Some common, fatal flaws in systematic reviews of observational studies.

When evidence from randomized controlled trials about the effectiveness and safety of an intervention is unclear, researchers may choose to review the nonrandomized evidence. All systematic reviews pose considerable challenges, and the level of methodological expertise required to undertake a useful review of nonrandomized intervention studies is both high and often severely underestimated. Using the example of the endometrial receptivity array, we review some common, critical flaws in systematic reviews of this nature, including errors in critical appraisal and meta-analysis.

Gynecological trials frequently exclude people based on their symptoms rather than their condition: a systematic review of Cochrane reviews and their component trials.

OBJECTIVES: To identify strategies used in recent randomized controlled trials (RCTs) and their associated Cochrane Reviews where patients with the same gynecological condition present with different symptoms but would plausibly benefit from a common intervention. STUDY DESIGN AND SETTING: We searched the Cochrane library (February 2022) for reviews in polycystic ovarian syndrome (PCOS) and endometriosis. Reviews were included if the intervention was intended to treat all condition-specific symptoms. For each trial we recorded the strategy used and the number of potentially eligible participants excluded as a direct result of the chosen strategy. For each review we recorded the numbers of RCTs and participants excluded on the basis of symptoms experienced. RESULTS: There were 89 distinct PCOS trials in 13 reviews, and 13 Endometriosis trials in 11 reviews. Most trials restricted their eligibility to participants with specific symptoms (55% PCOS, 46% endometriosis). The second most common strategy was to measure and analyze clinical outcomes that were not relevant to all participants (38% PCOS, 31% endometriosis). Reviews excluded 27% of trials in participants evaluating the same intervention in participants experiencing the same condition based on the outcomes measured in the trials. CONCLUSION: Most gynecological trials exclude patients who could benefit from treatment or measure outcomes not relevant to all participants. We introduce a taxonomy to describe trial design strategies for conditions with heterogeneous symptoms.

Phase II randomised, placebo-controlled, clinical trial of interleukin-1 receptor antagonist in intracerebral haemorrhage: BLOcking the Cytokine IL-1 in ICH (BLOC-ICH).

PURPOSE: Recombinant human interleukin-1 receptor antagonist (anakinra) is an anti-inflammatory with efficacy in animal models of stroke. We tested the effect of anakinra on perihaematomal oedema in acute intracerebral haemorrhage (ICH) and explored effects on inflammatory markers. METHODS: We conducted a multicentre, randomised, double-blind, placebo-controlled trial in patients with acute, spontaneous, supratentorial ICH between May 2019 and February 2021. Patients were randomised to 100 mg subcutaneous anakinra within 8 h of onset, followed by five, 12-hourly, 100 mg subcutaneous injections, or matched placebo. Primary outcome was oedema extension distance (OED) on a 72 h CT scan. Secondary outcomes included plasma C-reactive protein (CRP) and interleukin-6 (IL-6). FINDINGS: 25 patients (target = 80) were recruited, 14 randomised to anakinra, 11 to placebo. Mean age was 67 and 52% were male. The anakinra group had higher median baseline ICH volume (12.6 ml, interquartile range[IQR]:4.8-17.9) versus placebo (5.5 ml, IQR:2.1-10.9). Adjusting for baseline, 72 h OED was not significantly different between groups (mean difference OED anakinra vs placebo -0.05 cm, 95% confidence interval [CI]: -0.17-0.06, p = 0.336). There was no significant difference in area-under-the-curve to Day 4 for IL-6 and CRP, but a post-hoc analysis demonstrated IL-6 was 56% (95% CI: 2%-80%) lower at Day 2 with anakinra. There were 10 and 2 serious adverse events in anakinra and placebo groups, respectively, none attributed to anakinra. CONCLUSION: We describe feasibility for delivering anakinra in acute ICH and provide preliminary safety data. We lacked power to test for effects on oedema thus further trials will be required.

A study of prisms and therapy in attention loss after stroke (SPATIAL): A feasibility randomised controlled trial.

OBJECTIVE: Investigate feasibility and acceptability of prism adaptation training for people with inattention (spatial neglect), early after stroke, during usual care. DESIGN: Phase II feasibility randomised controlled trial with 3:1 stratified allocation to standard occupational therapy with or without intervention, and nested process evaluation. SETTING: Ten hospital sites providing in-patient stroke services. PARTICIPANTS: Screened positive for inattention more than one-week post-stroke; informal carers. Occupational therapists participated in qualitative interviews. INTERVENTION: Adjunctive prism adaptation training at the start of standard occupational therapy sessions for three weeks. MAIN MEASURES: Feasibility measures included recruitment and retention rates, intervention fidelity and attrition. Outcomes collected at baseline, 3 weeks and 12 weeks tested measures including Nottingham Extended Activities of Daily Living Scale. Acceptability was explored through qualitative interviews and structured questions. RESULTS: Eighty (31%) patients were eligible, 57 (71%) consented, 54 randomised (40:13, +1 exclusion) and 39 (74%) completed 12-week outcomes. Treatment fidelity was good: participants received median eight intervention sessions (IQR: 5, 12) lasting 4.7 min (IQR: 4.1, 5.0). All six serious adverse events were unrelated. There was no signal that patients allocated to intervention did better than controls. Twenty five of 35 recruited carers provided outcomes with excellent data completeness. Therapists, patients and carers found prism adaptation training acceptable. CONCLUSIONS: It is feasible and acceptable to conduct a high-quality definitive trial of prism adaptation training within occupational therapy early after stroke in usual care setting, but difficult to justify given no sign of benefit over standard occupational therapy. CLINICAL TRIAL REGISTRATION: https://www.isrctn.com/ Ref ISRCTN88395268.

Occupational differences in SARS-CoV-2 infection: analysis of the UK ONS COVID-19 infection survey.

BACKGROUND: Concern remains about how occupational SARS-CoV-2 risk has evolved during the COVID-19 pandemic. We aimed to ascertain occupations with the greatest risk of SARS-CoV-2 infection and explore how relative differences varied over the pandemic. METHODS: Analysis of cohort data from the UK Office of National Statistics COVID-19 Infection Survey from April 2020 to November 2021. This survey is designed to be representative of the UK population and uses regular PCR testing. Cox and multilevel logistic regression were used to compare SARS-CoV-2 infection between occupational/sector groups, overall and by four time periods with interactions, adjusted for age, sex, ethnicity, deprivation, region, household size, urban/rural neighbourhood and current health conditions. RESULTS: Based on 3 910 311 observations (visits) from 312 304 working age adults, elevated risks of infection can be seen overall for social care (HR 1.14; 95% CI 1.04 to 1.24), education (HR 1.31; 95% CI 1.23 to 1.39), bus and coach drivers (1.43; 95% CI 1.03 to 1.97) and police and protective services (HR 1.45; 95% CI 1.29 to 1.62) when compared with non-essential workers. By time period, relative differences were more pronounced early in the pandemic. For healthcare elevated odds in the early waves switched to a reduction in the later stages. Education saw raises after the initial lockdown and this has persisted. Adjustment for covariates made very little difference to effect estimates. CONCLUSIONS: Elevated risks among healthcare workers have diminished over time but education workers have had persistently higher risks. Long-term mitigation measures in certain workplaces may be warranted.

Surgical Outcome Measures in a Cohort of Patients at High Risk of Breast Cancer Treated by Bilateral Risk-Reducing Mastectomy and Breast Reconstruction.

BACKGROUND: Women with breast cancer-related genetic pathogenic variants (e.g., BRCA1 , BRCA2 ) or with a strong family history carry lifetime risks of developing breast cancer of up to 80 to 90 percent. A significant proportion of these women proceed to bilateral risk-reducing mastectomy. The authors aimed to document the surgical morbidity of risk-reducing mastectomy and establish whether a diagnosis of breast cancer at the time of surgery impacted outcomes. METHODS: Clinical details of 445 women identified as having a greater than 25 percent lifetime risk of developing breast cancer who underwent risk-reducing mastectomy and breast reconstruction were interrogated for surgical outcomes such as planned, unplanned, and emergency procedures; complication rates; length of stay; and longevity of breast reconstruction. These outcome measures were recorded in women diagnosed with breast cancer perioperatively (cancer group) and those without malignancy (benign group). RESULTS: Median follow-up was similar in both groups (benign group, 70 months; cancer group, 73 months). Patients were older in the cancer group than in the benign group (43 years versus 39 years; p < 0.001). Women in the cancer group required more planned procedures to complete reconstruction than those in the benign group (four versus two; p = 0.002). Emergency procedures, unplanned surgical interventions (e.g., capsulectomy), and postreconstruction complication rates were similar between groups. One in five women overall required revision surgery. Patients with autologous reconstructions had a revision rate of 1.24 per 1000 person-years compared with 2.52 per 1000 person-years in the implant reconstruction group. CONCLUSIONS: Women contemplating risk-reducing mastectomy can be reassured that this is a safe and effective procedure but will likely take multiple interventions. This knowledge should be integral to obtaining informed consent. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Workplace interventions to reduce the risk of SARS-CoV-2 infection outside of healthcare settings.

BACKGROUND: Although many people infected with SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) experience no or mild symptoms, some individuals can develop severe illness and may die, particularly older people and those with underlying medical problems. Providing evidence-based interventions to prevent SARS-CoV-2 infection has become more urgent with the spread of more infectious SARS-CoV-2 variants of concern (VoC), and the potential psychological toll imposed by the coronavirus disease 2019 (COVID-19) pandemic.   Controlling exposures to occupational hazards is the fundamental method of protecting workers. When it comes to the transmission of viruses, such as SARS-CoV-2, workplaces should first consider control measures that can potentially have the most significant impact. According to the hierarchy of controls, one should first consider elimination (and substitution), then engineering controls, administrative controls, and lastly, personal protective equipment (PPE). OBJECTIVES: To assess the benefits and harms of interventions in non-healthcare-related workplaces to reduce the risk of SARS-CoV-2 infection relative to other interventions, or no intervention. SEARCH METHODS: We searched MEDLINE, Embase, Web of Science, Cochrane COVID-19 Study Register, the Canadian Centre for Occupational Health and Safety (CCOHS), Clinicaltrials.gov, and the International Clinical Trials Registry Platform to 14 September 2021. We will conduct an update of this review in six months. SELECTION CRITERIA: We included randomised control trials (RCT) and planned to include non-randomised studies of interventions. We included adult workers, both those who come into close contact with clients or customers (e.g. public-facing employees, such as cashiers or taxi drivers), and those who do not, but who could be infected by co-workers. We excluded studies involving healthcare workers. We included any intervention to prevent or reduce workers' exposure to SARS-CoV-2 in the workplace, defining categories of intervention according to the hierarchy of hazard controls, i.e. elimination; engineering controls; administrative controls; personal protective equipment. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were incidence rate of SARS-CoV-2 infection (or other respiratory viruses), SARS-CoV-2-related mortality, adverse events, and absenteeism from work. Our secondary outcomes were all-cause mortality, quality of life, hospitalisation, and uptake, acceptability, or adherence to strategies. We used the Cochrane RoB 2 tool to assess the risk of bias, and GRADE methods to assess the certainty of evidence for each outcome. MAIN RESULTS: Elimination of exposure interventions We included one study examining an intervention that focused on elimination of hazards. This study is an open-label, cluster-randomised, non-inferiority trial, conducted in England in 2021. The study compared standard 10-day self-isolation after contact with an infected person to a new strategy of daily rapid antigen testing and staying at work if the test is negative (test-based attendance). The trialists hypothesised that this would lead to a similar rate of infections, but lower COVID-related absence. Staff (N = 11,798) working at 76 schools were assigned to standard isolation, and staff (N = 12,229) at 86 schools to the test-based attendance strategy.  The results between test-based attendance and standard 10-day self-isolation were inconclusive for the rate of symptomatic PCR-positive SARS-COV-2 infection rate ratio ((RR) 1.28, 95% confidence interval (CI) 0.74 to 2.21; 1 study, very low-certainty evidence)). The results between test-based attendance and standard 10-day self-isolation were inconclusive for the rate of any PCR-positive SARS-COV-2 infection (RR 1.35, 95% CI 0.82 to 2.21; 1 study, very low-certainty evidence). COVID-related absenteeism rates were 3704 absence days in 566,502 days-at-risk (6.5 per 1000 days at risk) in the control group and 2932 per 539,805 days-at-risk (5.4 per 1000 days at risk) in the intervention group (RR 0.83; 95% CI 0.55 to 1.25). The certainty of the evidence was downgraded to low, due to imprecision. Uptake of the intervention was 71 % in the intervention group, but not reported for the control intervention.  The trial did not measure other outcomes, SARS-CoV-2-related mortality, adverse events, all-cause mortality, quality of life, and hospitalisation. We found one ongoing RCT about screening in schools, using elimination of hazard strategies. Personal protective equipment We found one ongoing non-randomised study on the effects of closed face shields to prevent COVID-19 transmission. Other intervention categories We did not find studies in the other intervention categories. AUTHORS' CONCLUSIONS: We are uncertain whether a test-based attendance policy affects rates of PCR-postive SARS-CoV-2 infection (any infection; symptomatic infection) compared to standard 10-day self-isolation amongst school and college staff. Test-based attendance policy may result in little to no difference in absence rates compared to standard 10-day self-isolation. As a large part of the population is exposed in the case of a pandemic, an apparently small relative effect that would not be worthwhile from the individual perspective may still affect many people, and thus, become an important absolute effect from the enterprise or societal perspective.  The included study did not report on any other primary outcomes of our review, i.e. SARS-CoV-2-related mortality and adverse events. No completed studies were identified on any other interventions specified in this review, but two eligible studies are ongoing. More controlled studies are needed on testing and isolation strategies, and working from home, as these have important implications for work organisations.

Comparison of two questionnaires to diagnose obstructive defecation syndrome during pregnancy and post-natally.

INTRODUCTION AND HYPOTHESIS: Obstructive defecation syndrome (ODS) is a common urogynaecology presentation. This study compares two questionnaires, the electronic Personal Assessment Questionnaire (e-PAQ), used in urogynaecology clinics, with the ODS-Score (ODS-S), a simple validated scoring system used in colorectal clinics for diagnosing ODS, to identify patients with an ODS-S cut-off ≥9. METHODS: A total of 221 paired ODS-S and e-PAQ questionnaires were completed; 80 during the second trimester of pregnancy, 73 during the third and 68 post-natally, including women sustaining obstetric anal sphincter injury (OASI). e-PAQ score and ODS-S were compared and Pearson's correlation coefficient calculated. Areas under the curve assessed the diagnostic ability of e-PAQ scores to identify patients with ODS-S of ≥9. RESULTS: The e-PAQ and ODS-S scores showed a positive correlation in the second and third trimesters of pregnancy, post-natally and following OASI. Pearson's correlation coefficient was calculated (0.77; p < 0.001, 0.79; p < 0.001, 0.66; p = 0.001 and 0.79; p < 0.001 respectively). An e-PAQ evacuatory domain score of ≥33 identified women with an ODS score of ≥9 with a sensitivity and specificity of 71% and 94% in the second trimester, 86% and 95% third trimester and 78% and 97% in the OASI group respectively. Area under the curve was >0.90 for all groups. CONCLUSIONS: Comparison of e-PAQ evacuatory domain scores and ODS-S show a strong correlation, with an e-PAQ score of ≥33 promising for identifying women with an ODS score of ≥9, indicating ODS. This study will enable us to identify women during pregnancy and post-natally with ODS for whom early recognition and intervention may be beneficial.

Longitudinal effects of ivacaftor and medicine possession ratio in people with the Gly551Asp mutation: a 5-year study.

INTRODUCTION: Ivacaftor was the first therapy licensed to address the underlying defect in cystic fibrosis (CF). The improvements in lung function, nutritional status and pulmonary exacerbations in patients carrying a Gly551Asp mutation were greater than previously seen in clinical trials for other therapies. Limited data are available regarding long-term outcomes and adherence to ivacaftor outside clinical trials. METHODS: We conducted a 5-year single-centre retrospective study of people with CF carrying the Gly551Asp mutation who received ivacaftor. Clinical outcome data were extracted from medical notes and databases. Drug delivery data were used to assess medicine possession ratio (MPR). RESULTS: 35 people were included. After commencing ivacaftor, FEV1 improved by 9.6% (SE±1.59%) predicted by 6 months. Thereafter, FEV1 declined, and at 5 years had returned to pre-ivacaftor baseline. Ivacaftor did not alter annual rate of FEV1 decline (1.57% pre vs 1.82% post, p=0.74). Body mass index (BMI) increased for 4 years. There was a significant reduction in inpatient and total intravenous antibiotic days sustained over 5 years. MPR remained high but declined over time (-2.5±0.9% per year, p=0.007). FEV1 was better maintained in patients with higher MPRs. CONCLUSION: The addition of ivacaftor provides acute benefits for people with the Gly551Asp mutation and established lung disease. We report a sustained reduction in intravenous antibiotic use but following acute improvement in lung function, decline continues, and patients will continue to require medical observation and optimisation. Strategies to maintain high adherence should be a priority to prolong the benefits of ivacaftor.

Study design flaws and statistical challenges in evaluating fertility treatments.

Health interventions should be tested before being introduced into clinical practice, to find out whether they work and whether they are harmful. However, research studies will only provide reliable answers to these questions if they are appropriately designed and analysed. But these are not trivial tasks. We review some methodological challenges that arise when evaluating fertility interventions and explain the implications for a non-statistical audience. These include flexibility in outcomes and analyses; use of surrogate outcomes instead of live birth; use of inappropriate denominators; evaluating cumulative outcomes and time to live birth; allowing each patient or couple to contribute to a research study more than once. We highlight recurring errors and present solutions. We conclude by highlighting the importance of collaboration between clinical and methodological experts, as well as people with experience of subfertility, for realising high-quality research. LAY SUMMARY: We do research to find out whether fertility treatments are beneficial and to make sure they don't cause harm. However, research will only provide reliable answers if it is done properly. It is not unusual for researchers to make mistakes when they are designing research studies and analysing the data that we get from them. In this review, we describe some of the mistakes people make when they do research about fertility treatments and explain how to avoid them. These include challenges which arise due to the large number of things that can be measured and reported when looking to see if fertility treatments work; failure to check whether the treatment increases the number of live births; failing to include all study participants in calculations;challenges in studies where participants may have more than one treatment attempt. We conclude by highlighting the importance of collaboration between clinical and methodological experts, as well as people with experience of fertility problems.

Occupational differences in COVID-19 incidence, severity, and mortality in the United Kingdom: Available data and framework for analyses.

There are important differences in the risk of SARS-CoV-2 infection and death depending on occupation. Infections in healthcare workers have received the most attention, and there are clearly increased risks for intensive care unit workers who are caring for COVID-19 patients. However, a number of other occupations may also be at an increased risk, particularly those which involve social care or contact with the public. A large number of data sets are available with the potential to assess occupational risks of COVID-19 incidence, severity, or mortality. We are reviewing these data sets as part of the Partnership for Research in Occupational, Transport, Environmental COVID Transmission (PROTECT) initiative, which is part of the National COVID-19 Core Studies. In this report, we review the data sets available (including the key variables on occupation and potential confounders) for examining occupational differences in SARS-CoV-2 infection and COVID-19 incidence, severity and mortality. We also discuss the possible types of analyses of these data sets and the definitions of (occupational) exposure and outcomes. We conclude that none of these data sets are ideal, and all have various strengths and weaknesses. For example, mortality data suffer from problems of coding of COVID-19 deaths, and the deaths (in England and Wales) that have been referred to the coroner are unavailable. On the other hand, testing data is heavily biased in some periods (particularly the first wave) because some occupations (e.g. healthcare workers) were tested more often than the general population. Random population surveys are, in principle, ideal for estimating population prevalence and incidence, but are also affected by non-response. Thus, any analysis of the risks in a particular occupation or sector (e.g. transport), will require a careful analysis and triangulation of findings across the various available data sets.

Non-invasive cardiac stress studies may not offer significant benefit in pre-kidney transplant evaluation: A retrospective cohort study.

BACKGROUND: Screening with cardiac non-invasive stress studies (NISS) prior to listing for kidney transplantation can help in identifying treatable coronary disease and is considered an integral part of pre-kidney transplant evaluation. However, few studies assessed their effectiveness in all patients evaluated for transplantation in clinical practice. To evaluate the role of NISS in pre-kidney transplant evaluation we analyzed their impact prior to waitlisting in 1053 adult CKD-5 patients consecutively evaluated in Greater Manchester, UK during a 6-year period. METHODS: 918 waitlisted patients were grouped based on presence or absence of Diabetes or Cardio-Vascular Disease (CVD): Group-1 (255 DM-/CVD-/NISS-), Group-2 (368 DM-/CVD-/NISS+) and Group-3 (295 with DM or CVD). RESULTS: Group-2 patients had longer 'time-to-listing' (5.5months in Group-1 vs 6.9months in 'Normal-NISS' vs 9.9months in 'Abnormal-NISS', p<0.01) but none with 'Abnormal-NISS' needed coronary revascularization before listing. NISS was followed by revascularization in 8 Group-3 patients (3%). In multi-variate analyses, there was no association of NISS on death or MACE in listed patients. During follow up, Transplantation was the most significant factor associated with improved outcomes in all subgroups (HR:0.97, p<0.001). 135 patients were considered unsuitable for waitlisting, with NISS influencing management in 11 of these patients (8%). CONCLUSIONS: Pre-kidney transplant evaluation with NISS influenced clinical management in 19 of 1053 (2%) patients. Screening with NISS added limited benefit but contributes to significant delays in listing and adding resource implications. Further studies are needed to assess clinical and cost effectiveness of NISS in pretransplant evaluation to optimize outcomes and resources.

Feasibility of Gynaecologist Led Lynch Syndrome Testing in Women with Endometrial Cancer.

A barrier to Lynch syndrome testing is the need for prior genetic counselling, a resource demanding process for both patients and healthcare services. We explored the impact of gynaecologist led Lynch syndrome testing in women with endometrial cancer. Women were approached before surgery, on the day of surgery or during routine follow up. Lynch syndrome testing was offered irrespective of age, family history or tumour characteristics. Women's reasons for being tested were explored using the Motivations and Concerns for GeNEtic Testing (MACGNET) instrument. The short form State-Trait Anxiety Inventory (STAI-6) was used to measure anxiety levels. Only 3/305 women declined Lynch syndrome testing. In total, 175/220 completed MACGNET and STAI-6 psychological instruments. The consent process took an average of 7min 36sec (SD 5min 16sec) to complete. The point of care at which consent was taken (before, day of surgery, during follow up) did not influence motivation for Lynch syndrome testing. Anxiety levels were significantly lower when women were consented during follow up (mean reversed STAI-6 score 32 vs 42, p = 0.001). Anxiety levels were not affected by familial cancer history (p = 0.41). Gynaecologist led Lynch syndrome testing is feasible and may even be desirable in endometrial cancer, especially when offered during routine follow up.

Patient Decision Aids to Facilitate Shared Decision Making in Obstetrics and Gynecology: A Systematic Review and Meta-analysis.

OBJECTIVE: To assess the effectiveness of patient decision aids to facilitate shared decision making in obstetrics and gynecology. DATA SOURCES: We searched ClinicalTrials.gov, MEDLINE, CENTRAL, Cochrane Gynaecology and Fertility specialized register, CINAHL, and EMBASE from 1946 to July 2019. METHODS OF STUDY SELECTION: We selected randomized controlled trials comparing patient decision aids with usual clinical practice or a control intervention. TABULATION, INTEGRATION, AND RESULTS: Thirty-five randomized controlled trials, which reported data from 9,790 women, were included. Patient decision aids were evaluated within a wide range of clinical scenarios relevant to obstetrics and gynecology, including contraception, vaginal birth after cesarean delivery, and pelvic organ prolapse. Study characteristics and quality were recorded for each study. The meta-analysis was based on random-effects methods for pooled data. A standardized mean difference of 0.2 is considered small, 0.5 moderate, and 0.8 large. When compared with usual clinical practice, the use of patient decision aids reduced decisional conflict (standardized mean difference -0.23; 95% CI -0.36, to -0.11; 19 trials; 4,624 women) and improved patient knowledge (standardized mean difference 0.58; 95% CI 0.44 to 0.71; 17 trials; 4,375 women). There was no difference in patient anxiety (standardized mean difference -0.04; 95% CI -0.14 to 0.06; 12 trials; 2,714 women) or satisfaction (standardized mean difference 0.17; 95% CI 0.09 to 0.24; 6 trials; 2,718 women). CONCLUSION: Patient decision aids are effective in facilitating shared decision making and can be helpful in clinical practice to support patient centered care informed by the best evidence. SYSTEMATIC REVIEW REGISTRATION: PROSPERO International Register of Systematic Reviews, www.crd.york.ac.uk/prospero/89953, CRD42018089953.

Baseline Serum HE4 But Not Tissue HE4 Expression Predicts Response to the Levonorgestrel-Releasing Intrauterine System in Atypical Hyperplasia and Early Stage Endometrial Cancer.

The levonorgestrel-releasing intrauterine system (LNG-IUS) is a conservative management option for atypical hyperplasia (AH) and low grade early stage endometrial cancer (EEC), but around 1 in 3 patients fail to respond to treatment. The aim of this study was to investigate if serum and/or tissue HE4 expression could predict response to LNG-IUS therapy. Patients with AH or presumed Stage I EEC had serum and endometrial samples taken at baseline and at 3-month intervals over 12 months post-insertion of LNG-IUS. 74 patients were recruited and baseline demographics recorded. Of 57 patients for whom response was histologically determinable, 39 (68%) were responders and 18 (32%) non-responders. Mean baseline serum HE4 was significantly lower in responders (62.1 ± 1.1 pM, 95% confidence interval (CI) 52.7-73.2), compared to non-responders (125.6 ± 1.3 pM, 95% CI 74.5-211.7, p = 0.014), including when considering age, BMI, menopausal status, smoking status, and histological grade as covariables (p = 0.005). Baseline tissue HE4 expression was not significantly different in responders compared to non-responders (p = 0.999). Responders showed a significant mean reduction (-9.8 ± 3.4%, 95% CI -16.7 to -2.8%, p = 0.008) in serum HE4 between baseline and 3 months (p = 0.008), whereas non-responders showed no significant change (p = 0.676). Neither responders nor non-responders showed a significant percentage change in serum HE4 from baseline beyond 3 months (p > 0.05). Change in serum HE4 between baseline and 3 and 6 months and tissue HE4 tissue expression between baseline and 3, 6, and 12 months was not significantly different in responders compared to non-responders (p > 0.05). This study suggests that baseline serum HE4, but not baseline tissue HE4 expression, is independently predictive of response to the LNG-IUS and could be used to guide management decisions.

Opportunistic fungal infections in persons living with advanced HIV disease in Lagos, Nigeria; a 12-year retrospective study.

INTRODUCTION: Nigeria has a large estimated burden of AIDS-related mycoses. We aimed to determine the proportion of patients with AIDS-related opportunistic fungal infections (OFIs) at an urban antiretroviral treatment (ART) centre in Nigeria. METHODS: A retrospective analysis of a cohort of ART-naïve, HIV-infected patients, assessed for ART eligibility and ARTexperience at the PEPFAR outpatient clinic at Lagos University Teaching Hospital over a 12-year period (April 2004-February 2016) was conducted. RESULTS: During this period, 7,034 patients visited the clinic: 4,797 (68.2%) were female; 6161 patients had a recorded baseline CD4 count, and the median CD4 count was 184 cells/µl (IQR, 84-328). A baseline HIV-1 viral load (VL) was recorded for 5,908 patients; the median VL was 51,194 RNA copies/ml (IQR, 2,316-283,508) and 6,179/7046(88%) had initiated ART. Some 2,456 (34.9%) had a documented opportunistic infections, of whom 1,306 (18.6%) had an opportunistic fungal infection. The total number of OFI episodes was 1,632: oral candidiasis (n=1,473, 90.3%), oesophageal candidiasis (n=118; 8%), superficial mycoses (n=23; 1.6%), Pneumocystis pneumonia (PJP) (n=13; 0.8%), and cryptococcal meningitis(CM) (n=5; 0.4%). 113 (1.6%) were known to have died in the cohort. CONCLUSION: Approximately 1 in 5 HIV-infected patients in this retrospective cohort, most of whom had initiated ART, were clinically diagnosed with an OFI. Improved access to simple accurate diagnostic tests for CM and PJP should be prioritised for this setting.

A randomised controlled trial of bag-valve-mask teaching techniques.

BACKGROUND: Bag-valve-mask (BVM) ventilation is a vital skill in the management of the collapsed patient; however, the quality of BVM ventilation is a cause for concern. Modified techniques, designed to be easier for the novice practitioner, offer an opportunity to improve quality. One such modification is the 'LASOO' (Lift, Apply, Slide, Oppose, Observe) approach, which offers theoretical benefits over the traditionally taught 'CE' (finger shapes) technique. We conducted a randomised controlled trial (RCT) to determine whether LASOO was superior to CE in terms of tidal volume, when taught to novices in the skills-lab setting. We conducted a randomised controlled trial (RCT) to determine whether LASOO was superior to CE in terms of tidal volume, when taught to novices in the skills-lab setting METHODS: A total of 76 undergraduate health care students received a manikin-based teaching session on LASOO or CE. They then delivered 20 breaths (10 with each hand) to a modified airway manikin. The primary outcome was mean tidal volume; secondary outcomes were the proportion of breaths that achieved 150-mL and 400-mL threshold volumes. Subgroup analyses and statistical modelling were conducted for time-point, hand dominance and hand size. RESULTS: The mean tidal volume was 320 mL for CE and 304 mL for LASOO. The median percentage of attempts that exceeded 150 mL was 85 for CE and 82.5 for LASOO. The median percentage of attempts that exceeded 400 mL was 20 for CE and 20 for LASOO. The differences recorded between the techniques were not statistically significant. There was a small, statistically significant increase in tidal volume across both techniques with time-point and holding the mask with the non-dominant hand. DISCUSSION: LASOO is a viable alternative to CE. Educators may opt to teach either or both techniques, allowing students to choose the technique that they prefer.

Comparing long-term local recurrence rates of surgical and non-surgical management of close anterior margins in breast conserving surgery.

PURPOSE: While it is known that histologically involved margins lead to a higher local recurrence rate, re-excision of anterior margins is less common than that of radial margins. However, there are minimal long-term data on the oncological safety of non-surgical management of anterior margins. PATIENTS AND METHODS: A retrospective study was performed of all patients who underwent breast conserving surgery for breast cancer between 2000 and 2008 at two tertiary referral centres. A close margin was defined as disease within two mm of the resection margin (including disease at the margin). RESULTS: 6922 patients underwent surgery for invasive or in situ breast cancer of whom 277 patients had a close anterior margin alone after breast conserving surgery. Two hundred and twenty patients had non-surgical management of their margins, while 57 had re-excision surgery. Overall, there were 4/57 local recurrences in the surgical management group and 12/220 in the non-surgical management group. The local recurrence-free survival rate at 5 years was 98.2% (1 recurrence, 95% CI 87.8-99.7) in the surgical management group and 97.2% (6 recurrences, 95% CI 93.8-98.7) in the non-surgical management group. At 10 years, the rates were 92.2% (4 recurrences, 95% CI 80.3-97.0) in the surgical management group and 93.9% (12 recurrences, 95% CI 89.4-96.5) in the non-surgical management group. There was no significant difference found in the local recurrence rate between management groups (HR 1.24, 95% CI 0.40, 3.85; p = 0.71). CONCLUSIONS: Local recurrence rates are acceptable and similar in both the surgically and non-surgically managed groups. Non-surgical management of close anterior margins appears oncologically safe when combined with appropriate adjuvant therapy.