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.

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.

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.

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.

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.

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.

Social functioning and facial expression recognition in children with neurofibromatosis type 1.

BACKGROUND: This study examined social functioning and facial expression recognition (FER) in children with neurofibromatosis type 1 (NF1) compared to typically developing peers. Specifically, the current research aimed to identify hypothesised relationships between neurocognitive ability, FER and social functioning. METHOD: Children, ages 8 to 16, with NF1 (n = 23) and typically developing peers (n = 23) were recruited during regularly scheduled clinic visits and through advertisements on an institutional clinical trials website, respectively. Participants completed a measure of FER, an abbreviated intelligence test and questionnaires regarding their quality of life and behavioural functioning. Parents were also asked to complete questionnaires regarding the social-emotional and cognitive functioning of their child. RESULTS: As expected, there were significant differences between children with NF1 and typically developing peers across domains of social functioning and FER. Within the sample of children with NF1, there were no significant associations observed between cognitive measures, social functioning and facial recognition skills. CONCLUSION: Children with NF1 exhibited high rates of social impairment and weak FER skills compared to controls. The absence of associations between FER with cognitive and social variables, however, suggests something unique about this skill in children with NF1. Theoretical comparisons are made to children with autism spectrum disorders, as this condition may serve as a potentially useful model in better understanding FER in children with NF1.

Idd13 is involved in determining immunoregulatory DN T-cell number in NOD mice.

Immunoregulatory T cells have been identified as key modulators of peripheral tolerance and participate in preventing autoimmune diseases. CD4(-)CD8(-) (double negative, DN) T cells compose one of these immunoregulatory T-cell subsets, where the injection of DN T cells confers protection from autoimmune diabetes progression. Interestingly, genetic loci defining the function and number of CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) coincide with at least some autoimmune disease susceptibility loci. Herein, we investigate the impact of major insulin-dependent diabetes (Idd) loci in defining the number of DN T cells. We demonstrate that although Idd3, Idd5 and Idd9 loci do not regulate DN T-cell number, NOD mice congenic for diabetes resistance alleles at the Idd13 locus show a partial restoration in DN T-cell number. Moreover, competitive and non-competitive bone marrow chimera experiments reveal that DN T-cell number is defined by a bone marrow-intrinsic, but DN T-cell-extrinsic, factor. This suggests that non-autonomous candidate genes define DN T-cell number in secondary lymphoid organs. Together, our results show that the regulation of DN T-cell number in NOD mice is at least partially conferred by alleles at the Idd13 locus.

Increased protein expression of LHCG receptor and 17α-hydroxylase/17-20-lyase in human polycystic ovaries.

STUDY QUESTION: Does the expression of LHCG receptor (LHCGR) protein and key enzymes in the androgen biosynthetic pathway differ in normal human versus polycystic ovarian tissue? SUMMARY ANSWER: LHCGR and 17α-hydroxylase/17-20-lyase (CYP17A1) protein levels are increased in polycystic ovaries (PCOs). WHAT IS KNOWN ALREADY: The predominant source of excess androgen secretion in women with polycystic ovary syndrome (PCOS) is ovarian theca cells but few studies have directly assessed the presence and abundance of protein for key molecules involved in androgen production by theca, including LHCGR and the rate-limiting enzyme in androgen production, CYP17A1. STUDY DESIGN, SIZE, DURATION: This is a laboratory-based, cross-sectional study comparing protein expression of key molecules in the androgen biosynthetic pathway in archived ovarian tissue from women with normal ovaries (n = 10) with those with PCOs (n = 16). PARTICIPANTS/MATERIALS, SETTING, METHODS: A quantitative morphometric study was performed using sections of archived human ovaries (n = 26) previously characterized as normal or polycystic. The distribution and abundance of LHCGR, CYP17A1, 3ß-hydroxysteroid dehydrogenase type 2 (3ßHSDII) and 17ß-hydroxysteroid dehydrogenase type 5 (17ßHSD5) proteins were evaluated by immunohistochemistry and quantified. MAIN RESULTS AND THE ROLE OF CHANCE: A higher proportion of theca cells from anovulatory PCO expressed LHCGR protein when compared with control ovaries (P = 0.01). A significant increase in the intensity of immunostaining for CYP17A1 was identified in antral follicles in sections of PCO compared with ovaries from normal women (P = 0.04). LIMITATIONS, REASONS FOR CAUTION: As the study used formalin-fixed ovarian tissue sections, it was not possible to carry out studies 'in vitro' using the same ovarian tissues in order to also demonstrate increased functional activity of LHCGR and CYP17A1. WIDER IMPLICATIONS OF THE FINDINGS: The data are in keeping with the results of previous studies in isolated theca cells and support the notion of an intrinsic abnormality of theca cell androgen production in women with PCOS. STUDY FUNDING/COMPETING INTEREST(S): The research was supported by a Programme Grant, G0802782, from the Medical Research Council (MRC) UK and by the National Institute for Health Research (NIHR) Biomedical Research Centre based at Imperial College Healthcare NHS Trust and Imperial College London. F.V.C was supported by Capes Foundation (Brazilian Ministry of Education). The authors have no conflicts of interest to disclose.

Neurofibrillary tangles, amyotrophy and progressive motor disturbance in mice expressing mutant (P301L) tau protein.

Neurofibrillary tangles (NFT) composed of the microtubule-associated protein tau are prominent in Alzheimer disease (AD), Pick disease, progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD). Mutations in the gene (Mtapt) encoding tau protein cause frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17), thereby proving that tau dysfunction can directly result in neurodegeneration. Expression of human tau containing the most common FTDP-17 mutation (P301L) results in motor and behavioural deficits in transgenic mice, with age- and gene-dose-dependent development of NFT. This phenotype occurred as early as 6.5 months in hemizygous and 4.5 months in homozygous animals. NFT and Pick-body-like neuronal lesions occurred in the amygdala, septal nuclei, pre-optic nuclei, hypothalamus, midbrain, pons, medulla, deep cerebellar nuclei and spinal cord, with tau-immunoreactive pre-tangles in the cortex, hippocampus and basal ganglia. Areas with the most NFT had reactive gliosis. Spinal cord had axonal spheroids, anterior horn cell loss and axonal degeneration in anterior spinal roots. We also saw peripheral neuropathy and skeletal muscle with neurogenic atrophy. Brain and spinal cord contained insoluble tau that co-migrated with insoluble tau from AD and FTDP-17 brains. The phenotype of mice expressing P301L mutant tau mimics features of human tauopathies and provides a model for investigating the pathogenesis of diseases with NFT.

The acute abdomen in the older person.

The acute abdomen is a common condition in older people. Half of all presentations to hospital require admission, with a third requiring immediate surgery. The Royal College of Surgeons of England have reported a worryingly high mortality rate in the over 80s undergoing emergency surgery, with a 3-fold difference in mortality throughout the England, Wales and Northern Ireland. The aim of this article is to highlight the issues that older people face in relation to acute abdominal pathology.

Changing epidemiology of Clostridium difficile infection following the introduction of a national ribotyping-based surveillance scheme in England.

BACKGROUND: Marked increases in Clostridium difficile infection (CDI) incidence, driven by epidemic strain spread, is a global phenomenon. METHODS: The Clostridium difficile Ribotyping Network (CDRN) was established in 2007 as part of enhanced CDI surveillance in England, to facilitate the recognition and control of epidemic strains. We report on changes in CDI epidemiology in England in the first 3 years of CDRN. RESULTS: CDRN received 12,603 fecal specimens, comprising significantly (P < .05) increasing numbers and proportions of national CDI cases in 2007-2008 (n = 2109, 3.8%), 2008-2009 (n = 4774, 13.2%), and 2009-2010 (n = 5720, 22.3%). The C. difficile recovery rate was 90%, yielding 11,294 isolates for ribotyping. Rates of 9 of the 10 most common ribotypes changed significantly (P < .05) during 2007-2010. Clostridium difficile ribotype 027 predominated, but decreased markedly from 55% to 36% and 21% in 2007-2008, 2008-2009, and 2009-2010, respectively. The largest regional variations in prevalence occurred for ribotypes 027, 002, 015, and 078. Cephalosporin and fluoroquinolone use in CDI cases was reported significantly (P < .05) less frequently during 2007-2010. Mortality data were subject to potential reporting bias, but there was a significant decrease in CDI-associated deaths during 2007-2010, which may have been due to multiple factors, including reduced prevalence of ribotype 027. CONCLUSIONS: Access to C. difficile ribotyping was associated with significant changes in the prevalence of epidemic strains, especially ribotype 027. These changes coincided with markedly reduced CDI incidence and related mortality in England. CDI control programs should include prospective access to C. difficile typing and analysis of risk factors for CDI and outcomes.

Inferring biological mechanisms from spatial analysis: prediction of a local inhibitor in the ovary.

Female mammals are born with a lifetime's supply of oocytes individually enveloped in flattened epithelial cells to form primordial follicles. It is not clear how sufficient primordial follicles are maintained to sustain the reproductive lifespan, while providing an adequate supply of mature oocytes for ovulation. Locally produced growth factors are thought to be critical regulators of early follicle growth, but knowledge of their identity and source remains incomplete. Here, we have used a simple approach of spatial analysis of structures in histological tissue sections to identify likely sources of such regulatory molecules, narrowing the field for future screening for candidate growth factors or antagonists. We have quantified the relative spatial positions of primordial (resting) follicles and growing follicles in mice on days 4, 8, and 12 after birth, and calculated interfollicular distances. Follicles were significantly less likely to have started growing if they had 1 or more primordial follicles close by (within 10 mum), predicting that primordial follicles inhibit each other. This approach allows us to hypothesize that primordial follicles produce a diffusible inhibitor that prevents neighboring primordial follicles from growing. Such an approach has wide applicability within many branches of developmental and cell biology for studying spatial signaling within tissues and cells.

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.

The four-variable modification of diet in renal disease formula underestimates glomerular filtration rate in obese type 2 diabetic individuals with chronic kidney disease.

AIMS/HYPOTHESIS: GFR is commonly estimated using the four-variable Modification of Diet in Renal Disease (MDRD) formula and this forms the basis for classification of chronic kidney disease (CKD). We investigated the effect of obesity on the estimation of glomerular filtration rate in type 2 diabetic participants with CKD. METHODS: We enrolled 111 patients with type 2 diabetes mellitus in different stages of CKD. GFR was measured using (51)Cr-labelled EDTA plasma clearance and was estimated using the four-variable MDRD formula. RESULTS: The bias between estimated and measured GFR was -22.4 (-33.8 to -11.0) p < 0.001 in the obese group compared with -6.04 (-17.6 to -5.5) p = 0.299 in the non-obese group. When GFR was indexed to body surface area of 1.73 m(2), the bias remained significant at -9.4 (-13.4 to -5.4) p < 0.001 in the obese participants. CONCLUSIONS/INTERPRETATION: This study suggests that the four-variable MDRD formula significantly underestimates GFR in obese type 2 diabetic participants with CKD.

Extended multilocus variable-number tandem-repeat analysis of Clostridium difficile correlates exactly with ribotyping and enables identification of hospital transmission.

PCR ribotyping is currently used in many countries for epidemiological investigation to track transmission and to identify emerging variants of Clostridium difficile. Although PCR ribotyping differentiates over 300 types, it is not always sufficiently discriminatory for epidemiological investigations particularly for common ribotypes, e.g., ribotypes 027, 106, and 017. Multilocus variable-number tandem-repeat analysis (MLVA) is a highly discriminatory molecular subtyping method that has been applied to a number of bacterial species for high-level subtyping. Two MLVA typing schemes for C. difficile have been previously published, each utilizing seven variable-number tandem-repeat (VNTR) loci on the genome with four loci common to both schemes. Although these schemes are good genotyping methods with the ability to discriminate between isolates, they do not identify the ribotype. We show here that increasing the number of VNTR loci to 15, creating the extended MLVA (eMLVA) scheme, we have successfully subtyped all clinically significant ribotypes while still clustering isolates in concordance with PCR ribotyping. The eMLVA scheme developed here provides insight into the genetic diversity of the C. difficile population at both global and cross-infection clusters in patient levels, with the possibility of replacing PCR ribotyping.

New Measurement of the π0 radiative decay width.

High precision measurements of the differential cross sections for π0 photoproduction at forward angles for two nuclei, 12C and 208Pb, have been performed for incident photon energies of 4.9-5.5 GeV to extract the π0→γγ decay width. The experiment was done at Jefferson Lab using the Hall B photon tagger and a high-resolution multichannel calorimeter. The π0→γγ decay width was extracted by fitting the measured cross sections using recently updated theoretical models for the process. The resulting value for the decay width is Γ(π0→γγ)=7.82±0.14(stat)±0.17(syst) eV. With the 2.8% total uncertainty, this result is a factor of 2.5 more precise than the current Particle Data Group average of this fundamental quantity, and it is consistent with current theoretical predictions.

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.

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.

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.