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Ventilator-associated pneumonia commonly occurs in critically ill patients. Clinical suspicion results in overuse of antibiotics, which in turn promotes antimicrobial resistance. Detection of volatile organic compounds in the exhaled breath of critically ill patients might allow earlier detection of pneumonia and avoid unnecessary antibiotic prescription. We report a proof of concept study for non-invasive diagnosis of ventilator-associated pneumonia in intensive care (the BRAVo study). Mechanically ventilated critically ill patients commenced on antibiotics for clinical suspicion of ventilator-associated pneumonia were recruited within the first 24 h of treatment. Paired exhaled breath and respiratory tract samples were collected. Exhaled breath was captured on sorbent tubes and then analysed using thermal desorption gas chromatography-mass spectrometry to detect volatile organic compounds. Microbiological culture of a pathogenic bacteria in respiratory tract samples provided confirmation of ventilator-associated pneumonia. Univariable and multivariable analyses of volatile organic compounds were performed to identify potential biomarkers for a 'rule-out' test. Ninety-six participants were enrolled in the trial, with exhaled breath available from 92. Of all compounds tested, the four highest performing candidate biomarkers were benzene, cyclohexanone, pentanol and undecanal with area under the receiver operating characteristic curve ranging from 0.67 to 0.77 and negative predictive values from 85% to 88%. Identified volatile organic compounds in the exhaled breath of mechanically ventilated critically ill patients show promise as a useful non-invasive 'rule-out' test for ventilator-associated pneumonia., (© 2023 The Authors. Anaesthesia published by John Wiley & Sons Ltd on behalf of Association of Anaesthetists.)

Background: There are no contemporary data on healthcare-associated infections (HAIs) in New Zealand., Aims: To determine the epidemiology of HAIs, prevalence of medical devices, and microbiology of HAIs in adults in public hospitals in New Zealand., Methods: Point prevalence survey. Surveyors reviewed patients aged ≥18 years using the HAI definitions of the European Centres for Disease Prevention and Control. Device use and microbiology of HAIs were recorded., Findings: In total, 5468 patients were surveyed; 361 patients (6.6%) had 423 HAIs (7.7 HAIs per 100 patients). The most common HAIs were: surgical site infections (N=104, 25%), urinary tract infections (N=80, 19%), pneumonia (N=75, 18%) and bloodstream infections (N=55, 13%). Overall, 3585 patients (66%) had at least one device, with 2922 (53%) patients having a peripheral intravenous catheter. Sixty-nine (16%) HAIs were device-associated. On multi-variable analysis, independent risk factors for HAIs included the presence of a peripheral [odds ratio (OR) 2.0] or central (OR 5.7) intravenous catheter and clinical service. HAI rates were higher in surgical patients (OR 1.8), intensive care unit patients (OR 2.6) and rehabilitation/older persons' health patients (OR 2.4) compared with general medicine patients (P≤0.01 for all groups). In total, 301 organisms were identified. Clostridioides difficile infection was uncommon, accounting for 1.7% of all HAIs. Forty-two isolates (14%) were drug-resistant, and most (N=33, 79%) were Enterobacterales., Conclusion: This study established the most common HAIs and their risk factors in New Zealand. The high prevalence of device use underscores the need to ensure that proven multi-modal prevention interventions are in place. However, as less than half of HAIs are device- or surgery-associated, other intervention strategies will be required to reduce their burden., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Transgender healthcare is a rapidly evolving interdisciplinary field. In the last decade, there has been an unprecedented increase in the number and visibility of transgender and gender diverse (TGD) people seeking support and gender-affirming medical treatment in parallel with a significant rise in the scientific literature in this area. The World Professional Association for Transgender Health (WPATH) is an international, multidisciplinary, professional association whose mission is to promote evidence-based care, education, research, public policy, and respect in transgender health. One of the main functions of WPATH is to promote the highest standards of health care for TGD people through the Standards of Care (SOC). The SOC was initially developed in 1979 and the last version (SOC-7) was published in 2012. In view of the increasing scientific evidence, WPATH commissioned a new version of the Standards of Care, the SOC-8. Aim: The overall goal of SOC-8 is to provide health care professionals (HCPs) with clinical guidance to assist TGD people in accessing safe and effective pathways to achieving lasting personal comfort with their gendered selves with the aim of optimizing their overall physical health, psychological well-being, and self-fulfillment. Methods: The SOC-8 is based on the best available science and expert professional consensus in transgender health. International professionals and stakeholders were selected to serve on the SOC-8 committee. Recommendation statements were developed based on data derived from independent systematic literature reviews, where available, background reviews and expert opinions. Grading of recommendations was based on the available evidence supporting interventions, a discussion of risks and harms, as well as the feasibility and acceptability within different contexts and country settings. Results: A total of 18 chapters were developed as part of the SOC-8. They contain recommendations for health care professionals who provide care and treatment for TGD people. Each of the recommendations is followed by explanatory text with relevant references. General areas related to transgender health are covered in the chapters Terminology, Global Applicability, Population Estimates, and Education. The chapters developed for the diverse population of TGD people include Assessment of Adults, Adolescents, Children, Nonbinary, Eunuchs, and Intersex Individuals, and people living in Institutional Environments. Finally, the chapters related to gender-affirming treatment are Hormone Therapy, Surgery and Postoperative Care, Voice and Communication, Primary Care, Reproductive Health, Sexual Health, and Mental Health. Conclusions: The SOC-8 guidelines are intended to be flexible to meet the diverse health care needs of TGD people globally. While adaptable, they offer standards for promoting optimal health care and guidance for the treatment of people experiencing gender incongruence. As in all previous versions of the SOC, the criteria set forth in this document for gender-affirming medical interventions are clinical guidelines; individual health care professionals and programs may modify these in consultation with the TGD person., Competing Interests: Conflict of interests were reviewed as part of the selection process for committee members and at the end of the process before publication. No conflicts of interest were deemed significant or consequential., (© 2022 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Aim: To provide an updated systematic review concerning the impact of endoscopic ultrasound (EUS) in the modern era of oesophageal cancer staging., Materials and Methods: To update the previous systematic review, databases including MEDLINE and EMBASE were searched and studies published from 2005 onwards were selected. Studies reporting primary data in patients with oesophageal or gastro-oesophageal junction cancer who underwent radiological staging and treatment, regardless of intent, were included. The primary outcome was the reported change in management after EUS. Secondary outcomes were recurrence rate and overall survival. Two reviewers extracted data from included articles. This study was registered with PROSPERO (CRD42021231852)., Results: Eighteen studies with 11,836 patients were included comprising 2,805 patients (23.7%) who underwent EUS compared to 9,031 (76.3%) without EUS examination. Reported change of management varied widely from 0% to 56%. When used, EUS fine-needle aspiration precluded curative treatment in 37.5%-71.4%. Overall survival improvements ranged between 121 and 639 days following EUS intervention compared to patients without EUS. Smaller effect sizes were observed in a randomised controlled trial, compared to larger differences reported in observational studies., Conclusion: Current evidence for the effectiveness of EUS in oesophageal cancer pathways is conflicting and of limited quality. In particular, the extent to which EUS adds value to contemporary cross-sectional imaging techniques is unclear and requires formal re-evaluation., (Crown Copyright © 2022. Published by Elsevier Ltd. All rights reserved.)

Background: Nasal High Flow (NHF) therapy delivers flows of heated humidified gases up to 60 LPM (litres per minute) via a nasal cannula. Particles of oral/nasal fluid released by patients undergoing NHF therapy may pose a cross-infection risk, which is a potential concern for treating COVID-19 patients., Methods: Liquid particles within the exhaled breath of healthy participants were measured with two protocols: (1) high speed camera imaging and counting exhaled particles under high magnification (6 participants) and (2) measuring the deposition of a chemical marker (riboflavin-5-monophosphate) at a distance of 100 and 500 mm on filter papers through which air was drawn (10 participants). The filter papers were assayed with HPLC. Breathing conditions tested included quiet (resting) breathing and vigorous breathing (which here means nasal snorting, voluntary coughing and voluntary sneezing). Unsupported (natural) breathing and NHF at 30 and 60 LPM were compared., Results: Imaging: During quiet breathing, no particles were recorded with unsupported breathing or 30 LPM NHF (detection limit for single particles 33 μm). Particles were detected from 2 of 6 participants at 60 LPM quiet breathing at approximately 10% of the rate caused by unsupported vigorous breathing. Unsupported vigorous breathing released the greatest numbers of particles. Vigorous breathing with NHF at 60 LPM, released half the number of particles compared to vigorous breathing without NHF.Chemical marker tests: No oral/nasal fluid was detected in quiet breathing without NHF (detection limit 0.28 μL/m3). In quiet breathing with NHF at 60 LPM, small quantities were detected in 4 out of 29 quiet breathing tests, not exceeding 17 μL/m3. Vigorous breathing released 200-1000 times more fluid than the quiet breathing with NHF. The quantities detected in vigorous breathing were similar whether using NHF or not., Conclusion: During quiet breathing, 60 LPM NHF therapy may cause oral/nasal fluid to be released as particles, at levels of tens of μL per cubic metre of air. Vigorous breathing (snort, cough or sneeze) releases 200 to 1000 times more oral/nasal fluid than quiet breathing (p < 0.001 with both imaging and chemical marker methods). During vigorous breathing, 60 LPM NHF therapy caused no statistically significant difference in the quantity of oral/nasal fluid released compared to unsupported breathing. NHF use does not increase the risk of dispersing infectious aerosols above the risk of unsupported vigorous breathing. Standard infection prevention and control measures should apply when dealing with a patient who has an acute respiratory infection, independent of which, if any, respiratory support is being used., Clinical Trial Registration: ACTRN12614000924651., Competing Interests: Authors CJS, JFO, RK and PR are employees of the funder, Fisher and Paykel Healthcare. The specific roles of these authors are articulated in the ‘author contributions’ section. YJ and HH carried out statistical analyses under consulting service agreements with Fisher & Paykel Healthcare Ltd. This does not alter our adherence to PLOS ONE policies on sharing data and materials.” I am not aware that the work described in the manuscript has had any impact on product development or marketing, and I am not aware of any affiliation between any of the authors and any manufacturers competing with the funder.

Breast cancer-related lymphedema (BCRL) affects more than one in five women treated for breast cancer, and women remain at lifelong risk. Screening for BCRL is recommended by several national and international organizations for women at risk of BCRL, and multiple methods of objective screening measurement exist. The goal of this study was to compare the use of perometry and bioimpedance spectroscopy (BIS) for early identification of BCRL in a cohort of 138 prospectivelyscreened patients. At each screening visit, a patient's relative volume change (RVC) from perometer measurements and change in L-Dex from baseline (ΔL-Dex) using BIS was calculated. There was a negligible correlation between RVC and ΔL-Dex (r=0.195). Multiple thresholds of BCRL were examined: RVC ≥5% and ≥10% as well as and ΔL-Dex ≥6.5 and ≥10. While some patients developed an elevated RVC and ΔL-Dex, many demonstrated elevations in only one threshold category. Moreover, the majority of patients with RVC ≥5%, ΔL-Dex ≥6.5, or ΔL-Dex ≥10 regressed to non-elevated measurements without intervention. These findings suggest a role for combining multiple screening methods for early identification of BCRL; furthermore, BCRL diagnosis must incorporate patient symptoms and clinical evaluation with objective measurements obtained from techniques such as perometry and bioimpedance spectroscopy., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Patients treated for breast cancer are at risk of developing breast cancer-related lymphedema (BCRL). A significant proportion of patients treated for breast cancer are opting to undergo a contralateral prophylactic mastectomy (CPM). Currently, it remains unclear as to whether the relative volume change (RVC) equation may be used as an alternative to the weight adjusted change (WAC) equation to quantify BCRL in patients who undergo CPM. In order to simplify BCRL screening, our cohort of patients who underwent a CPM (n=310) was matched by BMI to a subset of patients who underwent unilateral breast surgery (n=310). Arm volume measurements were obtained via an optoelectronic perometer preoperatively, postoperatively, and in the follow-up setting every 6-12 months. The correlation of ipsilateral RVC and WAC values for those who underwent bilateral surgery was calculated (r=0.60). Contralateral WAC values for patients in both cohorts were compared, and there was no significant difference between the two distributions in variance (p=0.446). The RVC equation shows potential to be used to quantify ipsilateral postoperative arm volume changes for patients who undergo a CPM. However, a larger trial in which RVC and WAC values are prospectively assessed is needed., Competing Interests: The authors of this article and the planning committee members and staff have no relevant financial relationships with commercial interests to disclose., (Copyright by International Society of Lymphology.)

Background: Propensity score (PS) regression analysis can be used to minimize differences between cohorts in order to perform comparisons The aim of this study was to use PS analysis to examine the outcomes of oesophageal adenocarcinoma (OAC) treatment with surgery alone or neoadjuvant chemotherapy (NAC) followed by surgery (NACS), to see whether the benefits seen in a randomized trial (MRC OE02) were reproducible in a UK cancer network clinical practice., Methods: Consecutive patients undergoing potentially curative treatment for OAC in a regional cancer network were studied. Multiple regression models, including PS analysis, were developed to account for confounding factors. Primary outcome measures were disease-free (DFS) and overall (OS) survival., Results: A cohort of 440 patients was included in a regression analysis controlling for confounders (176 surgery alone, 264 NACS). NACS was associated with a higher positive margin status rate compared with surgery alone (42·4 versus 26·7 per cent respectively; P < 0·001), an inferior 5-year DFS rate (32·1 versus 56·9 per cent; P < 0·001) and a worse 5-year OS rate (27·5 versus 47·3 per cent; P < 0·001). On regression adjustment based on propensity scores, NACS was not associated with DFS (P = 0·220) or OS (P = 0·431). The Mandard tumour regression grade (TRG) score was significantly associated with DFS (hazard ratio (HR) 0·21, 95 per cent c.i. 0·07 to 0·70) and OS (HR 0·27, 0·13 to 0·59). Five-year DFS and OS rates related to TRG were 64 and 62 per cent respectively for 25 good responders versus 8·0 and 8·6 per cent for 127 poor responders (P < 0·001)., Conclusion: The prescription of NAC to all patients with OAC risks delay in effective treatment of patients who are relatively chemoresistant, given the variability in pathological response. Identification of patients with OAC who may derive the most benefit from NAC should be the focus., (© 2020 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of British Journal of Surgery Society.)

Background: Inflammation has an important role in cancer survival, yet whether serum markers of inflammation predict response to potentially curative neoadjuvant chemotherapy (NAC) in oesophageal adenocarcinoma (OAC) is controversial. This study aimed to determine whether the systemic inflammatory response (SIR) is associated with response to NAC and survival., Methods: Consecutive patients with OAC planned for surgery with curative intent received blood neutrophil and lymphocyte measurements at diagnosis to calculate the neutrophil to lymphocyte ratio (NLR). Pathological variables including pTNM stage, differentiation, vascular invasion and Mandard tumour regression grade (TRG) were recorded. TRGs 1 and 2 were taken to represent a good response, and the primary outcome was overall survival., Results: During follow-up of 136 patients, 36 patients (26·5 per cent) had recurrence and 69 (50·7 per cent) died. Receiver operating characteristic (ROC) curve analysis of NLR before NAC predicted poor TRG (area under the ROC curve 0·71, 95 per cent c.i. 0·58 to 0·83; P = 0·002). In univariable analysis, pT category (P < 0·001), pN category (P < 0·001), poor differentiation (P = 0·006), margin positivity (P = 0·001), poor TRG (P = 0·014) and NLR (dichotomized at 2·25; P = 0·017) were associated with poor overall survival, and NLR retained independent significance in multivariable analysis (hazard ratio 2·26, 95 per cent c.i. 1·03 to 4·93; P = 0·042)., Conclusion: The pretreatment NLR was associated with a pathological response to NAC and overall survival in patients with OAC., Antecedentes: La inflamación juega un importante papel en la supervivencia por cáncer, aunque aún no se sabe si los marcadores séricos de inflamación predicen la respuesta a la quimioterapia neoadyuvante (neoadjuvant chemotherapy, NAC) potencialmente curativa en el adenocarcinoma de esófago (oesophageal adenocarcinoma, OAC). Este estudio se propuso determinar si la respuesta inflamatoria sistémica (systemic inflammatory response, SIR) estaba asociada con la respuesta a la NAC y a la supervivencia. MÉTODOS: A pacientes consecutivos con OAC en los que se planificó cirugía con intención curativa se les determinó neutrófilos y linfocitos en sangre en el momento del diagnóstico para calcular la tasa neutrófilo-linfocito (neutrophil-lymphocyte ratio, NLR). Se registraron variables patológicas que incluían el estadio pTNM, diferenciación tumoral, invasión vascular y grado de regresión tumoral (tumour regression grade, TRG) de Mandard. Los grados TRG 1 y 2 fueron considerados como una buena respuesta y el resultado primario fue la supervivencia global (overall survival, OS)., Resultados: Durante el seguimiento de 136 pacientes, 36 pacientes (26,5%) presentaron recidiva y 69 pacientes (50,7%) fallecieron. El análisis de las características operativas del receptor (receiver-operator-characteristic, ROC) de NLR antes de la NAC predijo una pobre TRG (área bajo la curva ROC, AUC 0,71, i.c. del 95% 0,58-0,83, P = 0,002). En el análisis univariable, el estadio pT (P < 0,001), el estadio pN (P < 0,001), una pobre diferenciación tumoral (P = 0,006), un margen positivo (P = 0,001), una pobre TRG (P = 0,014) y la NLR (dicotomizada a 2,25, P = 0,017) se asociaron con una pobre OS, pero solamente la NLR (cociente de riesgos instantáneos, hazard ratio, HR 2,28, i.c. del 95% 1,03-4,93, P = 0,042) conservó la significación estadística como variable independiente en el análisis multivariable. CONCLUSIÓN: La NLR antes del tratamiento se asoció con respuesta patológica del OAC a la NAC y OS., (© 2020 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background: Surgeon-level operative mortality is widely seen as a measure of quality after gastric and oesophageal resection. This study aimed to evaluate this alongside a compound-level outcome analysis., Methods: Consecutive patients who underwent treatment including surgery delivered by a multidisciplinary team, which included seven specialist surgeons, were studied. The primary outcome was death within 30 days of surgery; secondary outcomes were anastomotic leak, Clavien-Dindo morbidity score, lymph node harvest, circumferential resection margin (CRM) status, disease-free (DFS), and overall (OS) survival., Results: The median number of annual resections per surgeon was 10 (range 5-25), compared with 14 (5-25) for joint consultant teams (P = 0·855). The median annual surgeon-level mortality rate was 0 (0-9) per cent versus an overall network annual operative mortality rate of 1·8 (0-3·7) per cent. Joint consultant team procedures were associated with fewer operative deaths (0·5 per cent versus 3·4 per cent at surgeon level; P = 0·027). The median surgeon anastomotic leak rate was 12·4 (range 9-20) per cent (P = 0·625 versus the whole surgical range), overall morbidity 46·5 (31-60) per cent (P = 0·066), lymph node harvest 16 (9-29) (P < 0·001), CRM positivity 32·0 (16-46) per cent (P = 0·003), 5-year DFS rate 44·8 (29-60) per cent and OS rate 46·5 (35-53) per cent. No designated metrics were independently associated with DFS or OS in multivariable analysis., Conclusion: Annual surgeon-level metrics demonstrated wide variations (fivefold), but these performance metrics were not associated with survival., (© 2019 The Authors. BJS Open published by John Wiley & Sons Ltd on behalf of BJS Society Ltd.)

Background/objectives: The iron-binding affinity of vaginal lactoferrin (Lf) reduces iron available to genital pathogens. We describe host reproductive, nutritional, infection and iron biomarker profiles affecting vaginal Lf concentration in young nulliparous and primigravid women in Burkina Faso., Subjects/methods: Vaginal eluates from women who had participated in a randomized, controlled periconceptional iron supplementation trial were used to measure Lf using a competitive double-sandwich ELISA. For this analysis samples from both trial arms were combined and pregnant and non-pregnant cohorts compared. Following randomization Lf was measured after 18 months (end assessment) for women remaining non-pregnant, and at two antenatal visits for those becoming pregnant. Associations between log Lf levels and demographic, anthropometric, infection and iron biomarker variables were assessed using linear mixed models., Results: Lf samples were available for 712 non-pregnant women at end assessment and for 303 women seen at an antenatal visit. Lf concentrations of pregnant women were comparable to those of non-pregnant, sexually active women. Lf concentration increased with mid-upper-arm circumference, (P = 0.047), body mass index (P = 0.018), Trichomonas vaginalis (P < 0.001) infection, bacterial vaginosis (P < 0.001), serum C-reactive protein (P = 0.048) and microbiota community state types III/IV. Adjusted Lf concentration was positively associated with serum hepcidin (P = 0.047), serum ferritin (P = 0.018) and total body iron stores (P = 0.042). There was evidence that some women maintained persistently high or low Lf concentrations from before, and through, pregnancy., Conclusion: Lf concentrations increased with genital infection, higher BMI, MUAC, body iron stores and hepcidin, suggesting nutritional and iron status influence homeostatic mechanisms controlling vaginal Lf responses.

Bracken fern is carcinogenic when fed to domestic and laboratory animals inducing bladder and ileal tumours and is currently classified as a possible human carcinogen by IARC. The carcinogenic illudane, ptaquiloside (PTQ) was isolated from bracken fern and is widely assumed to be the major bracken carcinogen. However, several other structurally similar illudanes are found in bracken fern, in some cases at higher levels than PTQ and so may contribute to the overall toxicity and carcinogenicity of bracken fern. In this review, we critically evaluate the role of illudanes in bracken fern induced toxicity and carcinogenicity, the mechanistic basis of these effects including the role of DNA damage, and the potential for human exposure in order to highlight deficiencies in the current literature. Critical gaps remain in our understanding of bracken fern induced carcinogenesis, a better understanding of these processes is essential to establish whether bracken fern is also a human carcinogen., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Aim: The principal aim of this study was to develop, pilot and evaluate an intervention intended to support the development of resilience and self-efficacy in parents of children with disabilities or complex health needs., Background: Previous research has found that families often experience physical, social and emotional stress in the context of living with and caring for their disabled child. The literature indicates that a key factor in determining how well the parents of these children cope with their situation may be how resilient and self-efficacious they are., Methods: A total of 16 parents of children with complex needs and disabilities were engaged in a series of guided conversations delivered during six contact visits with nurse co-researchers (community children's nurses who had received an intensive three-day preparation programme). The conversations, which were supported with additional material that was designed specifically for use in the study, were based around four key themes: emotional coping, practical coping, support networks and 'you and your child'. The impact of the intervention was evaluated using both qualitative and quantitative measures., Findings: When interviewed, parents reported increased self-belief and self-confidence and indicated that they felt better supported and stronger as a result of the intervention. This was consistent with the quantitative evaluation which identified significant improvements on scores for active coping and self-blame on the brief COPE inventory scale and for empathy and understanding and self-acceptance on the TOPSE scale. Scores on the self-report distress thermometer demonstrated a significant reduction in self-reported distress scores at the end of the intervention period.

Purpose: PET/CT is now integral to the staging pathway for potentially curable esophageal cancer (EC), primarily to identify distant metastases undetected by computed tomography. The aim of this study was to analyze the effect of PET/CT introduction on survival and assess patterns of recurrence after esophagectomy., Methods: A longitudinal cohort of EC patients staged between 1998 and 2016 were considered for inclusion. After co-variate adjustment using propensity scoring, a cohort of 496 patients (273 pre-PET/CT and 223 post-PET/CT) who underwent esophagectomy [median age 63 years (31-80), 395 males, 425 adenocarcinomas, 71 squamous cell carcinomas, 325 neoadjuvant therapy] were included. The primary outcome measure was overall survival (OS) based on intention to treat., Results: Three-year OS pre-PET/CT was 42.5% compared with 57.8% post-PET/CT (Chi 2 6.571, df 1, p = 0.004). On multivariable analysis, pT stage (HR 1.496 [95% CI 1.28-1.75], p < 0.0001), pN stage (HR 1.114 [95% CI 1.04-1.19], p = 0.001) and PET/CT staging (HR 0.688 [95% CI 0.53-0.89] p = 0.004) were independently associated with OS. Recurrent cancer was observed in 125 patients (51.4%) pre-PET/CT, compared with 74 patients post-PET/CT (37.8%, p = 0.004), and was less likely to be distant recurrence after PET/CT introduction (39.5 vs. 27.0%, p = 0.006)., Conclusions: Enhanced PET/CT staging is an important modality and independent factor associated with improved survival in patients undergoing esophagectomy for cancer.

Study Question: How much statistical power do randomised controlled trials (RCTs) and meta-analyses have to investigate the effectiveness of interventions in reproductive medicine?, Summary Answer: The largest trials in reproductive medicine are unlikely to detect plausible improvements in live birth rate (LBR), and meta-analyses do not make up for this shortcoming., What Is Known Already: Effectiveness of interventions is best evaluated using RCTs. In order to be informative, these trials should be designed to have sufficient power to detect the smallest clinically relevant effect. Similar trials can subsequently be pooled in meta-analyses to more precisely estimate treatment effects., Study Design, Size, Duration: A review of power and precision in 199 RCTs and meta-analyses from 107 Cochrane Reviews was conducted., Participants/materials, Setting, Methods: Systematic reviews published by Cochrane Gynaecology and Fertility with the primary outcome live birth were identified. For each live birth (or ongoing pregnancy) meta-analysis and for the largest RCT in each, we calculated the power to detect absolute improvements in LBR of varying sizes. Additionally, the 95% CIs of estimated treatment effects from each meta-analysis and RCT were recorded, as these indicate the precision of the result., Main Results and the Role of Chance: Median (interquartile range) power to detect an improvement in LBR of 5 percentage points (pp) (e.g. 25-30%) was 13% (8-21%) for RCTs and 16% (9-33%) for meta-analyses. No RCTs and only 2% of meta-analyses achieved 80% power to detect an improvement of 5 pp. Median power was high (85% for trials and 93% for meta-analyses) only in relation to 20 pp absolute LBR improvement, although substantial numbers of trials and meta-analyses did not achieve 80% power even for this improbably large effect size. Median width of 95% CIs was 25 pp and 21 pp for RCTs and meta-analyses, respectively. We found that 28% of Cochrane Reviews with LBR as the primary outcome contain no live birth (or ongoing pregnancy) data., Large-Scale Data: The data used in this study may be accessed at https://osf.io/852tn/?view&#95;only=90f1579ce72747ccbe572992573197bd., Limitations, Reasons for Caution: The design and analysis decisions used in this study are predicted to overestimate the power of trials and meta-analyses, and the size of the problem is therefore likely understated. For some interventions, it is possible that larger trials not reporting live birth or ongoing pregnancy have been conducted, which were not included in our sample. In relation to meta-analyses, we calculated power as though all participants were included in a single trial. This ignores heterogeneity between trials in a meta-analysis, and will cause us to overestimate power., Wider Implications of the Findings: Trials capable of detecting realistic improvements in LBR are lacking in reproductive medicine, and meta-analyses are not large enough to overcome this deficiency. This situation will lead to unwarranted pessimism as well as unjustified enthusiasm regarding reproductive interventions, neither of which are consistent with the practice of evidence-based medicine or the idea of informed patient choice. However, RCTs and meta-analyses remain vital to establish the effectiveness of fertility interventions. We discuss strategies to improve the evidence base and call for collaborative studies focusing on the most important research questions., Study Funding/competing Interest(s): There was no specific funding for this study. KS and SL declare no conflict of interest. AV consults for the Human Fertilisation and Embryology Authority (HFEA): all fees are paid directly to AV's employer. JW declares that publishing research benefits his career. SR is a Statistical Editor for Human Reproduction. JW and AV are Statistical Editors for Cochrane Gynaecology and Fertility. DRB is funded by the NHS as Scientific Director of a clinical IVF service., Prospero Registration Number: None., (© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology.)

Background: Lymph node metastases are a major prognostic indicator in oesophageal cancer. Radiological staging largely influences treatment decisions and is becoming more reliant on PET and CT. However, the sensitivity of these modalities is suboptimal and is known to under-stage disease. The primary aim of this study was to validate a published prognostic model in oesophageal cancer patients staged N0 with PET/CT, which showed that EUS nodal status was an independent predictor of survival. The secondary aim was to assess the prognostic significance of pathological lymph node metastases in this cohort., Methods: An independent validation cohort included 139 consecutive patients from a regional upper gastrointestinal cancer network staged N0 with PET/CT between 1st January 2013 and 31st June 2015. Replicating the original study, two Cox regression models were produced: one included EUS T-stage and EUS N-stage, and one included EUS T-stage and EUS N0 versus N+. The primary outcome of the prognostic model was overall survival (OS). Kaplan-Meier analysis assessed differences in OS between pathological node-negative (pN0) and node-positive (pN+) groups. A p value of < 0.05 was considered statistically significant., Results: The mean OS of the validation cohort was 29.8 months (95% CI 27.1-35.2). EUS T-stage was significantly and independently associated with OS in both models (p = 0.011 and p = 0.012, respectively). EUS N-stage and EUS N0 versus N+ were not significantly associated with OS (p = 0.553 and p = 0.359, respectively). There was a significant difference in OS between pN0 and pN+ groups (χ 2 13.315, df 1, p < 0.001)., Conclusion: Lymph node metastases have a significant detrimental effect on OS. This validation study did not replicate the results of the developed prognostic model but the continued benefit of EUS in patients staged N0 with PET/CT was demonstrated. EUS remains a valuable component of a multi-modality approach to oesophageal cancer staging.

Purpose: A positive circumferential resection margin (CRM) is regarded as a poor prognostic indicator in oesophageal cancer (OC) but its prediction can be challenging. MRI is used to predict a threatened CRM in rectal cancer but is not commonly performed in OC unlike PET/CT, which is now routinely used. Therefore, this study assessed the additional predictive value of PET-defined tumour variables compared with EUS and CT T-stage. The prognostic significance of CRM status was also assessed., Materials and Methods: This retrospective study included 117 consecutive patients [median age 64.0 (range 24-78), 102 males, 110 adenocarcinomas, 6 squamous cell carcinoma (SCC), 1 neuro-endocrine] treated between 1st March 2012 and 31st July 2015. A binary logistic regression model tested 5 staging variables; EUS T-stage (≤T2 vs ≥ T3), CT T-stage (≤T2 vs ≥ T3), PET metabolic tumour length (MTL), PET metabolic tumour width (MTW) and the maximum standardised uptake value (SUV max )., Results: The CRM was positive in 43.6%. Sixty-seven (57.3%) patients received neo-adjuvant chemotherapy (NACT), 31 patients (26.5%) underwent surgery alone and 19 patients (16.2%) had neo-adjuvant chemo-radiotherapy (NACRT). Median overall survival (OS) was 36.0 months (95% confidence interval (CI) 24.1-47.9) and the 2-year OS was 55.4%. A binary logistic regression model showed EUS ≥ T3 tumours were independently and significantly more likely to have a positive CRM than EUS ≤ T2 tumours (HR 5.188, 95% CI 1.265-21.273, p = 0.022). CT T-stage, PET MTL, PET MTW and SUV max were not significantly associated with CRM status (p = 0.783, 0.852, 0.605 and 0.413, respectively). There was a significant difference in OS between CRM positive and negative groups (X 2 4.920, df 1, p = 0.027)., Conclusion: Advanced EUS T-stage is associated with a positive CRM, but PET-defined tumour variables are unlikely to provide additional predictive information. This study demonstrates the continued benefit of EUS as part of a multi-modality OC staging pathway., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Aims: Treatment decision making and planning in patients with oesophageal cancer are guided by radiological measurement of length of disease (LoD). This study aimed to investigate differences in positron emission tomography (PET) and endoscopic ultrasound (EUS) LoD. Their prognostic significance was also assessed., Materials and Methods: LoD was measured from PET and EUS staging investigations by one observer for each modality. Bland-Altman analysis and Wilcoxon signed rank tests assessed agreement and differences in measurements. In terms of radiotherapy planning, the proportion of cases with a clinically significant difference of more than 2 cm between PET and EUS was also calculated. Univariable and multivariable analysis assessed association with overall survival. A P-value < 0.05 was considered statistically significant., Results: Consecutive patients (n = 160, median age 66.0 years [range 24-83], males = 124, adenocarcinomas = 115) staged with PET/CT and EUS between 2011 and 2014 were included. PET tended to under-measure LoD compared with EUS. The median PET and EUS LoD was 6.4 and 8.0 cm, respectively. PET and EUS LoD was significantly different (Z = -7.021, P < 0.001). EUS LoD was more than 2 cm longer than PET LoD in 61 cases (38.1%). In eight cases (5.0%), PET LoD was more than 2 cm longer than EUS LoD. Both variables had prognostic significance in univariable analysis, but were not independent predictors of overall survival., Conclusion: There are significant differences in PET and EUS measurement of LoD. This could affect clinical decision making and radiotherapy treatment planning. Clinically significant differences between EUS and PET LoD could lead to a risk of geographical miss in up to 38.1% of cases if the PET/CT measurement alone had been used for radiotherapy planning. These results highlight the continued benefit of EUS in the oesophageal cancer staging and treatment pathway., (Copyright © 2017 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Aims: To compare long-term HbA 1c changes associated with different insulin pumps during routine care in a large cohort of adults with Type 1 diabetes representative of other clinic populations., Methods: Observational, retrospective study of 508 individuals starting pump therapy between 1999 and 2014 (mean age, 40 years; 55% women; diabetes duration, 20 years; 94% Type 1 diabetes; median follow-up, 3.7 years). Mixed linear models compared covariate-adjusted HbA 1c changes associated with different pump makes., Results: The pumps compared were: 50% Medtronic, 24% Omnipod, 14% Roche and 12% Animas. Overall HbA 1c levels improved and improvements were maintained during a follow-up extending to 10 years (HbA 1c : pre-continuous subcutaneous insulin infusion (pre-CSII) vs. 12 months post CSII, 71 (61, 82) vs. 66 (56, 74) mmol/mol; 8.7 (7.7, 9.6) vs. 8.2 (7.3, 8.9)%; P < 0.0001). The percentage of individuals with HbA 1c ≥ 64 mmol/mol (8.0%) reduced from a pre-CSII level of 68% to 55%. After adjusting for baseline confounders, there were no between-pump differences in HbA 1c lowering (P = 0.44), including a comparison of patch pumps with traditional catheter pumps (P = 0.63). There were no significant (P < 0.05) between-pump differences in HbA 1c lowering in pre-specified subgroups stratified by pre-pump HbA 1c , age or diabetes duration. HbA 1c lowering was positively related to baseline HbA 1c (P < 0.001) and diabetes duration (P = 0.017), and negatively related to the number of years of CSII use (P = 0.024)., Conclusions: Under routine care conditions, there were no covariate-adjusted differences in HbA 1c lowering when comparing different pump makes, including a comparison of patch pumps vs. traditional catheter pumps. Therefore, the choice of CSII make should not be influenced by the desired degree of HbA 1c lowering., (© 2017 Diabetes UK.)

Aim: To evaluate the accuracy of contemporary N-staging and provide radiological-pathological correlation in patients with lymph node metastases (LNMs) that were radiologically staged N0., Materials and Methods: One hundred and twelve patients were included who underwent surgery alone (n=41) or neoadjuvant therapy (n=71) between October 2010 and December 2015. Contrast-enhanced computed tomography (CECT), endoscopic ultrasound (EUS), and combined positron-emission tomography (PET) and CT N-stage were compared to pathological N-stage [node-negative (N0) versus node-positive (N+) groups]. Fifty LNMs from 15 patients preoperatively staged as N0 were measured and the maximum size recorded., Results: Accuracy, sensitivity, and specificity of N0 versus N+ disease with CECT, EUS, and PET/CT was 54.5%, 39.7% and 77.3%, 55.4%, 42.6% and 75%, and 57.1% 35.3%, and 90.9%, respectively. All techniques were more likely to under-stage nodal disease; CECT (X 2 32.890, df=1, p<0.001), EUS (X 2 28.471, df=1, p<0.001), and PET/CT (X 2 50.790, df=1, p<0.001). PET/CT was more likely to under-stage nodal disease than EUS (p=0.031). Median LNM size was 3 mm, with 41 (82%) of LNMs measuring <6 mm and 22 (44%) classified as micro-metastases (≤2 mm)., Conclusion: This study has demonstrated poor N-staging accuracy in the modern era of radiological staging. Eighty-two percent of LNMs measured <6 mm, making direct identification extremely challenging on medical imaging. Future research should focus on investigating and developing alternative surrogate markers to predict the likelihood of LNMs., (Crown Copyright © 2017. Published by Elsevier Ltd. All rights reserved.)

Recent advances in embryo freezing technology together with growing concerns over multiple births have shifted the paradigm of appropriate IVF. This has led to the adoption of new performance indicators for ART clinics by national reporting schemes, such as those curated by the Society for Assisted Reproductive Technology (SART) and the Human Fertilization and Embryology Authority (HFEA). Using these organizations as case studies, we review several outcome measures from a statistical perspective. We describe several denominators that are used to calculate live birth rates. These include cumulative birth rates calculated from all fresh and frozen transfer procedures arising from a particular egg collection or cycle initiation, and live birth rates calculated per embryo transferred. Using data from both schemes, we argue that all cycles should be included in the denominator, regardless of whether or not egg collection and fertilization were successful. Excluding cancelled cycles reduces the impact of confounding due to patient characteristics but also removes policy and performance differences which we argue represent relevant sources of variation. It may be misleading to present prospective patients with essentially hypothetical measures of performance predicated on parity of ovarian stimulation and transfer policies. Although live birth per embryo has the advantage of encouraging single embryo transfer, we argue that it is prone to misinterpretation. This is because the likelihood of live birth is not proportional to the number of embryos transferred. We conclude that it is not possible to present a single measure that encompasses both effectiveness and safety. Instead, we propose that a set of clear, relevant outcome indicators is necessary to enable subfertile patients to make informed choices regarding whether and where to be treated., (© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Recent attention has highlighted the importance of reducing sedentary time for maintaining health and quality of life. However, it is unclear how changing sedentary behavior may influence executive functions and self-regulatory strategy use, which are vital for the long-term maintenance of a health behavior regimen. The purpose of this cross-sectional study is to examine the estimated self-regulatory and executive functioning effects of substituting 30 min of sedentary behavior with 30 min of light activity, moderate-to-vigorous physical activity (MVPA), or sleep in a sample of older adults. This study reports baseline data collected from low-active healthy older adults (N = 247, mean age 65.4 ± 4.6 years) recruited to participate in a 6 month randomized controlled exercise trial examining the effects of various modes of exercise on brain health and function. Each participant completed assessments of physical activity self-regulatory strategy use (i.e., self-monitoring, goal-setting, social support, reinforcement, time management, and relapse prevention) and executive functioning. Physical activity and sedentary behaviors were measured using accelerometers during waking hours for seven consecutive days at each time point. Isotemporal substitution analyses were conducted to examine the effect on self-regulation and executive functioning should an individual substitute sedentary time with light activity, MVPA, or sleep. The substitution of sedentary time with both sleep and MVPA influenced both self-regulatory strategy use and executive functioning. Sleep was associated with greater self-monitoring (B = .23, p = .02), goal-setting (B = .32, p < .01), and social support (B = .18, p = .01) behaviors. Substitution of sedentary time with MVPA was associated with higher accuracy on 2-item (B = .03, p = .01) and 3-item (B = .02, p = .04) spatial working memory tasks, and with faster reaction times on single (B = -23.12, p = .03) and mixed-repeated task-switching blocks (B = -27.06, p = .04). Substitution of sedentary time with sleep was associated with marginally faster reaction time on mixed-repeated task-switching blocks (B = -12.20, p = .07) and faster reaction time on mixed-switch blocks (B = 17.21, p = .05), as well as reduced global reaction time switch cost (B = -16.86, p = .01). Substitution for light intensity physical activity did not produce significant effects. By replacing sedentary time with sleep and MVPA, individuals may bolster several important domains of self-regulatory behavior and executive functioning. This has important implications for the design of long-lasting health behavior interventions. Trial Registration clinicaltrials.gov identifier NCT00438347.

Object: In recent conflicts, many UK personnel sustained head injuries requiring damage-control surgery and aeromedical transfer to the UK. This study aims to examine indications, complications and outcomes of UK military casualties undergoing craniectomy and cranioplasty from conflicts in Afghanistan and Iraq., Methods: The UK military Joint Theatre Trauma Registry (JTTR) was searched for all UK survivors in Afghanistan and Iraq between 2004 and 2014 requiring craniectomy and cranioplasty resulting from trauma., Results: Fourteen decompressive craniectomies and cranioplasties were performed with blast and gunshot wounds equally responsible for head injury. Ten survivors (71%) had an Injury Severity Score (ISS) of 75, normally designated as 'unsurvivable'. Most were operated on the day of injury. Seventy-one percent received a reverse question mark incision and 7% received a bicoronal incision. Seventy-nine percent had bone flaps discarded. Overall infection rate was 43%. Acinetobacter spp was the causative organism in 50% of cases. Median Glasgow Outcome Scale (GOS) at final follow-up was 4. All casualties had a GOS score greater than 3., Conclusions: Timely neurosurgical intervention is imperative for military personnel given high survival rates in those sustaining what are designated 'un-survivable' injuries. Early decompression facilitates safe aeromedical evacuation of casualties. Excellent outcomes validate the UK military trauma system and the stepwise performance gains throughout recent conflicts however trauma registers most evolving to have specific relevance to military casualties. In high-energy trauma with contamination and soft-tissue destruction, surgery should be conducted with regard for future soft tissue reconstruction. Bone flaps should be discarded and cranioplasty performed according to local preference. Facilities receiving military casualties should have specialist microbiological input mindful of the difficulties treating unusual microbes.

We conducted a randomised exploratory trial in children aged between one and sixteen years old to establish the time to achieve an end-tidal oxygen fraction ≥ 0.9 in three different positions: supine, and 30 and 45° head up. We recruited 120 children analysed in two age groups: 1-8 years and 9-16 years. The median (IQR [range]) time to reach the end point was 80 (59-114 [41-295]) s in the younger group and 150 (107-211 [44-405]) s in the older group, regardless of position (p = 0.0001). The end point was reached in 90% of children in approximately 160 s in the younger, and 271 s in the older, groups, respectively. There was no statistical difference between the three positions within each age group in the time to reach the endpoint (p = 0.59). Only two patients in the older age group could not reach the end point, due to poorly fitting facemasks. We conclude that pre-oxygenation can therefore be achieved effectively in most children, and that tilting children head up by 30 or 45° does not significantly reduce the time taken to achieve an end-tidal oxygen fraction of ≥ 0.9. The recommended period for pre-oxygenation in both groups should remain at 3 min but it should be noted that this may be insufficient for many older patients., (© 2016 The Association of Anaesthetists of Great Britain and Ireland.)

Aim: To determine the excess costs attributable to surgical site infections (SSI) following primary hip and knee joint arthroplasty at Auckland City Hospital., Methods: A retrospective case-control study. Cases were patients who developed a SSI following primary hip (THA) and knee arthroplasty (TKA) surgery within 90 days of the procedure. Cases were matched 1:2 with controls; patients whose primary hip and knee arthroplasty procedures were not complicated by infection. Controls were matched for age, gender, date of surgery, type of surgery, and ASA category. The length of stay (LOS) and hospital costs for the initial admission and subsequent readmission for infection were calculated from the clinical costing system at Auckland District Health Board., Results: Eleven cases were identified; 3 following TKA, 7 following THA, and 1 following hemiarthroplasty of the hip. Infections were classified as superficial, 1, joint space, 1, and deep incisional, 9. Five SSI were identified during the initial admission for joint arthroplasty and 6 patients were readmitted with an SSI. Compared to the control patients, SSIs were associated with an excess mean cost of $40,121 and an excess mean LOS of 42 days., Conclusions: There is a significant increase in LOS and cost associated with SSI following primary THA and TKA at Auckland City Hospital. In addition to the excess cost associated with SSI, there are also opportunity costs resulting from their impact on elective surgical waiting lists. This reinforces the significant positive economic impact a successful strategy to reduce SSIs associated with primary joint arthroplasty procedures will have.

Introduction: In the present study, we examined the influence of a home-based, DVD-delivered exercise intervention on daily sedentary time and breaks in sedentary time in older adults., Methods: Between 2010 and 2012, older adults (i.e., aged 65 or older) residing in Illinois (N = 307) were randomized into a 6-month home-based, DVD-delivered exercise program (i.e., FlexToBa; FTB) or a waitlist control. Participants completed measurements prior to the first week (baseline), following the intervention period (month 6), and after a 6 month no-contact follow-up (month 12). Sedentary behavior was measured objectively using accelerometers for 7 consecutive days at each time point. Differences in daily sedentary time and breaks between groups and across the three time points were examined using mixed-factor analysis of variance (mixed ANOVA) and analysis of covariance (ANCOVA)., Results: Mixed ANOVA models revealed that daily minutes of sedentary time did not differ by group or time. The FTB condition, however, demonstrated a greater number of daily breaks in sedentary time relative to the control condition (p = .02). ANCOVA models revealed a non-significant effect favoring FTB at month 6, and a significant difference between groups at month 12 (p = .02)., Conclusions: While overall sedentary time did not differ between groups, the DVD-delivered exercise intervention was effective for maintaining a greater number of breaks when compared with the control condition. Given the accumulating evidence emphasizing the importance of breaking up sedentary time, these findings have important implications for the design of future health behavior interventions.

>We previously reported on a comparison of the AccuProbe(®) Gen-Probe(®) MTBC assay (AccuProbe) (BioMérieux, Marcy L'Etoile, France) with the Becton Dickinson (BD) MGIT™ TBc Identification (TBc) Test (BD, Franklin Lakes, NJ, USA) in our laboratory. In the period following the shift from the AccuProbe assay to the TBc test, we obtained six false-negative results. On sequencing the mpt64 gene, we found that these false-negative cases had mutations in the mpt64 gene due to deletion, insertion or substitution. Despite the occurrence of false-negative results, we found that the reduced cost and minimal technical expertise, combined with a new testing algorithm, still make this test the preferred option for rapidly identifying Mycobacterium tuberculosis complex in MGIT cultures in a low TB burden country such as New Zealand.

Although randomized trials provide the most reliable evidence of a drug's safety and efficacy, there are situations where randomized trials are not possible or ethical. In this article we discuss when and how single-arm trials can be used to support full approval of oncology drugs. These include situations in which an unprecedented effect on tumor response is observed in a setting of high unmet medical need, clinical trial patients have been well characterized, enabling a target population to be clearly defined, experience exists in a sufficient number of patients to allow adequate assessment of the risk:benefit relationship, and a proper historical context can be provided for analysis. We also discuss how response rates might be considered predictive of long-term outcomes or clinically meaningful in and of themselves in certain contexts., (© 2015 American Society for Clinical Pharmacology and Therapeutics.)

Eggerthella lenta is an emerging pathogen that has been underrecognized due to historical difficulties with phenotypic identification. Until now, its pathogenicity, antimicrobial susceptibility profile, and optimal treatment have been poorly characterized. In this article, we report the largest cohort of patients with E. lenta bacteremia to date and describe in detail their clinical features, microbiologic characteristics, treatment, and outcomes. We identified 33 patients; the median age was 68 years, and there was no gender predominance. Twenty-seven patients (82%) had serious intra-abdominal pathology, often requiring a medical procedure. Of those who received antibiotics (28/33, 85%), the median duration of treatment was 21.5 days. Mortality from all causes was 6% at 7 days, 12% at 30 days, and 33% at 1 year. Of 26 isolates available for further testing, all were identified as E. lenta by both commercially available matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) systems, and none were found to harbor a vanA or vanB gene. Of 23 isolates which underwent susceptibility testing, all were susceptible to amoxicillin-clavulanate, cefoxitin, metronidazole, piperacillin-tazobactam, ertapenem, and meropenem, 91% were susceptible to clindamycin, 74% were susceptible to moxifloxacin, and 39% were susceptible to penicillin., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Death from head injuries has been a feature of conflicts throughout the world for centuries. The burden of mortality has been variously affected by the evolution in weaponry from war-hammers to explosive ordnance, the influence of armour on survivability and the changing likelihood of infection as a complicating factor. Surgery evolved from haphazard trephination to valiant, yet disjointed, neurosurgery by a variety of great historical surgeons until the Crimean War of 1853-1856. However, it was events initiated by the Great War of 1914-1918 that not only marked the development of modern neurosurgical techniques, but our approach to military surgery as a whole. Here the author describes how 100 years of conflict and the input and intertwining relationships between the 20th century's great neurosurgeons established neurosurgery in the United Kingdom and beyond.

We aimed to determine the incidence of Clostridium difficile infection (CDI), the molecular epidemiology of circulating C. difficile strains and risk factors for CDI among hospitalised children in the Auckland region. A cross-sectional study was undertaken of hospitalised children <15 years of age in two hospitals investigated for healthcare-associated diarrhoea between November 2011 and June 2012. Stool specimens were analysed for the presence of C. difficile using a two-step testing algorithm including polymerase chain reaction (PCR). C. difficile was cultured and PCR ribotyping performed. Demographic data, illness characteristics and risk factors were compared between children with and without CDI. Non-duplicate stool specimens were collected from 320 children with a median age of 1.2 years (range 3 days to 15 years). Forty-six patients (14 %) tested met the definition for CDI. The overall incidence of CDI was 2.0 per 10,000 bed days. The percentage of positive tests among neonates was only 2.6 %. PCR ribotyping showed a range of strains, with ribotype 014 being the most common. Significant risk factors for CDI were treatment with proton pump inhibitors [risk ratio (RR) 1.74, 95 % confidence interval (CI) 1.09-5.59; p = 0.002], presence of underlying malignancy (RR 2.71, 95 % CI 1.65-4.62; p = 0.001), receiving chemotherapy (RR 2.70, 95 % CI 1.41-4.83; p = 0.003) and exposure to antibiotics (RR 1.17, 95 % CI 0.99-1.17; p = 0.03). C. difficile is an important cause of healthcare-associated diarrhoea in this paediatric population. The notion that neonatal populations will always have high rates of colonisation with C. difficile may not be correct. Several risk factors associated with CDI among adults were also found to be significant.

Aim: To assess whether separate endoscopic ultrasound (EUS) lymph node (N)-staging is still of prognostic value in those staged node negative (N0) at combined positron-emission tomography/computed tomography (PET/CT) in patients with oesophageal cancer (OC)., Materials and Methods: One hundred and seventeen consecutive patients [median age 67 years; 88 male; 98 cases of adenocarcinoma, 19 cases of squamous cell carcinoma (SCC)] staged as N0 at PET/CT underwent EUS to record tumour (T)- and N-stage. The patients were subsequently separated into two groups: EUS N0 (n = 78) and EUS N+ (n = 39). Survival analysis using Kaplan-Meier and Cox's proportional hazard methods was performed. Primary outcome was overall survival from diagnosis., Results: EUS N-stage and EUS N0 versus EUS N+ (p = 0.005 and p = 0.001, respectively) were found to be significantly and independently associated with survival in two models of multivariate analysis, in patients staged N0 at PET/CT. EUS T-stage was significantly associated with survival on univariate analysis., Conclusion: EUS N-staging still has prognostic value in patients staged N0 at PET/CT. There is a significant difference in survival between EUS N0 and positive nodal EUS status in those staged N0 at PET/CT, suggesting PET/CT is unreliable for local staging. PET/CT and EUS continue to have complimentary roles in OC staging., (Crown Copyright © 2014. Published by Elsevier Ltd. All rights reserved.)

Our aim was to describe the epidemiology and incidence of community-onset invasive S. aureus disease in children presenting to our hospital, and to compare the clonal complexes and virulence genes of S. aureus strains causing invasive and non-invasive disease. The virulence gene repertoire of invasive disease isolates was characterized using DNA microarray and compared with the virulence gene repertoire of non-invasive S. aureus isolates. Over the study period, 163 children had an invasive S. aureus infection. There was no difference in the distribution of clonal complexes or in the prevalence of genes encoding virulence factors between invasive and non-invasive isolates. Future research should include a strong focus on identifying the host and environmental factors that, along with organism virulence factors, are contributing to the patterns of invasive S. aureus disease observed in New Zealand.

Epstein-Barr virus (EBV) DNAemia in the first year posttransplantation has been studied extensively. There is a paucity of information on prevalence and sequelae of EBV infection in adult renal transplantation beyond the first year. This single-center study examines the relationship between EBV DNAemia and demographic, immunosuppressive, hematologic and infection-related parameters in 499 renal transplant recipients between 1 month and 33 years posttransplant. Participants were tested repeatedly for EBV DNAemia detection over 12 months and clinical progress followed for 3 years. Prevalence of DNAemia at recruitment increased significantly with time from transplant. In multivariate adjusted analyses, variables associated with DNAemia included EBV seronegative status at transplant (p = 0.045), non-White ethnicity (p = 0.014) and previous posttransplant lymphoproliferative disease (PTLD) diagnosis (p = 0.006), while low DNAemia rates were associated with mycophenolate mofetil use (p < 0.0001) and EBV viral capsid antigen positive Epstein-Barr nuclear antigen-1 positive serostatus at transplant (p = 0.044). Patient and graft survival, rate of kidney function decline and patient reported symptoms were not significantly different between EBV DNAemia positive and negative groups. EBV DNAemia is common posttransplant and increases with time from transplantation, but EBV DNAemia detection in low-risk (seropositive) patients has poor specificity as a biomarker for future PTLD risk., (© Copyright 2014 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The role of treatments involving surgery versus definitive chemoradiotherapy (dCRT) for oesophageal cancer remains controversial., Methods: Consecutive patients with oesophageal cancer were studied. Those whose treatment involved surgery alone or who received neoadjuvant chemotherapy or chemoradiotherapy were compared with those receiving dCRT. Multiple regression models, including propensity scores, were developed to assess confounding factors associated with undergoing surgery or dCRT, and the risk-adjusted association between treatment and survival., Results: From a total of 727 patients, regression adjustment to control for bias created a cohort of 521 patients available for comparison (277 in the surgery group and 244 in the dCRT group). Local and distant recurrence rates were 10·1 and 22·0 per cent respectively after surgery, compared with 26·2 and 11·9 per cent following dCRT (P < 0·001). Median survival, and 2- and 5-year survival rates after surgery were 27 months, 53·8 and 31·0 per cent respectively, compared with 28 months, 54·2 and 31·9 per cent after dCRT (P = 0·918). On multivariable analysis, disease-free survival was related to endosonographic tumour category (hazard ratio (HR) 0·76, 95 per cent confidence interval 0·10 to 6·04 for T1; HR 1·57, 0·21 to 11·58 for T2; HR 2·12, 0·29 to 15·49 for T3; HR 3·07, 0·41 to 23·16 for T4; P = 0·003, in relation to T0 as reference), lymph node metastasis count (HR 1·10, 1·04 to 1·15; P < 0·001) and total disease length (HR 0·96, 0·93 to 1·00; P = 0·041)., Conclusion: There was no difference in survival after oesophageal cancer treatment involving surgery or dCRT., (© 2014 BJS Society Ltd. Published by John Wiley & Sons Ltd.)

Objective: This study compared the performance of two new bone-anchored hearing aids with older bone-anchored hearing aids that were not fully digital., Methods: Fourteen experienced bone-anchored hearing aid users participated in this cross-over study. Performance of their existing bone-anchored hearing aid was assessed using speech-in-noise testing and questionnaires. Participants were then fitted with either a Ponto Pro or a BP100 device. After four weeks of use with each new device, the same assessments were repeated., Results: Speech-in-noise testing for the 50 per cent signal-to-noise ratio (the ratio at which 50 per cent of responses were correct) showed no significant differences between the Ponto Pro and the BP100 devices (p = 0.1) However, both devices showed significant improvement compared with the participants' previous bone-anchored hearing aid devices (p < 0.001). There were no significant differences between the two new devices in the questionnaire data., Conclusion: Both fully digital bone-anchored hearing aids demonstrated superior speech processing compared with the previous generation of devices. There were no substantial differences between the two digital devices in either objective or subjective tests.

Aims: The aim of this study was to determine outcomes of a reconfigured centralised upper gastrointestinal (UGI) cancer service model, allied to an enhanced recovery programme, when compared with historical controls in a UK cancer network., Materials and Methods: Details of 606 consecutive patients diagnosed with UGI cancer were collected prospectively and outcomes before (n = 251) and after (n = 355) centralisation compared. Primary outcome measures were rates of curative treatment intent, operative morbidity, length of hospital stay and survival., Results: The rate of curative treatment intent increased from 21 to 36% after centralisation (P < 0.0001). Operative morbidity (mortality) and length of hospital stay before and after centralisation were 40% (2.5%) and 16 days, compared with 45% (2.4%) and 13 days, respectively (P = 0.024). The median and 1 year survival (all patients) improved from 8.7 months and 39.0% to 10.8 months and 46.8%, respectively, after centralisation (P = 0.032). On multivariate analysis, age (hazard ratio 1.894, 95% confidence interval 0.743-4.781, P < 0.0001), centralisation (hazard ratio 0.809, 95% confidence interval 0.668-0.979, P = 0.03) and overall radiological TNM stage (hazard ratio 3.905, 95% confidence interval 1.413-11.270, P < 0.0001) were independently associated with survival., Conclusion: These outcomes confirm the patient safety, quality of care and survival improvements achievable by compliance with National Health Service Improving Outcomes Guidance., (Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

We reported an association between elevated vancomycin MIC and 30-day mortality in patients with Staphylococcus aureus bacteraemia (SAB), including patients with methicillin-susceptible S. aureus (MSSA) treated with flucloxacillin. A detailed analysis of comorbidities and disease severity scores in the same cohort of patients was performed to ascertain if unknown clinical parameters may have influenced these results. The association between elevated vancomycin MIC and 30-day mortality in SAB remained significant (p 0.001) on multivariable logistic regression analysis even when accounting for clinical factors. In addition, the association persisted when restricting analysis to patients with MSSA bacteraemia treated with flucloxacillin. This suggests that elevated vancomycin MIC is associated with but not causally linked to an organism factor that is responsible for increased mortality., (© 2013 The Authors Clinical Microbiology and Infection © 2013 European Society of Clinical Microbiology and Infectious Diseases.)

Background: Thought disorder has been proposed as an indicator of schizotypy, which is considered to be necessary but not sufficient for the development of schizophrenia. It is unclear whether thought disorder is an indicator of susceptibility (i.e. an endophenotype) for schizophrenia. The goal of the present study was to elucidate the role of thought disorder in relation to schizotypy by examining its presence in high-risk individuals during mid-childhood. Method The sample consisted of 265 subjects drawn from the New York High-Risk Project. Individuals at high risk for schizophrenia (i.e. offspring of parents with schizophrenia) were compared with individuals at low risk for schizophrenia (i.e. offspring of parents with affective disorder or offspring of psychiatrically normal parents). Videotaped interviews were rated for thought disorder using the Scale for the Assessment of Thought, Language, and Communication (TLC). The same subjects were administered diagnostic interviews in late adolescence/early adulthood., Results: Although positive thought disorder was equally present in subjects with affective and non-affective psychoses, negative thought disorder (namely, poverty of speech and poverty of content of speech) was elevated only in subjects with schizophrenia-related psychosis. Logistic regression analyses revealed that negative thought disorder added to the prediction of schizophrenia-related psychosis outcomes over and above positive thought disorder., Conclusions: These findings suggest that negative thought disorder may have a specific association with schizotypy, rather than a more general association with psychosis. The findings also support consideration of negative thought disorder as an endophenotypic indicator of a schizophrenia diathesis.

Aim: To determine the correlation between 2-[(18)F]-fluoro-2-deoxy-d-glucose (FDG) positron-emission tomography/computed tomography (PET/CT) defined maximum standardized uptake value (SUVmax) and endoluminal ultrasound-defined tumour volume (EDTV) in patients with oesophageal cancer (OC) and their relative prognostic significance., Materials and Methods: One hundred and eighty-five consecutive patients with OC were staged using CT, endoscopic ultrasound (EUS), and PET/CT. The maximum potential EDTV was calculated (πr(2)L, where r = tumour thickness and L = total length of disease including proximal and distal lymph node metastases). Primary outcome measure was survival from diagnosis., Results: Ninety-one percent of patients (168/185) had FDG-avid tumours on PET/CT. SUVmax correlated positively and significantly with EDTV (Spearman's rho = 0.339, p = 0.001). On univariate analysis, survival was inversely related to the PET/CT lymph node metastasis count (LNMC, p = 0.015), EUS N stage (p = 0.002), EDTV (<48 cm(3), p = 0.001), EUS total length of disease (p = 0.001), SUVmax (p = 0.002), PET/CT N stage (p < 0.0001), and EUS LNMC (p < 0.0001). On multivariate analysis two factors were significantly and independently associated with survival: EDTV (HR, 3.118; 95% CI: 1.357-7.167; p = 0.007), and PET/CT N stage (HR, 0.496; 95% CI: 0.084-1.577; p = 0.022)., Conclusion: EDTV and PET/CT N stage were important predictors of survival and further research is needed to identify critical prognostic values., (Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Objectives: The aim of this cross-sectional study was to assess the vitamin D status and muscle function in children with NF1 compared with their unaffected siblings., Methods: NF1 children between 5 and 18 years of age and who had at least one unaffected sibling were identified. Serum concentrations of 25-hydroxyvitamin D (25(OH)D), calcium, inorganic phosphate, alkaline phosphate, parathyroid hormone and 1,25-dihydroxyvitamin D were measured. The Leonardo Mechanography Ground Reaction Force Platform (GRFP) was used to measure EFI, jump power, force and height., Results: There was no significant difference in 25(OH)D between NF1 subjects and unaffected siblings. Relative jump power and force were found to be significantly different. The adjusted means (95% confidence limits) of non-NF1 and NF1 children for relative jump power (W/kg), controlling for body mass and age, were 37.31 (34.14, 40.49) and 32.51 (29.34, 35.68), respectively (P=0.054); and force (N/kg), controlling for body mass, age and gender, were 25.79 (24.28, 27.30) and 21.12 (19.61, 22.63), respectively (P<0.0001). Jumping parameters were not related to serum 25(OH)D., Conclusions: There was no significant relationship between vitamin D status and NF1 status in children. NF1 children had significantly impaired jumping power and force, when compared to their unaffected siblings.

Objectives: Adapt a measure of frailty for use in a cohort study of European men and explore relationships with age, health related quality of life and falls., Design: Longitudinal cohort study., Setting: 8 European centers., Participants: 3047 men aged 40-79 participating in the European Male Ageing Study (EMAS)., Measurements: Frailty was assessed using an adaptation of the Cardiovascular Health Study criteria. Health related quality of life was evaluated using the Rand Short Form-36 (SF-36) questionnaire which comprises both mental and physical component scores. Self reported falls in the preceding 12 months were recorded at 2-year follow-up., Results: 78 men (2.6%) were classified as frail (≥3 criteria) and 821 (26.9%) as prefrail (1-2 criteria). The prevalence of frailty increased from 0.1% in men aged 40-49 up to 6.8% in men aged 70-79. Compared to robust men, both prefrail and frail men had lower health related quality of life. Frailty was more strongly associated with the physical than mental subscales of the SF-36. Frailty was associated with higher risk of falls OR (95% CI) 2.92 (1.52, 5.59)., Conclusions: Frailty, assessed by the EMAS criteria, increased in prevalence with age and was related to poorer health related quality of life and higher risk of falls in middle-aged and older European men. These criteria may help to identify a vulnerable subset of older men.

Background: The optimum multimodal treatment for oesophageal cancer, and the prognostic significance of histopathological tumour involvement of the circumferential resection margin (CRM+) are uncertain. The aims of this study were to determine the prognostic significance of CRM+ after oesophagectomy and to identify endosonographic (endoluminal ultrasonography (EUS)) features that predict a threatened CRM+., Methods: Two hundred and sixty-nine consecutive patients underwent potentially curative oesophagectomy (103 surgery alone, 124 neoadjuvant chemotherapy (CS) and 42 chemoradiotherapy (CRTS)). Primary outcome measures were disease-free survival (DFS) and overall survival (OS)., Results: CRM+ was reported in 98 (38.0%) of all, and in 90 (62.5%) of pT3 patients. Multivariate analysis of pathological factors revealed: lymphovascular invasion (HR 2.087, 95% CI 1.396-3.122, P<0.0001), CRM+ (HR 1.762, 95% CI 1.201-2.586, P=0.004) and lymph node metastasis count (HR 1.563, 95% CI 1.018-2.400, P=0.041) to be independently and significantly associated with DFS. Lymphovascular invasion (HR 2.160, 95% CI 1.432-3.259, P<0.001) and CRM+ (HR 1.514, 95% CI 1.000-2.292, P=0.050) were also independently and significantly associated with OS. Multivariate analysis revealed EUS T stage (T3 or T4, OR 24.313, 95% CI 7.438-79.476, P<0.0001) and use or not of CRTS (OR 0.116, 95% CI 0.035-0.382, P<0.0001) were independently and significantly associated with CRM+., Conclusion: A positive CRM was a better predictor of DFS and OS than standard pTNM stage.

Aims: Definitive chemoradiotherapy (dCRT) has been advocated as an alternative treatment for oesophageal carcinoma, but received criticism for perceived poorer locoregional disease control when compared with surgery. The aim of this study was to determine the relative incidence and pattern of oesophageal carcinoma recurrence after dCRT and surgery in patients receiving stage-directed therapy with curative intent., Materials and Methods: In total, 623 consecutive patients with oesophageal carcinoma (207 squamous cell carcinoma, 416 adenocarcinoma) were studied. The primary outcome measure was disease-free survival, adjusted for baseline differences in gender, age and histological cell type., Results: Three hundred and eleven patients deemed unsuitable for surgery on the grounds of performance status (n = 137), bulky local disease (n = 121) or personal choice (n = 53) received dCRT and 312 surgery (200 received neoadjuvant chemotherapy). Oesophageal carcinoma recurrence was diagnosed in 44.1% of patients after dCRT compared with 40.7% after surgery (P = 0.222). Locoregional recurrence was more common after dCRT than after surgery (24.1% versus 9.3%, P < 0.0001). In contrast, distant metastases were more common after surgery than after dCRT (22.8% versus 12.9%, P = 0.001). The median time to recurrence in patients receiving dCRT and surgery were 15 and 17 months, respectively (P = 0.052). Stage-related disease-free 2 year survival for dCRT versus surgery was: stage I (68.6 versus 85.6%, P = 0.069), stage II (36.9 versus 47.4%, P = 0.011), stage III (31.0 versus 28.6, P = 0.878), stage IVa (21.4 versus 26.3%, P = 0.710)., Conclusions: These findings provide further support for a randomised trial of dCRT versus surgery in both oesophageal squamous cell carcinoma and adenocarcinoma., (Copyright © 2012 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

Background: This study tested the hypothesis that endoluminal ultrasound (EUS) defined total length of disease (including both the primary tumor and the position and number of proximal and distal lymph nodes-ELoD) and the associated EUS lymph node metastasis count (ELNMC) are better predictors of outcome than endoscopic esophageal cancer (OC) length and radiological tumor node metastasis stage in patients who undergo potentially curative treatment with surgery or definitive chemoradiotherapy (dCRT)., Methods: A total of 645 consecutive patients diagnosed with OC and managed by a multidisciplinary team were staged by CT and EUS. The primary outcome measure was survival from date of diagnosis., Results: A total of 323 patients received surgery (208 neoadjuvant chemotherapy), and 322 who were deemed unsuitable for surgery received dCRT. Univariable analysis revealed that survival was related to EUS T (p < 0.0001), N (p < 0.0001), EUS primary tumor length (p = 0.037), ELoD (p = 0.011), ELNMC (p < 0.0001), and treatment type (p = 0.001). Multivariable analysis revealed two factors: ELoD (hazard ratio (HR), 0.961; 95 % confidence interval (CI), 0.925-0.998; p = 0.041) and ELNMC (HR, 1.08; 95 % CI, 1.015-1.15; p = 0.016) were independently associated with survival., Conclusions: ELoD and ELNMC should become part of routine OC radiological staging to optimize stage-directed therapeutic outcomes.

Background: Aspergillus spp. are the leading cause of invasive fungal infection in lung transplant recipients. We investigated the relationship between the isolation of Aspergillus spp. from the respiratory tract of lung transplant recipients and their risk of mortality., Methods: A retrospective, observational cohort study of all patients who received lung allografts between January 1999 and May 2011 at a single UK centre was performed. The time from transplantation to death was analysed using Cox regression models. Isolation of Aspergillus spp. from the respiratory tract was included as a covariate in the Cox regression model., Results: Two hundred-thirteen patients were included. The median follow-up time was 5 years during which 102 patients (47.9%) died. Aspergillus was isolated from 74 (34.7%) patients. Twenty patients (27%) had Aspergillus isolated in the first 60 days post-transplant. Forty-one patients (55.4%) in the Aspergillus group and 61 patients (43.9%) in the non-Aspergillus group died during follow-up. A hazard ratio of 2.2 (95% CI 1.5-3.3; P < 0.001) for death following a positive Aspergillus sample was observed., Conclusion: Isolation of Aspergillus spp. from patients following lung transplantation is associated with a significant increase in mortality. Novel preventative strategies are required to minimise the impact of Aspergillus in lung transplant recipients., (Copyright © 2012 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Extended spectrum beta-lactamase producing E. coli (ESBL-EC) are an emerging public health issue. In New Zealand (NZ), bla (CTX-M-14) and bla (CTX-M-15) are the most common ESBL genes. Although many studies describe risk factors for ESBL-EC, few describe risk factors for specific ESBL genes. Between January 2006 and December 2007, we characterized 108 consecutive, non-duplicate isolates of ESBL-EC at the Auckland Hospital laboratory. Demographic and clinical data were recorded. Of the 108, 54.6% (59) were CTX-M-15-EC, 26.9% (29) were CTX-M-14-EC and 12.09% were CTX-M-9 (13). The remaining seven isolates carried CTX-M-3 (3; 2.7%), CTX-M-65 (2; 1.8%), CTX-M-27 (1; 0.9%) and CTX-M-57 (1; 0.9%). CTX-M-15-EC were more likely than CTX-M-14-EC to be fluoroquinolone-resistant (86.4% versus 32.4%; p=0.006) and to be non-susceptible to amoxicillin-clavulanate (84.7% versus 41.4%; p=0.0001). Patients with CTX-M-15-EC were more likely to be of Indian ethnicity (34.5% versus 0%; p=0.0012) and to have travelled recently (31.6% versus 4%; p=0.0088). Patients with CTX-M-14-EC were more likely to have Chinese or South-East Asian ethnicity (48.1% versus 5.2%; p<0.0001) and to have no history of either travel or prior hospital admission (44% versus 8.9%; p=0.0006). These data imply that CTX-M-15 and CTX-M-14 producing E. coli are associated with distinct demographic subgroups in NZ.

The CTX-M family of extended-spectrum β-lactamases (ESBLs) is a significant global public health threat. The prevalence of specific bla (CTX-M) genes varies geographically, but bla (CTX-M-15) and bla (CTX-M-14) dominate in most countries. We applied the latest Clinical Laboratory Standards Institute (CLSI) interpretive criteria (M100-S20) to a diverse collection of ESBL-producing Escherichia coli strains obtained from clinical specimens in our laboratory. Whereas under previous CLSI recommendations all isolates in this strain collection would have been reported as ceftazidime-resistant, under the new recommendations, approximately 11% of CTX-M-15-producing E. coli and 93% of CTX-M-14-producing E. coli respectively tested as ceftazidime-susceptible. We also found that, whilst many CTX-M-14-producers had minimum inhibitory concentrations (MICs) less than the breakpoint of 4 mg/L, the MIC distribution for these strains was higher than that of wild-type E. coli, with one CTX-M-14-producing isolate having an MIC of >64 mg/L. Although the new CLSI recommendations imply that ceftazidime can be safely used to treat serious infections due to CTX-M-producing E. coli, clinical outcome data are lacking. Consequently, the widespread use of ceftazidime in this setting could have profound clinical implications.

Setting: Recently, Mycobacterium tuberculosis isolates have been described that test phenotypically susceptible to rifampicin (RMP) yet harbour genotypic rpoB mutations., Objective: 1) To investigate the impact of such mutations on clinical outcomes among RMP-susceptible isolates, and 2) to determine the prevalence of rpoB mutations among isoniazid (INH) monoresistant isolates at our laboratory and to describe the association between the presence of these mutations and clinical outcomes., Methods: M. tuberculosis isolates were screened for mutations in the rpoB gene using the Cepheid Gene-Xpert® MTB/RIF assay. Clinical correlation was made by reviewing patient case notes., Results: Isolates from 94 patients were found to have INH-resistant, RMP-susceptible profiles. Clinical information was available for 52 patients, including three whose isolates had rpoB mutations. All three of these patients had treatment failures, compared to two of 49 patients whose isolates did not have rpoB mutations (P = 0.0005)., Discussion: We demonstrate a significant association between the presence of rpoB gene mutations that are not detected at the current RMP critical concentration and treatment failure. We suggest that a review of the current RMP critical concentration is warranted to ensure that RMP is not used inappropriately for the treatment of phenotypically occult multidrug-resistant tuberculosis.

Background: Anti-Müllerian hormone (AMH) is increasingly used to quantify ovarian reserve, but it has not yet realized its full clinical potential in assisted reproduction technology. We investigated the possible benefits of using novel, stratified ovarian hyperstimulation protocols, tailored to individual AMH levels, compared with conventional stimulation., Methods: Retrospective data were collected from 769 women (first cycle of IVF, using fresh embryos), in a UK tertiary care unit: 346 women using conventional stimulation protocols; 423 women treated under new AMH-tailored protocols., Results: Embryo transfer rates increased significantly (79-87%: P= 0.002) after the introduction of AMH-tailored stimulation protocols. Pregnancy rate per cycle started and live birth rate also increased significantly compared with conventionally treated women (17.9-27.7%, P= 0.002 and 15.9-23.9%, P = 0.007, respectively). Moreover, in the AMH group, the incidence of the ovarian hyperstimulation syndrome (OHSS) fell significantly (6.9-2.3%, P = 0.002) and failed fertilization fell from 7.8 to 4.5%. The cost of fertility drug treatment fell by 29% per patient and the overall cost of clinical management of OHSS fell by 43% in the AMH group. GnRH antagonist protocols, introduced as part of AMH-tailored treatment, may have contributed to the observed improvements: however, within the AMH-tailored group, the live birth rate was not significantly different between agonist and antagonist-treated groups., Conclusions: Although large, prospective, multicentre studies are indicated, we have clearly demonstrated that individualized, AMH-guided, controlled ovarian hyperstimulation protocols significantly improved positive clinical outcomes, reduced the incidence of complications and reduced the financial burden associated with assisted reproduction.