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Background: Predicting the success of a Debridement, Antibiotics, and Implant Retention (DAIR) procedure for periprosthetic joint infection (PJI) for hip and knee joint arthroplasty remains a challenge. A failed DAIR might adversely affect the outcome of any future revision surgery for PJI. Hence, the ability to identify and optimize factors predictive of DAIR success would help target the procedure to the appropriate patient cohort and avoid unnecessary surgery for patients where a DAIR is unlikely to eradicate infection., Methods: A retrospective review of our prospective Bone Infection Group database was performed to identify all patients who underwent a DAIR of their primary or revision hip or knee arthroplasty. All patients had a confirmed PJI as per MSIS 2013 criteria and an outcome according to the MSIS working group outcome-reporting tool. DAIR surgery was then grouped into groups of "successful" or "unsuccessful" outcomes., Results: Sixty-four consecutive patients with an acute PJI underwent a DAIR procedure between 2009 and 2020, with 46 procedures performed for knees and 18 for hips. Treatment was successful in 69% (37 knees and 7 hips). The chance of a successful DAIR was significantly greater if performed at or within one week of symptom onset compared to greater than one-week duration (adjusted odds ratio (OR) 0.11; P = 0.027; 95% CI [0.02-0.78])). For DAIR performed at or within one week of symptom onset, the success rate was 93% for knees and 80% for hips. The chance of a successful DAIR however was not influenced by whether the surgeon was an arthroplasty or non-arthroplasty surgeon (OR 0.28; P = 0.13; 95% CI [0.05-1.48])). Isolated Streptococcus infection had a success rate of 100%. Next came Coagulase-negative Staphylococci (71%) and Methicillin-susceptible Staphylococcus Aureus (65%). Polymicrobial infection had the worst outcome, with a success rate of 40%., Conclusion: In our experience, DAIR surgery performed within one week of symptom onset significantly increased the chance of successful infection eradication. Collaborative work is required to ensure arthroplasty patients can access prompt appropriate surgical decision-making as soon as concerns arise, remove barriers to early assessment and minimise delays to surgery., Competing Interests: Declarations. Ethics approval and consent to participate: No formal ethical approval was required for completion of this study. Consent for publication: Not applicable. Competing interests: The authors declare no competing interests., (© 2024. Crown.)

Polyaniline composites consisting of carboxymethyl cellulose (CMC) have enhanced adsorption properties, but recent studies indicate that the oxidised species - dialdehyde carboxymethyl cellulose (DCMC) - outperforms CMC-based composites. However, these studies fail to study the effect of DCMC's aldehyde content and compare the composites with CMC-based composites; numerous experiments required to investigate each adsorbent for each factor limit such studies. We explored a way to study whether villi-structured polyaniline (VSPANI), its CMC composite (CMC/PANI), and its DCMC composites with 35% (DCMC(A)/PANI) and 77% (DCMC(B)/PANI) aldehyde content would be great adsorbents for removing bisphenol-A (BPA). We first customised a D-optimal screening design to alleviate the pitfalls of definitive screening design (DSD), hence estimating all the main effects: initial concentration, pH, flow rate, adsorbent amount, sample volume and type of adsorbent. We excluded CMC/PANI and DCMC(A)/PANI composites, both with low adsorption capacities of 56.57 and 57.27 mg/g from further investigation. The DSD followed to estimate all second-order effects through which we projected a response surface method (RSM) to optimise and model the active factors. Increasing the aldehyde content on the composites favoured adsorption, but there lacked evidence to suggest VSPANI and DCMC(B)/PANI differed significantly in performance. The models were numerically and graphically proven adequate, explaining 80% and 99% of the variation when predicting removal efficiency and adsorption capacity. VSPANI showed potential as an adsorbent for BPA removal with 85% removal efficiency and 129 mg/g adsorption capacity. This comprehensive approach, combining both designs, allows for sustainable investigation of multiple adsorbents and factors, minimising experimental waste.

Histopathology is a challenging interpretive discipline, and the level of confidence a pathologist has in their diagnosis is known to vary, which is conveyed descriptively in pathology reports. There has been little study to accurately quantify pathologists' diagnostic confidence or the factors that influence it. In this study involving sixteen pathologists from six NHS trusts, we assessed diagnostic confidence across multiple variables and four specialties. Each case was reported by four pathologists, with each pathologist reporting each case twice (on light microscopy (LM) and digital pathology (DP)). For each diagnosis, pathologists recorded their confidence on a 7-point Likert scale. This provided 16,187 diagnoses and associated confidence scores for analysis. All variables investigated were found to be significantly predictive of diagnostic confidence, except level of pathologist experience. Confidence was lower for difficult to report cases, cases where there was inter- and intra-pathologist variation in the diagnosis, and cases where the pathologist made an incorrect diagnosis. Confidence was higher, although nominally, for LM diagnoses than DP (rate ratio 1.09 (95% CI 1.01-1.18), p = 0.035), although results indicate pathologists are confident to report on DP. Lowest confidence scores were seen in areas of known diagnostic complexity and cases with quality issues. High confidence in incorrect diagnoses were almost invariably attributed to interpretive diagnostic differences which occurred across both rare and common lesions. The results highlight the value of external quality control schemes and the benefits of selective peer review when reporting., (© 2024. The Author(s).)

Microbial contamination and the need for sustainable food production are driving the shift toward biodegradable food packaging materials. There is an urgent need to develop smart food packaging materials that can prevent contamination and prolong the shelf life of meat. To achieve this, the physical-chemical characteristics of polyvinyl alcohol (PVA)-based packaging films were enhanced through incorporation of lactic acid and anthocyanins to act as a pH indicator. The mechanical, hydrophilic, barrier, and antibacterial properties of the composite films were then evaluated to test the ability of the film to act as a packaging material. In addition, the surface morphology was studied by scanning electron microscopy (SEM), the functional groups by Fourier transform infrared (FTIR) spectroscopy, optical transparency using ultraviolet-visible (UV-vis) spectrophotometer, crystallinity by powder diffraction, and their thermal properties by thermal gravimetric analysis (TGA). The films had a swelling degree (SD) of 222.60 ± 21.19%, dry content (DC) of 70.56 ± 2.54%, moisture content (MC) of 29.44 ± 2%, ALRO moisture (AM) content of 41.85 ± 5.06, and total soluble matter (TSM) of 8.05 ± 1.05%. Moreover, incorporation of lactic acid enhanced the mechanical and the thermal properties of the films but it reduced their optical transparency. The water vapor permeability (WVP) was found to be 14.32 × 10 -3  g -1  s -1  Pa -1 and it inhibited the growth of Escherichia coli (EC) (10.67 ± 0.58 cm), Staphylococcus aureus (SA) (10.50 ± 0.40 cm), Pseudomonas aeruginosa (PA) (10.33 ± 0.58 cm), and Staphylococcus epidermidis (11 ± 1 cm) but not Bacillus subtilis (BS). The film's hue changed from red to green over time when used as a packaging material for meat under ambient condition indicating a deterioration in freshness. In conclusion, the developed packaging film exhibited enhanced mechanical, antimicrobial, and hydrophilic properties and it can be used to store and relay information when stored meat begins to decompose through a visible color change of the films., Competing Interests: The authors declare no conflicts of interest., (© 2024 The Author(s). Food Science & Nutrition published by Wiley Periodicals LLC.)

Aims: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples., Methods: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies., Results: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either., Conclusions: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used., (© 2024 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Aims: Comorbidities play a significant role towards the pathophysiology of heart failure with preserved ejection fraction (HFpEF), characterized by abnormal macrovascular function and altered ventricular-vascular coupling. However, our understanding of the role of comorbidities and arterial stiffness in HFpEF remains incomplete. We hypothesized that HFpEF is preceded by a cumulative rise in arterial stiffness as cardiovascular comorbidities accumulate, beyond that associated with ageing., Methods and Results: Arterial stiffness was assessed using pulse wave velocity (PWV) in five groups: Group A, healthy volunteers (n = 21); Group B, patients with hypertension (n = 21); Group C, hypertension and diabetes mellitus (n = 20); Group D, HFpEF (n = 21); and Group E, HF with reduced ejection fraction (HFrEF) (n = 11). All patients were aged 70 and above. Mean PWV increased from Groups A to D (PWV 10.2, 12.2, 13.0, and 13.7 m/s, respectively) as vascular comorbidities accumulated independent of age, renal function, haemoglobin, obesity (body mass index), smoking status, and hypercholesterolaemia. HFpEF exhibited the highest PWV and HFrEF displayed near-normal levels (13.7 vs. 10 m/s, P = 0.003). PWV was inversely related to peak oxygen consumption (r = -0.304, P = 0.03) and positively correlated with left ventricular filling pressures (E/e') on echocardiography (r = -0.307, P = 0.014)., Conclusions: This study adds further support to the concept of HFpEF as a disease of the vasculature, underlined by an increasing arterial stiffness that is driven by vascular ageing and accumulating vascular comorbidities, for example, hypertension and diabetes. Reflecting a pulsatile arterial afterload associated with diastolic dysfunction and exercise capacity, PWV may provide a clinically relevant tool to identify at-risk intermediate phenotypes (e.g. pre-HFpEF) before overt HFpEF occurs., (© 2023 The Authors. ESC Heart Failure published by John Wiley & Sons Ltd on behalf of European Society of Cardiology.)

Aim: To determine the impact of the COVID-19 pandemic on Resuscitation Council UK Advanced Life Support (ALS) and Immediate Life Support (ILS) course numbers and outcomes., Methods: We conducted a before-after study using course data from the Resuscitation Council UK Learning Management System between January 2018 and December 2021, using 23 March 2020 as the cut-off between pre- and post-pandemic periods. Demographics and outcomes were analysed using chi-squared tests and regression models., Results: There were 90,265 ALS participants (51,464 pre-; 38,801 post-) and 368,140 ILS participants (225,628 pre-; 142,512 post-). There was a sharp decline in participants on ALS/ILS courses due to COVID-19. ALS participant numbers rebounded to exceed pre-pandemic levels, whereas ILS numbers recovered to a lesser degree with increased uptake of e-learning versions. Mean ALS course participants reduced from 20.0 to 14.8 post-pandemic (P < 0.001).Post-pandemic there were small but statistically significant decreases in ALS Cardiac Arrest Simulation Test pass rates (from 82.1 % to 80.1 % (OR = 0.90, 95 % CI = 0.86-0.94, P < 0.001)), ALS MCQ score (from 86.6 % to 86.0 % (mean difference = -0.35, 95 % CI -0.44 to -0.26, P < 0.001)), and overall ALS course results (from 95.2 %to 94.7 %, OR = 0.92, CI = 0.85-0.99, P = 0.023). ILS course outcomes were similar post-pandemic (from 99.4 % to 99.4 %, P = 0.037)., Conclusion: COVID-19 caused a sharp decline in the number of participants on ALS/ILS courses and an accelerated uptake of e-learning versions, with the average ALS course size reducing significantly. The small reduction in performance on ALS courses requires further research to clarify the contributing factors., (© 2023 The Author(s).)

Phase II/III clinical trials are efficient two-stage designs that test multiple experimental treatments. In stage 1, patients are allocated to the control and all experimental treatments, with the data collected from them used to select experimental treatments to continue to stage 2. Patients recruited in stage 2 are allocated to the selected treatments and the control. Combined data of stage 1 and stage 2 are used for a confirmatory phase III analysis. Appropriate analysis needs to adjust for selection bias of the stage 1 data. Point estimators exist for normally distributed outcome data. Extending these estimators to time to event data is not straightforward because treatment selection is based on correlated treatment effects and stage 1 patients who do not get events in stage 1 are followed-up in stage 2. We have derived an approximately uniformly minimum variance conditional unbiased estimator (UMVCUE) and compared its biases and mean squared errors to existing bias adjusted estimators. In simulations, one existing bias adjusted estimator has similar properties as the practically unbiased UMVCUE while the others can have noticeable biases but they are less variable than the UMVCUE. For confirmatory phase II/III clinical trials where unbiased estimators are desired, we recommend the UMVCUE or the existing estimator with which it has similar properties., (© 2022 The Authors. Statistics in Medicine published by John Wiley & Sons Ltd.)

Analytical processes involving sample preparation, separation, and quantifying analytes in complex mixtures are indispensable in modern-day analysis. Each step is crucial to enriching correct and informative results. Therefore, sample preparation is the critical factor that determines both the accuracy and the time consumption of a sample analysis process. Recently, several promising sample preparation approaches have been made available with environmentally friendly technologies with high performance. As a result of its many advantages, solid-phase extraction (SPE) is practiced in many different fields in addition to the traditional methods. The SPE is an alternative method to liquid-liquid extraction (LLE), which eliminates several disadvantages, including many organic solvents, a lengthy operation time and numerous steps, potential sources of error, and high costs. SPE advanced sorbent technology reorients with various functions depending on the structure of extraction sorbents, including reversed-phase, normal-phase, cation exchange, anion exchange, and mixed-mode. In addition, the commercial SPE systems are disposable. Still, with the continual developments, the restricted access materials (RAM) and molecular imprinted polymers (MIP) are fabricated to be active reusable extraction cartridges. This review will discuss all the theoretical and practical principles of the SPE techniques, focusing on packing materials, different forms, and performing factors in recent and future advances. The information about novel methodological and instrumental solutions in relation to different variants of SPE techniques, solid-phase microextraction (SPME), in-tube solid-phase microextraction (IT-SPME), and magnetic solid-phase extraction (MSPE) is presented. The integration of SPE with analytical chromatographic techniques such as LC and GC is also indicated. Furthermore, the applications of these techniques are discussed in detail along with their advantages in analyzing pharmaceuticals, biological samples, natural compounds, pesticides, and environmental pollutants, as well as foods and beverages., (© 2022. The Author(s).)

Importance: Guidelines recommend that cardiac rehabilitation (CR) exercise training should not start until 6 weeks after sternotomy, although this is not evidence based. Limited data suggest that starting earlier is not detrimental, but clinical trials are needed., Objective: To compare the effectiveness and safety of CR exercise training started either 2 weeks (early CR) or 6 weeks (usual-care CR) after sternotomy., Design, Setting, and Participants: This was an assessor-blind, noninferiority, parallel-group, randomized clinical trial that conducted participant recruitment from June 12, 2017, to March 17, 2020. Participants were consecutive cardiac surgery sternotomy patients recruited from 2 outpatient National Health Service rehabilitation centers: University Hospital, Coventry, UK, and Hospital of St Cross, Rugby, UK., Interventions: Participants were randomly assigned to 8 weeks of twice-weekly supervised CR exercise training starting either 2 weeks (early CR) or 6 weeks (usual-care CR) after sternotomy. Exercise training adhered to existing guidelines, including functional strength and cardiovascular components., Main Outcomes and Measures: Outcomes were assessed at baseline (inpatient after surgery), after CR (10 or 14 weeks after sternotomy), and 12 months after randomization. The primary outcome was the change in 6-minute walk test distance from baseline to after CR. Secondary outcomes included safety, functional fitness, and quality of life., Results: A total of 158 participants (mean [SD] age, 63 [11.5] years, 133 male patients [84.2%]) were randomly assigned to study groups; 118 patients (usual-care CR, 61 [51.7%]; early CR, 57 [48.3%]) were included in the primary analysis. Early CR was not inferior to usual-care CR (noninferiority margin, 35 m); the mean change in 6-minute walk distance from baseline to after CR was 28 m greater in the early CR group (95% CI, -11 to 66; P = .16). Mean differences for secondary outcomes were not statistically significant, indicating noninferiority of early CR. There were 46 vs 58 adverse events and 14 vs 18 serious adverse events in usual-care CR and early CR, respectively. There was no difference between the groups in the likelihood of participants having an adverse or serious adverse event., Conclusions and Relevance: Starting exercise training from 2 weeks after sternotomy was as effective as starting 6 weeks after sternotomy for improving 6-minute walk distance. With appropriate precautions, clinicians and CR professionals can consider starting exercise training as early as 2 weeks after sternotomy., Trial Registration: ClinicalTrials.gov Identifier: NCT03223558.

Introduction: gestational diabetes mellitus is an emerging global public health threat due to adverse health outcomes. This study aimed to determine the risk factors for caesarean delivery and macrosomia among women with gestational diabetes in Nyeri County, Kenya., Methods: this study used a cross-section design. Randomly, 152 women with gestational diabetes and attending antenatal clinics and maternity were enrolled in this study. Data was collected using a questionnaire upon consent. Data were subjected to binary logistic regression and binomial multiple logistic regression., Results: the mean age of the women with gestational diabetes was 30.86 (SD 5.81) years. Among women with gestational diabetes, a proportion of 59.9% (n=91) delivered through caesarean delivery. The positive history of diabetes in a family, previous positive history of gestational diabetes and positive previous adverse obstetric history increased chances of caesarean section delivery by more than 3.824 (95% CI = 1.001-14.608, p=0.05), 10.331 (95% CI = 2.464-43.308, p=0.001) and 7.051 (95% CI = 1.577-31.801, 0.01) folds, respectively. Fetal macrosomia incidence was 42.1% (n=64) among women with gestational diabetes. The primary level of education, previous positive history of gestational diabetes and previous positive adverse obstetric history increased the likelihood of fetal macrosomia by more than 6.289 (95% CI = 1.241-31.870, p=0.03), 5.390 (95% CI = 1.498-19.386, p=0.01) and (95% CI = 5.804 1.349-18.423, p=0.02) folds, respectively., Conclusion: antenatal health care programs and delivery facilities should be strengthened in women with gestational diabetes to improve the risk associated with caesarean delivery and fetal macrosomia., Competing Interests: The authors declare no competing interest., (Copyright: Peter Kimani Njogu et al.)

Background: Digital pathology (DP) has the potential to fundamentally change the way that histopathology is practised, by streamlining the workflow, increasing efficiency, improving diagnostic accuracy and facilitating the platform for implementation of artificial intelligence-based computer-assisted diagnostics. Although the barriers to wider adoption of DP have been multifactorial, limited evidence of reliability has been a significant contributor. A meta-analysis to demonstrate the combined accuracy and reliability of DP is still lacking in the literature., Objectives: We aimed to review the published literature on the diagnostic use of DP and to synthesise a statistically pooled evidence on safety and reliability of DP for routine diagnosis (primary and secondary) in the context of validation process., Methods: A comprehensive literature search was conducted through PubMed, Medline, EMBASE, Cochrane Library and Google Scholar for studies published between 2013 and August 2019. The search protocol identified all studies comparing DP with light microscopy (LM) reporting for diagnostic purposes, predominantly including H&E-stained slides. Random-effects meta-analysis was used to pool evidence from the studies., Results: Twenty-five studies were deemed eligible to be included in the review which examined a total of 10 410 histology samples (average sample size 176). For overall concordance (clinical concordance), the agreement percentage was 98.3% (95% CI 97.4 to 98.9) across 24 studies. A total of 546 major discordances were reported across 25 studies. Over half (57%) of these were related to assessment of nuclear atypia, grading of dysplasia and malignancy. These were followed by challenging diagnoses (26%) and identification of small objects (16%)., Conclusion: The results of this meta-analysis indicate equivalent performance of DP in comparison with LM for routine diagnosis. Furthermore, the results provide valuable information concerning the areas of diagnostic discrepancy which may warrant particular attention in the transition to DP., Competing Interests: Competing interests: DRJS has worked in the past as a member of the Philips Digital Pathology advisory board., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objectives: To explore the utilisation of pharmacy-based sexual and reproductive health services (SRHS) in order to optimise delivery and identify barriers to access., Methods: The health provider Umbrella offers six SRHS from over 120 pharmacies in Birmingham (England). In this retrospective study, data collected between August 2015 and August 2018 were used to analyse uptake, user characteristics and attendance patterns according to day of the week., Results: A total of 60 498 requests for a pharmacy service were included in the analysis. Emergency contraception (50.4%), condoms (33.1%) and STI self-sampling kits (9.6%) accounted for more than 90% of all requests. A lower uptake of services was observed for the contraceptive injection (0.6%), oral contraception (5.4%) and chlamydia treatment (1.0%). Services were most likely to be requested by those self-identifying as female (85.6%), and those aged 16-24 years (53.8%). Based on available ethnicity data (n=54 668), most requests for a service were made by White/White British individuals (43.4%) and Asian/Asian British people (23.1%). The largest number of services were delivered on Mondays (20.9%) and the lowest on Sundays (5.0%). A high proportion of requests for services on Saturdays (57.0%), Sundays (67.6%) and Mondays (54.4%) were made by females presenting for emergency contraception., Conclusion: The evaluation of healthcare utilisation is important to help refine and optimise the delivery of services. However, information relating to pharmacy-based SRHS is scarce and often limited to a single type of service provision. Overall, a wide range of pharmacy-based services were accessed by a diverse range of people, suggesting that pharmacies are a suitable provider of many SRHS. However, the routinely collected data analysed in the study had several limitations restricting the analysis. Sexual health providers should ensure they collect data which are as comprehensive as is possible in order to help understand the utilisation of services., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims: There are reports of a marked increase in perioperative mortality in patients admitted to hospital with a fractured hip during the COVID-19 pandemic in the UK, USA, Spain, and Italy. Our study aims to describe the risk of mortality among patients with a fractured neck of femur in England during the early stages of the COVID-19 pandemic., Methods: We completed a multicentre cohort study across ten hospitals in England. Data were collected from 1 March 2020 to 6 April 2020, during which period the World Health Organization (WHO) declared COVID-19 to be a pandemic. Patients ≥ 60 years of age admitted with hip fracture and a minimum follow-up of 30 days were included for analysis. Primary outcome of interest was mortality at 30 days post-surgery or postadmission in nonoperative patients. Secondary outcomes included length of hospital stay and discharge destination., Results: In total, 404 patients were included for final analysis with a COVID-19 diagnosis being made in 114 (28.2%) patients. Overall, 30-day mortality stood at 14.4% (n = 58). The COVID-19 cohort experienced a mortality rate of 32.5% (37/114) compared to 7.2% (21/290) in the non-COVID cohort (p < 0.001). In adjusted analysis, 30-day mortality was greatest in patients who were confirmed to have COVID-19 (odds ratio (OR) 5.64, 95% confidence interval (CI) 2.95 to 10.80; p < 0.001) with an adjusted excess risk of 20%, male sex (OR 2.69, 95% CI 1.37 to 5.29; p = 0.004) and in patients with ≥ two comorbidities (OR 4.68, CI 1.5 to 14.61; p = 0.008). Length of stay was also extended in the COVID-19 cohort, on average spending 17.6 days as an inpatient versus 12.04 days in the non-COVID-19 group (p < 0.001)., Conclusion: This study demonstrates that patients who sustain a neck of femur fracture in combination with COVID-19 diagnosis have a significantly higher risk of mortality than would be normally expected.Cite this article: Bone Joint Open 2020;1-11:697-705., (© 2020 Author(s) et al.)

Colorectal cancer (CRC) is characterized by complex interplay between macroenvironmental factors and tumour microenvironment, leading to variable outcomes in CRC patients. To date, there is still a need to identify macroenvironment/microenvironment factors that could define subgroup of patients that would benefit from specific anti-cancer treatment in order to improve patient selection for individualized targeted-based therapy. Aim of this study was to evaluate associations between metabolic parameters and KRAS status in metastatic CRC (mCRC) according to a new tumour site classification. Retrospective data were extracted from a total of 201 patients diagnosed with mCRC between 2012 and 2017 extracted from an established CRC database at our tertiary institute. Clinical-pathological data, including age, gender, BMI, hypertension, diabetes, pre-CRC diagnosis serum lipid levels and KRAS status were recorded. Categorical characteristics were compared using chi-squared test. Continuous characteristics were compared using Mann-Whitney U test. Log rank test was used to compare hazards for survival. In all comparisons, a two-sided P value <0.05 was considered statistically significant. Out of 201 patients, 170 patients with complete serum lipid profile were included in the analysis. In recto-sigmoid cancers there was a statistically significant association between high cholesterol:high-density lipoprotein (chol:HDL) ratio and KRAS mutation (OR 2.69, 95% CI 1.1-6.4, p = 0,02). In non recto-sigmoid cancers, high cholesterol was associated with KRAS WT (OR 0.39, CI 0.15-0.97, p = 0.04). In 22 patients with KRAS mutated recto-sigmoid cancer stage IV at diagnosis normal chol:HDL ratio was associated with a trend to better survival (p = 0.06). High chol:HDL ratio was significantly associated with KRAS mutated metastatic recto-sigmoid cancers. A subgroup of mCRC patients with KRAS mutated recto-sigmoid cancer may benefit from optimal lipid lowering treatment.

Aim: To identify participant, course characteristics and centre factors associated with participant satisfaction and ALS outcomes., Methods: 17,690 participants enrolled on ALS courses between 1st December 2017 and 30th November 2018. Participant, course and centre characteristics were explored in relation to course learning outcomes and participant experience. Learning outcomes were assessed through a post-course MCQ score and technical and non-technical skills through a cardiac arrest simulation test (CAS-Test). Successful completion of knowledge and skill-based assessments led to overall course success. Participant feedback was collected on a post-course questionnaire. Multivariable analyses identified variables associated with course outcomes and feedback. Adjusted funnel plots compared inter-course centre outcomes., Results: Mean post-course MCQ score was 86.7% (SD = 6.7). First attempt CAS-Test pass rate was 82.6% and overall course pass rate 94.4%. Participant characteristics explained the majority of variation between course centres. Characteristics associated with knowledge, skill and course outcomes were age, prior experience, pre-course MCQ score, course type, ethnicity, place of work, profession and seniority. Feedback scores were predicted by course type, pre-course MCQ, ethnicity, profession and seniority., Conclusion: This is the first study to identify variables associated with both ALS feedback scores and assessment outcomes. It has demonstrated that both course outcomes and participant experience are similar across a large number of course centres. Identifying the demographic traits of participants who may struggle with ALS, may enable bespoke support from an earlier stage. Analysis of feedback scores and outcomes enables ongoing appraisal and targeted improvement of the Resuscitation Council UK ALS course., (Copyright © 2020 Elsevier B.V. All rights reserved.)

In personalized medicine, it is often desired to determine if all patients or only a subset of them benefit from a treatment. We consider estimation in two-stage adaptive designs that in stage 1 recruit patients from the full population. In stage 2, patient recruitment is restricted to the part of the population, which, based on stage 1 data, benefits from the experimental treatment. Existing estimators, which adjust for using stage 1 data for selecting the part of the population from which stage 2 patients are recruited, as well as for the confirmatory analysis after stage 2, do not consider time to event patient outcomes. In this work, for time to event data, we have derived a new asymptotically unbiased estimator for the log hazard ratio and a new interval estimator with good coverage probabilities and probabilities that the upper bounds are below the true values. The estimators are appropriate for several selection rules that are based on a single or multiple biomarkers, which can be categorical or continuous., (© 2020 The Authors. Statistics in Medicine published by John Wiley & Sons, Ltd.)

The COVID-19 pandemic has led to an unprecedented response in terms of clinical research activity. An important part of this research has been focused on randomized controlled clinical trials to evaluate potential therapies for COVID-19. The results from this research need to be obtained as rapidly as possible. This presents a number of challenges associated with considerable uncertainty over the natural history of the disease and the number and characteristics of patients affected, and the emergence of new potential therapies. These challenges make adaptive designs for clinical trials a particularly attractive option. Such designs allow a trial to be modified on the basis of interim analysis data or stopped as soon as sufficiently strong evidence has been observed to answer the research question, without compromising the trial's scientific validity or integrity. In this article, we describe some of the adaptive design approaches that are available and discuss particular issues and challenges associated with their use in the pandemic setting. Our discussion is illustrated by details of four ongoing COVID-19 trials that have used adaptive designs., Competing Interests: Martin Posch reports grants from Novartis Pharma AG, grants from Mediconomics GmbH, grants from Merck KGaA, grants from Abbott Laboratories, grants from Almirall, outside the submitted work. He is also a member of the IMI Project Consortium EU-PEARL., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Objective: Low-potassium diets are recommended to reduce serum potassium (Sk) and prevent complications of chronic kidney disease (CKD), but evidence underpinning this recommendation has not been systematically reviewed and synthesized. We conducted a systematic review comparing change in Sk, CKD progression, and mortality between those on a low-potassium versus unrestricted potassium diet., Methods: We searched Medline, AMED, PsycINFO, CINAHL, Cochrane Central Register of Controlled Trials, and Clinicaltrials.org from inception to 3 April 2018. We included randomized and observational studies that compared these outcomes in adults with CKD who ate a restricted versus unrestricted amount of dietary potassium. We pooled mean change in Sk and adjusted hazard ratios of disease progression and mortality using random-effects meta-analyses., Results: We identified 5,563 articles, of which seven studies (3,489 participants) met our inclusion criteria. We found very low-quality evidence that restricted (1,295 mg/d) versus unrestricted (1,570 mg/d) dietary potassium lowered Sk by -0.22 mEq/L (95% confidence interval [CI]: -0.33, -0.10; I 2  = 0%). Lower (1,725 mg/d) versus higher (4,558 mg/d) dietary potassium was not significantly associated with disease progression (hazard ratio [HR]: 1.14; 95% CI: 0.77, 1.70; I 2  = 57%). Lower (1,670 mg/d), compared with higher (4,414 mg/d) dietary potassium intake was associated with a 40% reduction in mortality hazard (HR: 0.60; 95% CI: 0.40, 0.89; I 2  = 56%)., Conclusions: Very-low-quality evidence supports consensus that dietary potassium restriction reduces Sk in normokalemia and is associated with a reduced risk of death in those with CKD. High-quality randomized controlled trials are needed., (Copyright © 2019 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)

Background: Obstructive sleep apnoea (OSA) and polycystic ovary syndrome (PCOS) are associated with significant comorbidities and commonly coexist. The primary aim of this study was to examine the relationship between OSA and quality of life (QoL) in women with PCOS., Methods: We conducted an observational cross-sectional study. PCOS was diagnosed according to the Rotterdam criteria. Women with increased risk of OSA, based on the Berlin questionnaire or the Epworth Sleepiness Scale (ESS), had home-based polysomnography performed (ALICE PDx). Participants were divided into two groups: (a) PCOS only: women with normal ESS and low-risk Berlin questionnaire (no sleep studies performed), or women with normal sleep studies [oxygen desaturation index (ODI) < 5 events/hour]; and (b) PCOS+OSA: women with PCOS and OSA ODI ⩾ 5. QoL was assessed using the World Health Organization QoL questionnaire (WHOQOL-BREF) and the PCOS health-related quality of life questionnaire (PCOSQ)., Results: A total of 39 women were included; age (mean ± SD) was 32.2 ± 8.9 years, weight 92.5 ± 23.7 kg and body mass index (BMI) 34.1 ± 7.9 kg/m 2 ; 38.5% ( n  = 15) had OSA. Compared with women with PCOS only, women with PCOS+OSA had higher BMI, HbA1c, C-reactive protein and low-density lipoprotein. ODI was independently associated with impaired QoL. Excessive daytime sleepiness (EDS) was independently associated with anxiety, depression and impaired QoL., Conclusions: OSA is highly prevalent and is associated with impaired QoL and worse metabolic profile in women with PCOS. Interventional studies are needed to examine the impact of OSA in women with PCOS., Clinicaltrialsgov Identifier: NCT03065322., Competing Interests: Conflict of interest statement: The authors declare the following conflicts of interest: AAT is a Clinician Scientist supported by the National Institute for Health Research (NIHR). NIHR Clinical Lectureship supported HK. The views expressed in this publication are those of the authors and not necessarily those of the NHS, the National Institute for Health Research or the Department of Health., (© The Author(s), 2020.)

Background: Recurrent pregnancy loss (RPL) is associated with the loss of endometrial mesenchymal stem-like progenitor cells (eMSC). DPP4 inhibitors may increase homing and engraftment of bone marrow-derived cells to sites of tissue injury. Here, we evaluated the effect of the DPP4 inhibitor sitagliptin on eMSC in women with RPL, determined the impact on endometrial decidualization, and assessed the feasibility of a full-scale clinical trial., Methods: A double-blind, randomised, placebo-controlled feasibility trial on women aged 18 to 42 years with a history of 3 or more miscarriages, regular menstrual cycles, and no contraindications to sitagliptin. Thirty-eight subjects were randomised to either 100 mg sitagliptin daily for 3 consecutive cycles or identical placebo capsules. Computer generated, permuted block randomisation was used to allocate treatment packs. Colony forming unit (CFU) assays were used to quantify eMSC in midluteal endometrial biopsies. The primary outcome measure was CFU counts. Secondary outcome measures were endometrial thickness, study acceptability, and first pregnancy outcome within 12 months following the study. Tissue samples were subjected to explorative investigations., Findings: CFU counts following sitagliptin were higher compared to placebo only when adjusted for baseline CFU counts and age (RR: 1.52, 95% CI: 1.32-1.75, P<0.01). The change in CFU count was 1.68 in the sitagliptin group and 1.08 in the placebo group. Trial recruitment, acceptability, and drug compliance were high. There were no serious adverse events. Explorative investigations showed that sitagliptin inhibits the expression of DIO2, a marker gene of senescent decidual cells., Interpretation: Sitagliptin increases eMSCs and decreases decidual senescence. A large-scale clinical trial evaluating the impact of preconception sitagliptin treatment on pregnancy outcome in RPL is feasible and warranted., Funding: Tommy's Baby Charity., Clinical Trial Registration: EU Clinical Trials Register no. 2016-001120-54., Competing Interests: Declaration of competing interest Dr Brosens reports grants from Tommy's Baby Charity, grants from Juntendo University, Japan, during the conduct of the study. In addition, Dr Brosens has filed a UKIPO patent application (no.1911947.8) pertaining to the use of SCARA5 and DIO2 as endometrial biomarkers to assess the risk of miscarriage. Dr Quenby reports grants from Tommy's baby Charity, during the conduct of the study. The other authors have nothing to disclose., (Crown Copyright © 2019. Published by Elsevier B.V. All rights reserved.)

Background: Acute mountain sickness (AMS) is a cluster of symptoms that commonly occur in those ascending to high altitudes. Symptoms can include headaches, nausea, insomnia and fatigue. Exposure to high altitude can also lead to high-altitude cerebral oedema (HACE), which is a potential cause of death whilst mountaineering. Generally, AMS precedes the development of HACE. Historical studies have demonstrated the effectiveness of regular dexamethasone administration in reducing the symptoms of AMS. However, the mechanism by which dexamethasone works to reduce symptoms AMS remains poorly understood. Further studies, simulating altitude using hypoxic tents, have characterised the effect of prolonged exposure to normobaric hypoxia on cerebral oedema and blood flow using MRI. This randomised trial assesses the effect of dexamethasone on hypoxia-induced cerebral oedema in healthy adult volunteers., Methods/design: D4H is a double-blind placebo-controlled randomised trial assessing the effect of dexamethasone on hypoxia-induced cerebral oedema. In total, 20 volunteers were randomised in pairs to receive either 8.25 mg dexamethasone or normal saline placebo intravenously after 8 h of hypoxia with an FiO 2 of 12%. Serial MRI images of the brain and spinal cord were obtained at hours 0, 7, 11, 22 and 26 of the study along with serum and urinary markers to correlate with the severity of cerebral oedema and the effect of the intervention., Discussion: MRI has been used to identify changes in cerebral vasculature in the development of AMS and HACE. Dexamethasone is effective at reducing the symptoms of AMS; however, the mechanism of this effect is unknown. If this study demonstrates a clear objective benefit of dexamethasone in this setting, future studies may be able to demonstrate that dexamethasone is an effective therapy for oedema associated with brain and spinal cord ischaemia beyond AMS., Trial Registration: Clinicaltrials.gov, NCT03341676 . Registered on 14 November 2017.

Background: Prehospital recognition of sepsis may inform case management by ambulance clinicians, as well as inform transport decisions. The objective of this study was to develop a prehospital sepsis screening tool for use by ambulance clinicians., Methods: We derived and validated a sepsis screening tool, utilising univariable logistic regression models to identify predictors for inclusion, and multivariable logistic regression to generate the SEPSIS score. We utilised a retrospective cohort of adult patients transported by ambulance (n = 38483) to hospital between 01 July 2013 and 30 June 2014. Records were linked using LinkPlus® software. Successful linkage was achieved in 33289 cases (86%). Eligible patients included adult, non-trauma, non-mental health, non-cardiac arrest cases. Of 33289 linked cases, 22945 cases were eligible. Eligible cases were divided into derivation (n = 16063, 70%) and validation (n = 6882, 30%) cohorts. The primary outcome measure was high risk of severe illness or death from sepsis, as defined by the National Institute for Health and Care Excellence Sepsis guideline., Results: 'High risk of severe illness or death from sepsis' was present in 3.7% of derivation (n = 593) and validation (n = 254) cohorts. The SEPSIS score comprises the following variables: age, respiratory rate, peripheral oxygen saturations, heart rate, systolic blood pressure, temperature and level of consciousness (p < 0.001 for all variables). Area under the curve was 0.87 (95%CI 0.85-0.88) for the derivation cohort, and 0.86 (95%CI 0.84-0.88) for the validation cohort. In an undifferentiated adult medical population, for a SEPSIS score ≥ 5, sensitivity was 0.37 (0.31-0.44), specificity was 0.96 (0.96-0.97), positive predictive value was 0.27 (0.23-0.32), negative predictive value was 0.97 (0.96-0.97), positive likelihood value was 13.5 (9.7-18.73) and the negative likelihood value was 0.83 (0.78-0.88)., Conclusion: This is the first screening tool developed to identify NICE high risk of severe illness or death from sepsis. The SEPSIS score is significantly associated with high risk of severe illness or death from sepsis on arrival at the Emergency Department. It may assist ambulance clinicians to identify those patients with sepsis in need of antibiotic therapy. However, it requires external validation, in clinical practice by ambulance clinicians, in an independent population.

Recently, several study designs incorporating treatment effect assessment in biomarker-based subpopulations have been proposed. Most statistical methodologies for such designs focus on the control of type I error rate and power. In this paper, we have developed point estimators for clinical trials that use the two-stage adaptive enrichment threshold design. The design consists of two stages, where in stage 1, patients are recruited in the full population. Stage 1 outcome data are then used to perform interim analysis to decide whether the trial continues to stage 2 with the full population or a subpopulation. The subpopulation is defined based on one of the candidate threshold values of a numerical predictive biomarker. To estimate treatment effect in the selected subpopulation, we have derived unbiased estimators, shrinkage estimators, and estimators that estimate bias and subtract it from the naive estimate. We have recommended one of the unbiased estimators. However, since none of the estimators dominated in all simulation scenarios based on both bias and mean squared error, an alternative strategy would be to use a hybrid estimator where the estimator used depends on the subpopulation selected. This would require a simulation study of plausible scenarios before the trial., (© 2018 The Authors. Statistics in Medicine Published by John Wiley & Sons Ltd.)

Introduction: Current guidelines recommend abstinence from supervised cardiac rehabilitation (CR) exercise training for 6 weeks post-sternotomy. This practice is not based on empirical evidence, thus imposing potentially unnecessary activity restrictions. Delayed participation in CR exercise training promotes muscle atrophy, reduces cardiovascular fitness and prolongs recovery. Limited data suggest no detrimental effect of beginning CR exercise training as early as 2 weeks post-surgery, but randomised controlled trials are yet to confirm this. The purpose of this trial is to compare CR exercise training commenced early (2 weeks post-surgery) with current usual care (6 weeks post-surgery) with a view to informing future CR guidelines for patients recovering from sternotomy., Methods and Analysis: In this assessor-blind randomised controlled trial, 140 cardiac surgery patients, recovering from sternotomy, will be assigned to 8 weeks of twice-weekly supervised CR exercise training commencing at either 2 weeks (early CR) or 6 weeks (usual care CR) post-surgery. Usual care exercise training will adhere to current UK recommendations. Participants in the early CR group will undertake a highly individualised 2-3 week programme of functional mobility, strength and cardiovascular exercise before progressing to a usual care CR programme. Outcomes will be assessed at baseline (inpatient), pre-CR (2 or 6 weeks post-surgery), post-CR (10 or 14 weeks post-surgery) and 12 months. The primary outcome will be change in 6 min walk distance. Secondary outcomes will include measures of functional fitness, quality of life and cost-effectiveness., Ethics and Dissemination: Recruitment commenced on July 2017 and will complete by December 2019. Results will be disseminated via national governing bodies, scientific meetings and peer-reviewed journals., Trial Registration Number: NCT03223558; Pre-results., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Objectives: To determine the contemporary effectiveness of exercise-based cardiac rehabilitation (CR) in terms of all-cause mortality, cardiovascular mortality and hospital admissions., Data Sources: Studies included in or meeting the entry criteria for the 2016 Cochrane review of exercise-based CR in patients with coronary artery disease., Study Eligibility Criteria: Randomised controlled trials (RCTs) of exercise-based CR versus a no-exercise control whose participants were recruited after the year 2000., Study Appraisal and Synthesis Methods: Two separate reviewers independently screened the characteristics of studies. One reviewer quality appraised any new studies and assessed their risk of bias using the Cochrane Collaboration's recommended risk of bias tool. Data were reported as the risk difference (95% CI)., Results: We included 22 studies with 4834 participants (mean age 59.5 years, 78.4% male). We found no differences in outcomes between exercise-based CR and a no-exercise control at their longest follow-up period for: all-cause mortality (19 studies; n=4194; risk difference 0.00, 95% CI -0.02 to 0.01, P=0.38) or cardiovascular mortality (9 studies; n=1182; risk difference -0.01, 95% CI -0.02 to 0.01, P=0.25). We found a small reduction in hospital admissions of borderline statistical significance (11 studies; n=1768; risk difference -0.05, 95% CI -0.10 to -0.00, P=0.05)., Conclusions and Implications of Key Findings: Our analysis indicates conclusively that the current approach to exercise-based CR has no effect on all-cause mortality or cardiovascular mortality, when compared with a no-exercise control. There may be a small reduction in hospital admissions following exercise-based CR that is unlikely to be clinically important., Prospero Registration Number: CRD42017073616., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aims: To determine patient and health service factors associated with variation in hospital mortality among resuscitated cases of out-of-hospital cardiac arrest (OHCA) with acute coronary syndrome (ACS)., Methods: In this cohort study, we used the Myocardial Ischaemia National Audit Project database to study outcomes in patients hospitalised with resuscitated OHCA due to ACS between 2003 and 2015 in the United Kingdom. We analysed variation in inter-hospital mortality and used hierarchical multivariable regression models to examine the association between patient and health service factors with hospital mortality., Results: We included 17604 patients across 239 hospitals. Overall hospital mortality was 28.7%. In 94 hospitals that contributed at least 60 cases, mortality by hospital ranged from 10.7% to 66.3% (median 28.6%, IQR 23.2% to 39.1%)). Patient and health service factors explained 36.1% of this variation. After adjustment for covariates, factors associated with higher hospital mortality included increasing serum glucose, ST-Elevation myocardial infarction (STEMI) diagnosis, and initial admission to a primary percutaneous coronary intervention (pPCI) capable hospital. Hospital OHCA volume was not associated with mortality. The key modifiable factor associated with lower mortality was early reperfusion therapy in STEMI patients., Conclusion: There was wide variation in inter-hospital mortality following resuscitated OHCA due to ACS that was only partially explained by patient and health service factors. Hospital OHCA volume and pPCI capability were not associated with lower mortality. Early reperfusion therapy was associated with lower mortality in STEMI patients., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Aims: Emergency front of neck access (FONA) is the final step in a Can't Intubate-Can't Oxygenate (CICO) scenario. In view of maintaining simplicity and promoting standardized training, the 2015 Difficult Airway Society guidelines recommend surgical cricothyroidotomy using scalpel, bougie, and tube (SBT) as the preferred technique., Material and Methods: We undertook a survey over a 2-week period to evaluate the knowledge and training, preferred rescue technique, and confidence in performing the SBT technique. Data were collected from both anesthetists and surgeons., Results: One hundred and eighty-nine responses were collected across four hospitals in the United Kingdom. The majority of participants were anesthetists (55%). One hundred and eleven (59%) respondents were aware of the national guidelines (96.2% among anesthetists and 12.9% among surgeons). Only 71 (37.6%) respondents indicated that they had formal FONA training within the last one year. Seventy-five anesthetists (72.8%) knew that SBT equipment was readily available in their department, while most surgeons (81.2%) did not know what equipment available. One hundred and five (55.5%) respondents were confident in performing surgical cricothyroidotomy in a situation where the membrane was palpable and only in 33 (17.5%) where the cricothyroid membrane was not palpable., Conclusion: This survey has demonstrated that despite evidence of good training for anesthetists in FONA, there are still shortfalls in the training and knowledge of our surgical colleagues. In an emergency, surgeons may be required to assist or secure an airway in a CICO situation. Regular multidisciplinary training of all clinicians working with anesthetized patients should be encouraged and supported., Competing Interests: There are no conflicts of interest.

The association of antiretroviral therapy (ART) with diabetes is inconsistent and varies widely across primary epidemiological studies. A comprehensive and more precise estimate of this association is fundamental to establishing a plausible causal link between ART and diabetes. We identified epidemiological studies that compared mean fasting plasma glucose (FPG) concentrations and proportions of diabetes and metabolic syndrome between HIV-infected patients naïve and exposed to ART. Mean difference in FPG concentrations and odds ratios of diabetes and metabolic syndrome were pooled using random-effects meta-analyses. Data on 20 178 participants from 41 observational studies were included in the meta-analyses. Mean FPG concentrations (Pooled mean difference: 4.66 mg/dL; 95% confidence interval [CI], 2.52 to 6.80; 24 studies) and the odds of diabetes (Pooled odds ratios: 3.85; 95% CI, 2.93 to 5.07; 10 studies) and metabolic syndrome (Pooled odds ratios: 1.45; 95% CI, 1.03 to 2.03; 18 studies) were significantly higher among ART-exposed patients, compared to their naïve counterparts. ART was also associated with significant increases in FPG levels in studies with mean ART duration ≥18 months (Pooled mean difference: 4.97 mg/dL; 95% CI, 3.10 to 6.84; 14 studies), but not in studies with mean ART duration <18 months (Pooled mean difference: 4.40 mg/dL, 95% CI, -0.59 to 9.38; 7 studies). ART may potentially be the single most consistent determinant of diabetes in people living with HIV worldwide. However, given the preponderance of cross-sectional studies in the meta-analysis, the association between ART and diabetes cannot be interpreted as cause and effect., (Copyright © 2017 John Wiley & Sons, Ltd.)

Aim: To establish variables which are associated with favourable Advanced Life Support (ALS) course assessment outcomes, maximising learning effect., Method: Between 1 January 2013 and 30 June 2014, 8218 individuals participated in a Resuscitation Council (UK) e-learning Advanced Life Support (e-ALS) course. Participants completed 5-8h of online e-learning prior to attending a one day face-to-face course. e-Learning access data were collected through the Learning Management System (LMS). All participants were assessed by a multiple choice questionnaire (MCQ) before and after the face-to-face aspect alongside a practical cardiac arrest simulation (CAS-Test). Participant demographics and assessment outcomes were analysed., Results: The mean post e-learning MCQ score was 83.7 (SD 7.3) and the mean post-course MCQ score was 87.7 (SD 7.9). The first attempt CAS-Test pass rate was 84.6% and overall pass rate 96.6%. Participants with previous ALS experience, ILS experience, or who were a core member of the resuscitation team performed better in the post-course MCQ, CAS-Test and overall assessment. Median time spent on the e-learning was 5.2h (IQR 3.7-7.1). There was a large range in the degree of access to e-learning content. Increased time spent accessing e-learning had no effect on the overall result (OR 0.98, P=0.367) on simulated learning outcome., Conclusion: Clinical experience through membership of cardiac arrest teams and previous ILS or ALS training were independent predictors of performance on the ALS course whilst time spent accessing e-learning materials did not affect course outcomes. This supports the blended approach to e-ALS which allows participants to tailor their e-learning experience to their specific needs., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Young people (aged 16-24 years) with long-term health conditions can disengage from health services, resulting in poor health outcomes, but clinicians in the UK National Health Service (NHS) are using digital communication to try to improve engagement. Evidence of effectiveness of this digital communication is equivocal. There are gaps in evidence as to how it might work, its cost, and ethical and safety issues., Objective: Our objective was to understand how the use of digital communication between young people with long-term conditions and their NHS specialist clinicians changes engagement of the young people with their health care; and to identify costs and necessary safeguards., Methods: We conducted mixed-methods case studies of 20 NHS specialist clinical teams from across England and Wales and their practice providing care for 13 different long-term physical or mental health conditions. We observed 79 clinical team members and interviewed 165 young people aged 16-24 years with a long-term health condition recruited via case study clinical teams, 173 clinical team members, and 16 information governance specialists from study NHS Trusts. We conducted a thematic analysis of how digital communication works, and analyzed ethics, safety and governance, and annual direct costs., Results: Young people and their clinical teams variously used mobile phone calls, text messages, email, and voice over Internet protocol. Length of clinician use of digital communication varied from 1 to 13 years in 17 case studies, and was being considered in 3. Digital communication enables timely access for young people to the right clinician at the time when it can make a difference to how they manage their health condition. This is valued as an addition to traditional clinic appointments and can engage those otherwise disengaged, particularly at times of change for young people. It can enhance patient autonomy, empowerment and activation. It challenges the nature and boundaries of therapeutic relationships but can improve trust. The clinical teams studied had not themselves formally evaluated the impact of their intervention. Staff time is the main cost driver, but offsetting savings are likely elsewhere in the health service. Risks include increased dependence on clinicians, inadvertent disclosure of confidential information, and communication failures, which are mostly mitigated by young people and clinicians using common-sense approaches., Conclusions: As NHS policy prompts more widespread use of digital communication to improve the health care experience, our findings suggest that benefit is most likely, and harms are mitigated, when digital communication is used with patients who already have a relationship of trust with the clinical team, and where there is identifiable need for patients to have flexible access, such as when transitioning between services, treatments, or lived context. Clinical teams need a proactive approach to ethics, governance, and patient safety., (©Frances Griffiths, Carol Bryce, Jonathan Cave, Melina Dritsaki, Joseph Fraser, Kathryn Hamilton, Caroline Huxley, Agnieszka Ignatowicz, Sung Wook Kim, Peter K Kimani, Jason Madan, Anne-Marie Slowther, Mark Sujan, Jackie Sturt. Originally published in the Journal of Medical Internet Research (http://www.jmir.org), 10.04.2017.)

Background: The transition from association to causation could represent a fundamental step for taking preventive action against hypertension and its complications, especially among HIV-infected persons on antiretroviral therapy in sub-Saharan African countries., Methods: 406 consecutive HIV-infected adults attending a tertiary HIV clinic in semi-urban Nigeria were prospectively recruited between August and November 2014. These participants were stratified by antiretroviral treatment status. A propensity score matching model was fitted to examine the causal average treatment effects on the treated (ATT) of antiretroviral therapy on blood pressure. Propensity score matching entailed using nearest neighbour matching with a calliper width of 0.2 to achieve similarity in the baseline characteristics between participants naïve and exposed to antiretroviral therapy., Results: Matching HIV-infected patients naïve and exposed to antiretroviral therapy on the propensity score yielded a total of 303 participants - 229 antiretroviral-exposed and 74 antiretroviral-naïve - matched without any residual differences in the baseline characteristics between both groups of patients. In this propensity score-matched sample, the estimated ATT for the effects of antiretroviral therapy on systolic (7.85mmHg, 95% CI 3.72 to 15.68) and diastolic blood pressure (7.45mmHg, 95% CI 4.99 to 13.61) were statistically significant (P<0.001 for each)., Conclusions: There is a high probability that the epidemiological association between antiretroviral therapy and increased blood pressure be causal in nature among people living with HIV in sub-Saharan African settings. HIV-infected patients commencing antiretroviral treatment in these settings may require regular hypertension screening and other cardiovascular risk assessments., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Unlabelled: We assessed the proximity of neurological structures to arthroscopic portals in a cadaveric study and through a systematic review. Arthroscopy was performed on ten cadaveric wrists. Subsequently the specimens were dissected to isolate the superficial branch of the radial nerve, the dorsal branch of the ulnar nerve, the posterior interosseous nerve and the extensor tendons. We measured the distances from the nerves to common portals. For the systematic review Pubmed and EMBASE were searched on the 31 May 2014 for cadaveric studies reporting the proximity of neurological structures to any arthroscopic wrist portal. In the cadaveric study, partial injuries were seen to six extensor tendons and one posterior interosseous nerve; it was assumed this was due to creation of the portals. Seven published studies were included in the systematic review. The dorsal sensory branch of the ulnar nerve was found to be at risk by performing the 6 Ulnar, 6 Radial and ulnar midcarpal portals, the sensory branch of the radial nerve by the 1-2 and 3-4 portals and the posterior interosseous nerve by the 3-4 and 4-5 portals., Level of Evidence: V., (© The Author(s) 2016.)

Although more than one in two HIV-infected persons may develop central fat accumulation soon after commencing antiretroviral therapy, the association between antiretroviral therapy and body fat changes has not been consistent across primary epidemiological studies. We conducted a systematic review with meta-analyses to estimate the pooled effects of antiretroviral therapy on different measures of body fat, and to examine factors that potentially modify these effects. We searched for studies that compared body mass index, waist circumference, combined overweight/obesity, and central obesity between HIV-infected adults naive and exposed to antiretroviral therapy. Random-effects subgroup and meta-regression analyses were performed to identify potential effect-modifiers of the pooled associations. Sixty studies, comprising data on 53,199 HIV-infected participants, were eligible for the meta-analyses. Antiretroviral therapy was associated with increased body mass index (SMD: 0.17 kg/m2; 95% CI: 0.07-0.26), waist circumference (SMD: 0.20 cm; 95% CI: 0.07-0.33), overweight/obesity (borderline significance: OR: 1.36; 95% CI: 0.99-1.86), and abdominal obesity (OR: 1.49; 95% CI: 1.16-1.90). In addition, antiretroviral therapy was associated with significant increases in body mass index, overweight/obesity, and central obesity among patients with CD4 counts < 350 cells/mm3, but not among patients with higher CD4 counts (Pinteraction < 0.05 for all). Overall, exposure to antiretroviral therapy was associated with increased risks of generalized and central obesity, and risks may be exacerbated by lower CD4 counts. These findings suggest that weight management and obesity prevention programs may be worth considering as part of routine HIV care.

Background: The 'classical' technique of rapid sequence induction (RSI) of anaesthesia was described in 1970. With the introduction of new drugs and equipment in recent years, a wide variation in this technique has been used. The role of cricoid pressure is controversial because of the lack of scientific evidence. Moreover, gentle mask ventilation has been recommended in situations such as obesity and critically ill patients, to prevent hypoxaemia during the apnoeic period. In identifying multiple techniques, we conducted a national postal survey to establish the current practice of RSI in the UK., Methods: A survey consisting of 17 questions was created and posted to 255 National Health Service (NHS) hospitals in the UK. We included two copies of the questionnaire in each envelope; one to be completed by the airway lead (consultant anaesthetist with responsibility of overseeing the standard of airway training and implementing national airway guidelines and recommendations within their institution) and the other by a trainee in the same department. The difference in responses from consultants and trainees were assessed using the χ(2) test and the Fisher's exact test., Results: In total we received 272 responses (response rate 53%) of which 266 (58% from consultants and 42% from trainees) were analysed. A majority of the respondents (68%) pre-oxygenated by monitoring end-tidal oxygen concentration and 76% of the respondents use 20-25° head up tilt for all RSIs. Propofol is the most commonly used induction agent (64% of all respondents). Opioid has been used by 80% of respondents and only 18% of respondents use suxamethonium for all patients and others choose rocuronium or suxamethonium based on clinical situation. Although 92% of anaesthetists use cricoid pressure, 83% of them never objectively measure the force used. During the apnoeic period 17% of the respondents use gentle mask ventilation., Conclusions: Our survey demonstrated a persistent variation in the practice of RSI amongst the anaesthetists in the UK. The 'classical' technique of RSI is now seldom used. Therefore there is a clear need for developing consistent guidelines for the practice of RSI., (© The Author 2016. Published by Oxford University Press on behalf of the British Journal of Anaesthesia. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: The use of cardiac arrest educational debriefing has been associated with improvements in cardiopulmonary resuscitation (CPR) quality and patient outcome. The practical challenges associated with delivering some debriefing approaches may not be generalisable to the UK health setting. The aim of this study was to evaluate the deliverability and effectiveness of three cardiac arrest debriefing approaches that were tailored to UK working practice., Methods: We undertook a before/after study at three hospital sites. During the post-intervention period of the study, three cardiac arrest educational debriefing models were implemented at study hospitals (one model per hospital). To evaluate the effectiveness of the interventions, CPR quality and patient outcome data were collected from consecutive adult cardiac arrest events attended by the hospital cardiac arrest team. The primary outcome was chest compression depth., Results: Between November 2011 and July 2014, 1198 cardiac arrest events were eligible for study inclusion (782 pre-intervention; 416 post-intervention). The quality of CPR was high at baseline. During the post-intervention period, cardiac arrest debriefing interventions were delivered to 191 clinicians on 344 occasions. Debriefing interventions were deliverable in practice, but were not associated with a clinically important improvement in CPR quality. The interventions had no effect on patient outcome., Conclusion: The delivery of these cardiac arrest educational debriefing strategies was feasible, but did not have a large effect on CPR quality. This may be attributable to the high-quality of CPR being delivered in study hospitals at baseline., Trial Registration: ISRCTN39758339., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Owing to antiretroviral drug-induced endothelial dysfunction, HIV-infected patients on antiretroviral therapy (ART) may have elevated blood pressure. We conducted a systematic review and meta-analysis to estimate the effects of ART on blood pressure levels and hypertension risk among HIV-infected populations worldwide. We sought articles that compared the mean blood pressure measurements and hypertension prevalence between HIV-infected adults naive and exposed to ART. Thirty-nine studies comprising 44 903 participants met the inclusion criteria. Overall, systolic (mean difference (MD) 4.52 mm Hg, 95% confidence interval (CI) 2.65-6.39, I(2)=68.1%, 19 studies) and diastolic blood pressure levels (MD 3.17 mm Hg, 95% CI 1.71-4.64, I(2)=72.5%, 16 studies) were significantly higher among ART-exposed patients compared with treatment-naive patients. Similarly, the risk of hypertension was significantly higher among ART-exposed patients, such that among 28 908 ART-exposed patients, 4195 (14.5%) had hypertension compared with 950 of 9086 (10.5%) in those who were treatment-naive (odds ratio 1.68, 95% CI 1.35-2.10, I(2)=81.5%, 32 studies). In summary, exposure to ART is significantly associated with increased systolic and diastolic blood pressure levels, and increased risk of hypertension, regardless of study-level sociodemographic differences. This meta-analysis supports the need for population-based strategies to reduce the risk of high blood pressure among people living with HIV on ART.

Aims: Digital pathology (DP) offers advantages over glass slide microscopy (GS), but data demonstrating a statistically valid equivalent (i.e. non-inferior) performance of DP against GS are required to permit its use in diagnosis. The aim of this study is to provide evidence of non-inferiority., Methods and Results: Seventeen pathologists re-reported 3017 cases by DP. Of these, 1009 were re-reported by the same pathologist, and 2008 by a different pathologist. Re-examination of 10 138 scanned slides (2.22 terabytes) produced 72 variances between GS and DP reports, including 21 clinically significant variances. Ground truth lay with GS in 12 cases and with DP in nine cases. These results are within the 95% confidence interval for existing intraobserver and interobserver variability, proving that DP is non-inferior to GS. In three cases, the digital platform was deemed to be responsible for the variance, including a gastric biopsy, where Helicobacter pylori only became visible on slides scanned at the ×60 setting, and a bronchial biopsy and penile biopsy, where dysplasia was reported on DP but was not present on GS., Conclusions: This is one of the largest studies proving that DP is equivalent to GS for the diagnosis of histopathology specimens. Error rates are similar in both platforms, although some problems e.g. detection of bacteria, are predictable., (© 2015 The Authors. Histopathology published by John Wiley & Sons Ltd.)

Background: Previous studies of HIV-infected patients have shown significant associations between highly active antiretroviral therapy (HAART) and increased blood pressure; however, the mechanisms involved are less clear. Therefore, we sought to investigate the potential impact of body fat changes in mediating the effects of HAART on blood pressure changes among people living with HIV., Methods: Four hundred six consenting patients (≥18 years of age) attending a tertiary HIV clinic in semi-urban Nigeria were recruited between August and November 2014 as part of a cross-sectional study. We performed bias-corrected bootstrap tests of mediation using 95 % confidence intervals (CI) to determine the mediating effects of body mass index and waist circumference (mediators) on the total effects of HAART exposure (primary predictor) on blood pressure (outcome), while controlling for age, sex and other potential confounders., Results: Waist circumference remained a significant partial mediator of the total effects of HAART exposure on increasing systolic blood pressure (coefficient: 1.01, 95 % CI: 0.33 to 2.52, 11 % mediated) and diastolic blood pressure (coefficient: 0.68, 95 % CI: 0.26 to 1.89, 9 % mediated) after adjusting for age, sex, smoking status, CD4 count and duration of HIV infection. No significant mediating effect was observed with body mass index alone or in combination with waist circumference after adjusting for all potential confounders., Conclusion: Waist circumference significantly mediates the effects of HAART on blood pressure in persons living with HIV, independent of the role of traditional risk factors. The use of waist circumference as a complementary body fat measure to body mass index may improve the clinical prediction of hypertension in HIV-infected patients on antiretroviral therapy.

Background: Studies have shown that blended approaches combining e-learning with face-to-face training reduces costs whilst maintaining similar learning outcomes. The preferences in learning approach for healthcare providers to this new style of learning have not been comprehensively studied. The aim of this study is to evaluate the acceptability of blended learning to advanced resuscitation training., Methods: Participants taking part in the traditional and blended electronic advanced life support (e-ALS) courses were invited to complete a written evaluation of the course. Participants' views were captured on a 6-point Likert scale and in free text written comments covering the content, delivery and organisation of the course. Proportional-odds cumulative logit models were used to compare quantitative responses. Thematic analysis was used to synthesise qualitative feedback., Results: 2848 participants from 31 course centres took part in the study (2008-2010). Candidates consistently scored content delivered face-to-face over the same content delivered over the e-learning platform. Candidates valued practical hands on training which included simulation highly. Within the e-ALS group, a common theme was a feeling of "time pressure" and they "preferred the face-to-face teaching". However, others felt that e-ALS "suited their learning style", was "good for those recertifying", and allowed candidates to "use the learning materials at their own pace"., Conclusions: The e-ALS course was well received by most, but not all participants. The majority felt the e-learning module was beneficial. There was universal agreement that the face-to-face training was invaluable. Individual learning styles of the candidates affected their reaction to the course materials., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Objective: To evaluate the effect of implementing real-time audiovisual feedback with and without postevent debriefing on survival and quality of cardiopulmonary resuscitation quality at in-hospital cardiac arrest., Design: A two-phase, multicentre prospective cohort study., Setting: Three UK hospitals, all part of one National Health Service Acute Trust., Patients: One thousand three hundred and ninety-five adult patients who sustained an in-hospital cardiac arrest at the study hospitals and were treated by hospital emergency teams between November 2009 and May 2013., Interventions: During phase 1, quality of cardiopulmonary resuscitation and patient outcomes were measured with no intervention implemented. During phase 2, staff at hospital 1 received real-time audiovisual feedback, whereas staff at hospital 2 received real-time audiovisual feedback supplemented by postevent debriefing. No intervention was implemented at hospital 3 during phase 2., Measurements and Main Results: The primary outcome was return of spontaneous circulation. Secondary endpoints included other patient-focused outcomes, such as survival to hospital discharge, and process-focused outcomes, such as chest compression depth. Random-effect logistic and linear regression models, adjusted for baseline patient characteristics, were used to analyze the effect of the interventions on study outcomes. In comparison with no intervention, neither real-time audiovisual feedback (adjusted odds ratio, 0.62; 95% CI, 0.31-1.22; p=0.17) nor real-time audiovisual feedback supplemented by postevent debriefing (adjusted odds ratio, 0.65; 95% CI, 0.35-1.21; p=0.17) was associated with a statistically significant improvement in return of spontaneous circulation or any process-focused outcome. Despite this, there was evidence of a system-wide improvement in phase 2, leading to improvements in return of spontaneous circulation (adjusted odds ratio, 1.87; 95% CI, 1.06-3.30; p=0.03) and process-focused outcomes., Conclusions: Implementation of real-time audiovisual feedback with or without postevent debriefing did not lead to a measured improvement in patient or process-focused outcomes at individual hospital sites. However, there was an unexplained system-wide improvement in return of spontaneous circulation and process-focused outcomes during the second phase of the study.

During the development of new therapies, it is not uncommon to test whether a new treatment works better than the existing treatment for all patients who suffer from a condition (full population) or for a subset of the full population (subpopulation). One approach that may be used for this objective is to have two separate trials, where in the first trial, data are collected to determine if the new treatment benefits the full population or the subpopulation. The second trial is a confirmatory trial to test the new treatment in the population selected in the first trial. In this paper, we consider the more efficient two-stage adaptive seamless designs (ASDs), where in stage 1, data are collected to select the population to test in stage 2. In stage 2, additional data are collected to perform confirmatory analysis for the selected population. Unlike the approach that uses two separate trials, for ASDs, stage 1 data are also used in the confirmatory analysis. Although ASDs are efficient, using stage 1 data both for selection and confirmatory analysis introduces selection bias and consequently statistical challenges in making inference. We will focus on point estimation for such trials. In this paper, we describe the extent of bias for estimators that ignore multiple hypotheses and selecting the population that is most likely to give positive trial results based on observed stage 1 data. We then derive conditionally unbiased estimators and examine their mean squared errors for different scenarios., (©2015 The Authors. Statistics in Medicine Published by JohnWiley & Sons Ltd.)