomy, and correlation with location is required.

Genome-wide methylation profiling in granulosa lutein cells of women with polycystic ovary syndrome (PCOS).

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder amongst women of reproductive age, whose aetiology remains unclear. To improve our understanding of the molecular mechanisms underlying the disease, we conducted a genome-wide DNA methylation profiling in granulosa lutein cells collected from 16 women suffering from PCOS, in comparison to 16 healthy controls. Samples were collected by follicular aspiration during routine egg collection for IVF treatment. Study groups were matched for age and BMI, did not suffer from other disease and were not taking confounding medication. Comparing women with polycystic versus normal ovarian morphology, after correcting for multiple comparisons, we identified 106 differentially methylated CpG sites with p-values <5.8 × 10-8 that were associated with 88 genes, several of which are known to relate either to PCOS or to ovarian function. Replication and validation of the experiment was done using pyrosequencing to analyse six of the identified differentially methylated sites. Pathway analysis indicated potential disruption in canonical pathways and gene networks that are, amongst other, associated with cancer, cardiogenesis, Hedgehog signalling and immune response. In conclusion, these novel findings indicate that women with PCOS display epigenetic changes in ovarian granulosa cells that may be associated with the heterogeneity of the disorder.

Author Correction: LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Expression of genes controlling steroid metabolism and action in granulosa-lutein cells of women with polycystic ovaries.

INTRODUCTION: Aberrant function of granulosa cells has been implicated in the pathophysiology of PCOS. MATERIALS & METHODS: Granulosa lutein (GL) cells were collected during oocyte retrieval for IVF/ICSI. RT-qPCR was used to compare gene expression between 12 control women, 12 with ovulatory PCO and 12 with anovulatory PCOS. To examine which genes are directly regulated by androgens, GL cells from an additional 12 control women were treated in-vitro with 10 nM dihydrotestosterone (DHT). RESULTS: GL cells from women with PCOS showed reduced expression of CYP11A1 3-fold (p = 0.005), HSD17B1 1.8-fold (p = 0.02) and increased expression of SULT1E1 7-fold (p = 0.0003). Similar results were seen in ovulatory women with PCO. GL cells treated with 10 nM DHT showed a 4-fold (p = 0.03) increase in expression of SULT1E1 and a 5-fold reduction in SRD5A1 (p = 0.03). CONCLUSIONS: These findings support the notion that aberrant regulation of steroid metabolism or action play a part in ovarian dysfunction in PCOS.

Neural processing of food cues in pre-pubertal children.

BACKGROUND/OBJECTIVES: Neuroimaging investigations of brain pathways involved in reward and motivation have primarily focused on adults. This study sought to identify brain responses to visual food cues and explore its relationships with adiposity and sex in pre-pubertal children. METHODS: Brain responses to palatable food vs. non-food cues were measured in 53 children (age: 8.18 ± .66 years; sex: 22 boys, 31 girls) after an overnight fast. Whole-brain analysis (cluster-correction Z > 2.3, P < .05) was performed to examine brain food cue reactivity and its relationships with adiposity and sex. RESULTS: Greater brain activity in response to food vs. non-food cues was observed in regions implicated in reward (orbital frontal cortex, striatum), taste (insula, postcentral gyrus), appetite (hypothalamus), emotion (amygdala), memory (hippocampus), visual processing (occipital cortex) and attention (parietal cortex). A negative association was found between percent body fat and food cue reactivity in the medial prefrontal cortex and lateral orbital frontal cortex adjusting for age and sex. Boys compared with girls had increased food cue reactivity in right hippocampus and visual cortex. CONCLUSIONS: These data suggest that body fat and sex are important moderators of brain food cue reactivity in children.

Granulosa cells from human primordial and primary follicles show differential global gene expression profiles.

STUDY QUESTION: Can novel genetic candidates involved in follicle dormancy, activation and integrity be identified from transcriptomic profiles of isolated granulosa cells from human primordial and primary follicles? SUMMARY ANSWER: The granulosa cell compartment of the human primordial and primary follicle was extensively enriched in signal transducer and activator of transcription 3 (STAT3) and cAMP-response element binding protein (CREB) signalling, and several other putative signalling pathways that may also be mediators of follicle growth and development were identified. WHAT IS KNOWN ALREADY: Mechanistic target of rapamycin kinase (mTOR) signalling and the factors Forkhead Box L2 (FOXL2) and KIT proto-oncogene receptor tyrosine kinase (KITL) may be involved in defining the early steps of mammalian follicular recruitment through complex bidirectional signalling between the oocyte and granulosa cells. cAMP/protein kinase K (PKA)/CREB signalling is a feature of FSH-induced regulation of granulosa cell steroidogenesis that is essential to normal human fertility. STUDY DESIGN, SIZE, DURATION: A class comparison study was carried out on primordial follicles (n = 539 follicles) and primary follicles (n = 261) follicles) donated by three women having ovarian tissue cryopreserved before chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: RNA samples from isolates of laser capture micro-dissected oocytes and follicles from the primordial and primary stage, respectively, were sequenced on the HiSeq Illumina platform. Data mapping, quality control, filtering, FPKM (fragments per kilobase of exon per million) normalization and comparisons were performed. The granulosa cell contribution in whole follicle isolates was extracted in silico. Modelling of complex biological systems was performed using Ingenuity Pathway Analysis (IPA). For validation of transcriptomic findings, we performed quantitative RT-PCR of selected candidate genes. Furthermore, we interrogated the in situ localization of selected corresponding proteins using immunofluorescence. MAIN RESULTS AND THE ROLE OF CHANCE: Our differentially expressed gene analysis revealed a number of transcripts in the granulosa cells to be significantly down- (736 genes) or up- (294 genes) regulated during the human primordial-to-primary follicle transition. The IPA analysis revealed enriched canonical signalling pathways not previously associated with granulosa cells from human primordial and primary follicles. Immunofluorescent staining of human ovarian tissue explored the intra-ovarian localization of FOG2, and FOXL2, which revealed the presence of forkhead box L2 (FOXL2) in both oocytes and granulosa cells in primary follicles, with a more enriched staining in the granulosa cells in primary follicles. Friend of GATA 2 (FOG2) stained strongly in oocytes in primordial follicles, with a shift towards granulosa cell as follicle stage advanced. LARGE SCALE DATA: http://users-birc.au.dk/biopv/published_data/ernst_et_al_GC_2017/. LIMITATIONS REASONS FOR CAUTION: This is a descriptive study, and no functional assays were employed. The study was based on a limited number of patients, and it is acknowledged that natural biological variance exists in human samples. Strict filters were applied to accommodate the in silico extraction of the granulosa cell contribution. In support of this, quantitative RT-PCR was used to confirm selected candidate genes, and immunofluorescent staining was employed to interrogate the intra-ovarian distribution of selected corresponding proteins. Moreover, it is unknown whether the primordial follicles analysed represent those still in the resting pool, or those from the cohort that have entered the growing pool. WIDER IMPLICATIONS OF THE FINDINGS: We present, for the first time, a detailed description of global gene activity in the human granulosa cell compartment of primordial and primary follicles. These results may be utilized in the development of novel clinical treatment strategies aimed at improving granulosa cell function. STUDY FUNDING/COMPETING INTEREST(S): E.H.E. was supported by the Health Faculty, Aarhus University and Kong Christian Den Tiendes Fond. K.L.H. was supported by a grant from Fondens til Lægevidenskabens Fremme and Kong Christian Den Tiendes Fond. No authors have competing interests to declare.

LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer.

Complex regulatory networks control epithelial-to-mesenchymal transition (EMT) but the underlying epigenetic control is poorly understood. Lysine-specific demethylase 1 (LSD1) is a key histone demethylase that alters the epigenetic landscape. Here we explored the role of LSD1 in global epigenetic regulation of EMT, cancer stem cells (CSCs), the tumour microenvironment, and therapeutic resistance in breast cancer. LSD1 induced pan-genomic gene expression in networks implicated in EMT and selectively elicits gene expression programs in CSCs whilst repressing non-CSC programs. LSD1 phosphorylation at serine-111 (LSD1-s111p) by chromatin anchored protein kinase C-theta (PKC-θ), is critical for its demethylase and EMT promoting activity and LSD1-s111p is enriched in chemoresistant cells in vivo. LSD1 couples to PKC-θ on the mesenchymal gene epigenetic template promotes LSD1-mediated gene induction. In vivo, chemotherapy reduced tumour volume, and when combined with an LSD1 inhibitor, abrogated the mesenchymal signature and promoted an innate, M1 macrophage-like tumouricidal immune response. Circulating tumour cells (CTCs) from metastatic breast cancer (MBC) patients were enriched with LSD1 and pharmacological blockade of LSD1 suppressed the mesenchymal and stem-like signature in these patient-derived CTCs. Overall, LSD1 inhibition may serve as a promising epigenetic adjuvant therapy to subvert its pleiotropic roles in breast cancer progression and treatment resistance.

The direct and indirect effects of kisspeptin-54 on granulosa lutein cell function.

STUDY QUESTION: What are the in vivo and in vitro actions of kisspeptin-54 on the expression of genes involved in ovarian reproductive function, steroidogenesis and ovarian hyperstimulation syndrome (OHSS) in granulosa lutein (GL) cells when compared with traditional triggers of oocyte maturation? SUMMARY ANSWER: The use of kisspeptin-54 as an oocyte maturation trigger augmented expression of genes involved in ovarian steroidogenesis in human GL cells including, FSH receptor (FSHR), LH/hCG receptor (LHCGR), steroid acute regulatory protein (STAR), aromatase, estrogen receptors alpha and beta (ESR1, ESR2), 3-beta-hydroxysteroid dehydrogenase type 2 (3BHSD2) and inhibin A (INHBA), when compared to traditional maturation triggers, but did not alter markers of OHSS. WHAT IS KNOWN ALREADY: hCG is the most widely used trigger of oocyte maturation, but is associated with an increased risk of OHSS. The use of GnRH agonists to trigger oocyte maturation is a safer alternative to hCG. More recently, kisspeptin-54 has emerged as a novel therapeutic option that safely triggers oocyte maturation even in women at high risk of OHSS. Kisspeptin indirectly stimulates gonadotropin secretion by acting on hypothalamic GnRH neurons. Kisspeptin and its receptor are also expressed in the human ovary, but there is limited data on the direct action of kisspeptin on the ovary. STUDY DESIGN SIZE, DURATION: Forty-eight women undergoing IVF treatment for infertility consented to kisspeptin-54 triggering and/or granulosa cell collection and were included in the study. Twelve women received hCG, 12 received GnRH agonist and 24 received kisspeptin-54 to trigger oocyte maturation. In the kisspeptin-54 group, 12 received one injection of kisseptin-54 (9.6 nmol/kg) and 12 received two injections of kisspeptin-54 at a 10 h interval (9.6 nmol/kg × 2). PARTICIPANTS/MATERIALS, SETTING, METHODS: Follicular fluid was aspirated and pooled from follicles during the retrieval of oocytes for IVF/ICSI. GL cells were isolated and either RNA extracted immediately or cultured in vitro ± kisspeptin or hCG. MAIN RESULTS AND THE ROLE OF CHANCE: GL cells from women who had received kisspeptin-54 had a 14-fold and 8-fold higher gene expression of FSHR and a 2-fold (ns) and 2.5-fold (P < 0.05) higher expression of LHCGR than GL cells from women who had received hCG or GnRH agonist, respectively. CYP19A1 expression was 3.6-fold (P < 0.05) and 4.5-fold (P < 0.05) higher, STAR expression was 3.4-fold (P < 0.01) and 1.8-fold (P < 0.05) higher, HSD3B2 expression was 7.5- (P < 0.01) and 2.5-fold higher (P < 0.05), INHBA was 2.5-fold (P < 0.01) and 2.5-fold (P < 0.01) higher in GL cells from women who had received kisspeptin-54 than hCG or GnRHa, respectively. ESR1 (P < 0.05) and ESR2 (P < 0.05) both showed 3-fold higher expression in cells from kisspeptin treated than GnRHa treated women. Markers of vascular permeability and oocyte growth factors were unchanged (VEGFA, SERPINF1, CDH5, amphiregulin, epiregulin). Gene expression of kisspeptin receptor was unchanged. Whereas treating GL cells in vitro with hCG induced steroidogenic gene expression, kisspeptin-54 had no significant direct effects on either OHSS genes or steroidogenic genes. LIMITATIONS REASONS FOR CAUTION: Most women in the study had PCOS, which may limit applicability to other patient groups. For the analysis of the in vitro effects of kisspeptin-54, it is important to note that GL cells had already been exposed in vivo to an alternate maturation trigger. WIDER IMPLICATIONS OF THE FINDINGS: The profile of serum gonadotropins seen with kisspeptin administration compared to other triggers more closely resemble that of the natural cycle as compared with hCG. Thus, kisspeptin could potentially permit an ovarian environment augmented for steroidogenesis, in particular progesterone synthesis, which is required for embryo implantation. STUDY FUNDING/COMPETING INTEREST(S): Dr Owens is supported by an Imperial College London PhD Scholarship. Dr Abbara is supported by an National Institute of Health Research Academic Clinical Lectureship. The authors do not have any conflict of interest to declare. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT01667406.

Exploring the impact of pharmacist-led feedback on prescribing behaviour: A qualitative study.

BACKGROUND: Prescribing errors occur frequently in hospital settings. Interventions to influence prescribing behaviour are needed with feedback one potential intervention to improve prescribing practice. Doctors have reported a lack of feedback on their prescribing previously whilst the literature exploring the impact of feedback on prescribing behaviour is limited. OBJECTIVES: To explore the impact of pharmacist-led feedback on prescribing behaviour. METHODS: Semi-structured interviews were conducted with doctors who had received prescribing error feedback. A topic guide was used to explore the type of error and what impact feedback was having on prescribing behaviour. All interviews were transcribed verbatim and analysed thematically using a framework approach. RESULTS: Twenty-three prescribers were interviewed and 65 errors discussed over 38 interviews. Key themes included; affective behaviour, learning outcome, prescribing behaviour and likelihood of error recurrence. Feedback was educational whilst a range of adaptive prescribing behaviours were also reported. Prescribers were more mindful and engaged with the prescribing process whilst feedback facilitated reflection, increased self-awareness and informed self-regulation. Greater information and feedback-seeking behaviours were reported whilst prescribers also reported greater situational awareness, and that they were making fewer prescribing errors following feedback. CONCLUSIONS: Pharmacist-led feedback was perceived to positively influence prescribing behaviour. Reported changes in prescriber behaviour resonate with the non-technical skills (NTS) of prescribing with prescribers adapting their prescribing behaviour depending on the environment and prescribing conditions. A model of prescribing is proposed with NTS activated in response to error provoking conditions. These findings have implications for prescribing education to make it a more contextualised educational process.

Dormancy and activation of human oocytes from primordial and primary follicles: molecular clues to oocyte regulation.

STUDY QUESTION: Do specific transcriptome dynamics in human oocytes from primordial and primary follicles identify novel pathways in oocyte activation? SUMMARY ANSWER: The transcriptomic profiles in oocytes from primordial and primary follicles, respectively, revealed several new canonical pathways as putative mediators of oocyte dormancy and activation. WHAT IS KNOWN ALREADY: Cellular signaling pathways including PI3K/AKT and AKT/mTOR as well as TGF-ß and IGF signaling are known to regulate the primordial-to-primary transition in mammalian follicle development. STUDY DESIGN, SIZE, DURATION: We performed a class comparison study on human oocytes from primordial (n = 436) and primary (n = 182) follicles donated by three women having ovarian tissue cryopreserved before chemotherapy. PARTICIPANTS/MATERIALS, SETTING, METHODS: RNA was extracted from oocytes from primordial and primary follicles isolated by Laser Capture Microdissection, and submitted to the HiSeq Illumina platform. Data mapping, quality control, filtering and expression analysis were performed using Tophat (2.0.4), Cufflinks (2.0.2), BWA (0.6.2) and software R. Modeling of complex biological systems was performed using the IPA® software. Finally, qPCR and immunohistochemistry were employed to explore expression and localization of selected genes and products in human ovarian tissue. MAIN RESULTS AND THE ROLE OF CHANCE: We found 223 and 268 genes down-regulated and up-regulated, respectively, in the oocytes during the human primordial-to-primary follicle transition (P < 0.05 and/or FPKM fold-change >2). IPA® enrichment analysis revealed known pathways ('mTOR Signaling', 'PI3K/AKT Signaling' and 'PTEN Signaling') as well as enriched canonical pathways not previously associated with human ovarian follicle development such as 'ErB Signaling' and 'NGF Signaling' in the down-regulated category and 'Regulation of eIF4 and P70S6K Signaling' and 'HER-2 Signaling in Breast Cancer' in the up-regulated group. Additionally, immunohistochemistry on human ovarian tissue explored the intraovarian localization of VASA, FOXO1 and eIF4E. LARGE SCALE DATA: http://users-birc.au.dk/biopv/published_data/ernst_2017/. LIMITATIONS, REASONS FOR CAUTION: This is a descriptive analysis and no functional studies were performed. The study was based on a limited number of patients and the experimental design could not take into account the natural biological variance in human samples. Therefore, qPCR was used to confirm selected genes alongside immunohistochemical stainings. WIDER IMPLICATIONS OF THE FINDINGS: This study shows, for the first time, a detailed molecular description of global gene transcription activities in oocytes from primordial and primary follicles, respectively. Knowing the global transcription profiles of human oocyte dormancy and activation are important in developing new clinical applications. STUDY FUNDING/COMPETING INTEREST(S): E.H.E. was supported by Health Faculty, Aarhus University and Kong Christian Den Tiendes Fond. K.H. and S.F. were supported by an MRC (UK) project grant MR/M012638/1. K.L.H. was supported by grants from Fonden til Lægevidenskabens Fremme, Kong Christian Den Tiendes Fond. K.L.H. and L.S. were supported by the IDEAS grant from Aarhus University Research Foundation (AUFF). There are no conflicts of interest.

Investigation of community carriage rates of Clostridium difficile and Hungatella hathewayi in healthy volunteers from four regions of England.

Faecal samples from 1365 healthy asymptomatic volunteers from four regions in England were screened for the presence of Clostridium difficile between December 2013 and July 2014. The carriage rate of C. difficile in healthy patients was 0.5%, which is lower than reported previously. This study demonstrates that the true community reservoir of C. difficile in the healthy UK population is very low and is, therefore, unlikely to be a reservoir for infections diagnosed in the hospital setting.

Treatment of pediatric cerebral radiation necrosis: a systematic review.

Cerebral radiation necrosis (CRN) is a toxicity of radiation therapy that can result in significant, potentially life-threatening neurologic deficits. Treatment for CRN has included surgical resection, corticosteroids, hyperbaric oxygen therapy (HBOT), and bevacizumab, but no consensus approach has been identified. We reviewed the available literature to evaluate efficacy of treatment approaches. Using methods specified in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines when possible, we conducted searches of Ovid MEDLINE, Embase and Pubmed to identify studies reporting on outcomes for children (≤21 years old) with CRN. Eligible studies from 1990 to 2014 describing central nervous system (CNS) radiation necrosis with details of both treatment and outcomes were included. Eleven studies meeting criteria were identified. Of the nine studies with total patient denominators, 37 of 806 patients developed CRN (incidence = 4.6 %). Patients received treatment courses of steroids alone (n = 13), steroids with bevacizumab (n = 11) or HBOT (n = 12). Patients who failed to respond to steroids were more likely to be older than steroid-responsive patients (p = 0.009). With the exception of steroid-related adverse events, there was only one report of an adverse event (brainstem stroke) potentially attributable to intervention (bevacizumab). Those who received proton beam RT were both younger (p = 0.001) and had a shorter time to development of CRN (p = 0.079). The most common treatment following steroid initiation was addition of bevacizumab or HBOT, with good success and minimal toxicity. However, randomized controlled trials are needed to establish a definitive treatment algorithm that can be applied to children affected by CRN.