Analysis of exhaled breath to identify critically ill patients with ventilator-associated pneumonia.

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.

Prevalence of healthcare-associated infections in public hospitals in New Zealand, 2021.

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.

The impact of endoscopic ultrasound on the management and outcome of patients with oesophageal cancer: an update of a systematic review.

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.

Methods for quantifying breast cancer-related lymphedema in patients undergoing a contralateral prophylactic mastectomy.

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.

Comparison of perometry-based volumetric arm measurements and bioimpedance spectroscopy for early identification of lymphedema in a prospectively-screened cohort of breast cancer patients.

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.

Assessment of dispersion of airborne particles of oral/nasal fluid by high flow nasal cannula therapy.

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.

Propensity score regression analysis of oesophageal adenocarcinoma treatment with surgery alone or neoadjuvant chemotherapy.

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.

ANTECEDENTES: El análisis de regresión por puntaje de propensión (propensity score, PS) puede ser utilizado para minimizar las diferencias entre cohortes a la hora de hacer comparaciones. El objetivo de este estudio fue utilizar el PS para analizar los resultados del tratamiento del adenocarcinoma de esófago (oesophageal adenocarcinoma, OAC), tanto con cirugia sola (surgery, S) o con quimioterapia neoadyuvante (neoadjuvant chemotherapy, NAC) seguida de cirugía (NACS) para determinar si los beneficios del ensayo aleatorizado MRC OE02 eran reproducibles en la práctica clínica de una red de cáncer del Reino Unido. MÉTODOS: Se estudiaron pacientes consecutivos sometidos a tratamiento potencialmente curativo por OAC en una red de cáncer regional. Se desarrollaron modelos de regresión múltiple, incluyendo PS, para poder ajustar por factores de confusión. Las medidas de resultado primario fueron supervivencia libre de enfermedad (disease-free survival, DFS) y la supervivencia global (overall survival, OS). RESULTADOS: Se incluyó una cohorte de 440 pacientes en un análisis de regresión controlando por factores de confusión (176 S, 264 NACS). NACS se asoció con margen positivo (NACS versus S, 42,4% versus 26,7%, P < 0,001), menor DFS a los 5 años (32,1% versus 56,9, P < 0,001) y peor OS a los 5 años (27,5% versus 47,3%, P < 0,001). En el ajuste de la regresión basada en las puntuaciones de propensión, NACS no se asoció a DFS (P = 0,220) ni a OS (P = 0,431). El grado de regresión tumoral de Mandard (tumour regression grade, TRG) se asoció significativamente con DFS (cociente de riesgos instantáneos, hazard ratio, HR 0,21, i.c. del 95% 0,13-0,59). La DFS y OS a los 5 años en relación con TRG fue 63,6% y 61,5% versus 8,0% y 8,6% (P < 0,001) para buenos y pobres respondedores, respectivamente. CONCLUSIÓN: La indicación de NAC a todos los pacientes con OAC representa un riesgo de demorar un tratamiento efectivo para aquellos pacientes que son relativamente quimiorresistentes, dada la variabilidad en la respuesta patológica. Identificar a los pacientes con OAC que obtendrían el mayor beneficio de la NAC debería centrar el foco de atención.

Neutrophil to lymphocyte ratio as a predictor of response to neoadjuvant chemotherapy and survival in oesophageal adenocarcinoma.

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.

Value of individual surgeon performance metrics as quality assurance measures in oesophagogastric cancer surgery.

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.

ANTECEDENTES: La mortalidad operatoria relacionada con el nivel del cirujano se contempla ampliamente como una medida de calidad tras la resección esofágica. Este estudio tenía como objetivo evaluar este aspecto junto con un análisis de resultados conjuntos a nivel de procedimientos. MÉTODOS: Se estudiaron los pacientes consecutivos que fueron tratados, incluyendo el tratamiento quirúrgico, efectuado por un equipo multidisciplinar formado por siete cirujanos especialistas. La variable principal de resultados era la mortalidad a durante los primeros 30 días de la cirugía, y las variables secundarias fueron la fuga anastomótica, la gravedad de la puntuación de morbilidad de Clavien-Dindo, el número de ganglios linfáticos obtenidos, el estado del margen circunferencial (circumferential margin, CRM), la supervivencia libre de enfermedad (disease-free survival, DFS) y la supervivencia global (overall survival, OS). RESULTADOS: La mediana del número anual de resecciones por cirujano fue de 10 (rango 5-25, P = 0,855). El nivel de la mediana de mortalidad anual por cirujano fue del 0% (0-9,1) y la mortalidad operatoria anual global del equipo de 1,8% (0-3,7, P = 0,389). Los procedimientos conjuntos del equipo consultor se asociaron con menos muertes operatorias (0,5 versus 3,4%, P = 0,027). La tasa mediana (rango) de fuga anastomótica por cirujano fue del 12% (9-20, P = 0,625), la morbilidad global del 46,7% (31-60, P = 0,003), la DFS a los 5 años del 44,8% (28,6-60,0, P = 0,257) y la OS del 46,5% (35,0-52,5, P = 0,573). Ningún factor mostró una asociación independiente con la DFS o la OS en el análisis multivariable. CONCLUSIÓN: Las medidas anuales a nivel de cirujano demostraron amplias variaciones (9 veces), pero estas medidas de rendimiento no se asociaron con la supervivencia.

The role of bracken fern illudanes in bracken fern-induced toxicities.

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.

Mucosal lactoferrin response to genital tract infections is associated with iron and nutritional biomarkers in young Burkinabé women.

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.

Are interventions in reproductive medicine assessed for plausible and clinically relevant effects? A systematic review of power and precision in trials and meta-analyses.

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_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.

Propensity score analysis of 18-FDG PET/CT-enhanced staging in patients undergoing surgery for esophageal cancer.

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 (Chi2 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.

Enhancing resilience and self-efficacy in the parents of children with disabilities and complex health needs.

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.

Radiological prediction of positive circumferential resection margin in oesophageal cancer.

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 (SUVmax). 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 SUVmax 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 (X2 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.

Additional value of EUS in oesophageal cancer patients staged N0 on PET/CT: validation of a prognostic model.

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 (χ2 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.

Impact of Positron Emission Tomography and Endoscopic Ultrasound Length of Disease Difference on Treatment Planning in Patients with Oesophageal Cancer.

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.

Comparison of different insulin pump makes under routine care conditions in adults with Type 1 diabetes.

AIMS: To compare long-term HbA1c 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 HbA1c changes associated with different pump makes. RESULTS: The pumps compared were: 50% Medtronic, 24% Omnipod, 14% Roche and 12% Animas. Overall HbA1c levels improved and improvements were maintained during a follow-up extending to 10 years (HbA1c : 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 HbA1c ≥ 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 HbA1c 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 HbA1c lowering in pre-specified subgroups stratified by pre-pump HbA1c , age or diabetes duration. HbA1c lowering was positively related to baseline HbA1c (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 HbA1c 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 HbA1c lowering.

Developments in IVF warrant the adoption of new performance indicators for ART clinics, but do not justify the abandonment of patient-centred measures.

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.

Accuracy of contemporary oesophageal cancer lymph node staging with radiological-pathological correlation.

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 (X2 32.890, df=1, p<0.001), EUS (X2 28.471, df=1, p<0.001), and PET/CT (X2 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.