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IntroductionIvacaftor 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 aGly551Aspmutation 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.MethodsWe conducted a 5-year single-centre retrospective study of people with CF carrying theGly551Aspmutation who received ivacaftor. Clinical outcome data were extracted from medical notes and databases. Drug delivery data were used to assess medicine possession ratio (MPR).Results35 people were included. After commencing ivacaftor, FEV1improved by 9.6% (SE±1.59%) predicted by 6 months. Thereafter, FEV1declined, and at 5 years had returned to pre-ivacaftor baseline. Ivacaftor did not alter annual rate of FEV1decline (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). FEV1was better maintained in patients with higher MPRs.ConclusionThe addition of ivacaftor provides acute benefits for people with theGly551Aspmutation 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.

Introduction: Nigeria has a large estimated burden of AIDS-related mycoses. We aimed to determine the proportion of pa- tients 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 ART- experience at the PEPFAR outpatient clinic at Lagos University Teaching Hospital over a 12-year period (April 2004-Feb- ruary 2016) was conducted. Results: During this period, 7,034 patients visited the clinic: 4,797 (68.2%) were female; 6161 patients had a recorded base- line 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 pri- oritised for this setting. Keywords: Opportunistic fungal infections; ART Adherence; Advanced HIV disease.

Background No consensus on the management of symptomatic cysts or abscesses of the Bartholin's gland exists. Objectives To assess the effectiveness and safety of surgical interventions for a symptomatic Bartholin's cyst or abscess. Search strategy We searched bibliographical databases from inception to April 2019. Selection criteria Randomised trials evaluating a surgical intervention for the treatment of a symptomatic Bartholin's cyst or abscess. Data collection and analysis Eight trials, reporting data from 699 women, were included. Study characteristics and methodological quality were recorded for each trial. Summary estimates were calculated using random-effects methods. Main results When considering the recurrence of a symptomatic Bartholin's cyst or abscess, the evidence was consistent with notable effects in either direction (risk ratio [RR] 0.76; 95% confidence interval [CI] 0.41-1.40) when comparing marsupialisation with incision, drainage and insertion of a Word catheter. Limited inference could be made when comparing marsupialisation with incision, drainage and silver nitrate insertion (RR 1.00; 95% CI 0.57-1.75), and incision, drainage and cavity closure (RR 0.25; 95% CI 0.01-4.89). There was limited reporting of secondary outcomes, including haematoma, infectious morbidity and persistent dyspareunia. Conclusions Current randomised trial evidence does not support the use of any single surgical intervention for the treatment of a symptomatic cyst or abscess of the Bartholin's gland. Prospective registration PROSPERO: International Prospective Register of Systematic Reviews; CRD42018088553. Tweetable abstract Further research is needed to identify an effective treatment for #Bartholin's cyst or abscess. @jamesmnduffy.

BackgroundRisk of SARS-CV-2 infection has been strongly linked to occupation, with specific occupational sectors such as health care, food production, and transport, particularly affected. To better understand the potential risks by occupational sector we investigated the reported risks of COVID-19 infection and mortality for employees in the three sectors.MethodsWe performed a rapid review of observational studies reporting COVID-19 risk for employees in health care, food manufacturing, and transport sectors. All studies published in the peer-review and pre-print literature between March 2020 and June 2021 were considered. The primary outcome measure was COVID-19 infection, with COVID-19 related mortality and hospitalisation considered as secondary measures. We extracted odds ratios/relative risks (and standard errors) comparing workers in each sector to within study reference category. To avoid complications due to study heterogeneity, we simply produced descriptive forest plots where possible utilising the odds ratios that have been adjusted for demographics.ResultsEight studies were identified from Norway (one), and California (one), and the UK (five). Three studies at time of writing were peer reviewed, and five of the eight were cohort studies. Food production was the least well investigated with limited evidence of increased infection, severe infection or mortality compared to the ‘other’ groups. Healthcare and transport show wide variation in the odds ratios reported. Public facing roles did indicate greater infection risk, specifically in the first wave. ConclusionsConsiderable study heterogeneity is present, particularly with respect to the chosen reference groups, meaning objective comparisons are limited here. However, as would be expected public facing roles, especially in the first wave, did appear to experience increased infection. Further prospective work with subject level data is needed to better understand the occupational risks.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. 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.

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. 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). 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). 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.

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.

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&rsquo, 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.

Sir, We would like to thank Sharma and colleagues for their interest in our recent study evaluating the effectiveness and safety of surgical interventions for Bartholin’s cyst or abscess.1Their response highlights the unique opportunity offered by randomised trials, and their syntheses into meta‐analyses, to assess patient reported outcomes. We would strongly encourage researchers to select, collect and report patient reported outcomes in future research evaluating interventions for Bartholin’s cyst or abscess.2The primary outcome should be the outcome of greatest therapeutic importance to the study’s prospective hypothesis. There is currently no consensus regarding the selection of outcomes and methods of definition or measurement for randomized trials evaluating interventions for Bartholin’s cyst or abscess.3 In the absence of a standardized approach, researchers have made arbitrary decisions when choosing among several important outcomes.4 It would be useful for healthcare professionals, researchers, and women with lived experience of Bartholin’s cyst or abscess to engage in a formal consensus development process to agree appropriate primary and secondary outcomes.3We agree the use of adjuvant antibiotics is an important consideration. They were not reported by any of the included trials.5We have no experience of marsupialization performed under local anaesthetic. In our opinion, this approach would need to be evaluated within a research setting. The recent COVID-19 pandemic would provide additional impetus to undertake this much needed research.James M. N. Duffy 1,2, Emma Kirk 3, BJG Illingworth 4, K Stocking 5,Marian Showell 61 Institute for Women’s Health, University College London, London, United Kingdom.2 King’s Fertility, Fetal Medicine Research Foundation, London, United Kingdom.3 Department of Obstetrics and Gynaecology, Royal Free London NHS Trust, London, United Kingdom.4 North West Anglia NHS Foundation Trust, Peterborough City Hospital, Peterborough, UK5 Centre for Biostatistics, Division of Population Health, Health Services Research and Primary Care, University of Manchester, Manchester, UK6 Cochrane Gynaecology and Fertility Group, University of Auckland, Auckland, New Zealand.

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 &plusmn, 1.1 pM, 95% confidence interval (CI) 52.7&ndash, 73.2), compared to non-responders (125.6 &plusmn, 1.3 pM, 95% CI 74.5&ndash, 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 (&minus, 9.8 &plusmn, 3.4%, 95% CI &minus, 16.7 to &minus, 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 &gt, 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 &gt, 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.

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.

BackgroundScreening 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.Methods918 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).ResultsGroup-2 patients had longer 'time-to-listing' (5.5months in Group-1 vs 6.9months in 'Normal-NISS' vs 9.9months in 'Abnormal-NISS', pConclusionsPre-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.

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.

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.

Aim: Delayed presentation in acute testicular torsion increases risk of testicular loss. We investigated whether there is a delay in presentation with suspected torsion in patients from an ethnic minority. Patients and methods: A retrospective audit of patients undergoing scrotal exploration for suspected torsion from September 2014 to September 2019 was completed. Notes were used to identify time between onset of pain and presentation to hospital. Patients’ ethnicity was identified through voluntary demographic information. Median time to presentation was compared between ethnic minorities and white British patients, as well as exploration findings. Results: Ethnic minority patients ( n=29) with suspected torsion presented significantly later with a median of 19 hours (range 1.3–192) compared to 4 hours (0.5–96) in white British patients ( n=65). ( pConclusion(s): In our population, ethnic minorities present later with acute scrotal pain, increasing their risk of testicular loss. More study is required to identify causes of delayed presentation in these patients with the aim of improving health education. Level of evidence: 3

IntroductionNovel, evidence-based treatments are required for treatment-resistant post-traumatic stress disorder (PTSD). 3,4-Methylenedioxymethamphetamine (MDMA) has beneficially augmented psychotherapy in several small clinical trials.ObjectivesTo review the use of MDMA-assisted psychotherapy in treatment-resistant PTSD.MethodsSystematic searches of four databases were conducted from inception to February 2020. A meta-analysis was performed on trials which were double-blinded, randomised, and compared MDMA-assisted psychotherapy to psychotherapy and placebo. The primary outcomes were the differences in Clinician Administered PTSD Scale (CAPS-IV) score and Beck’s Depression Inventory (BDI). Secondary outcome measures included neurocognitive and physical adverse effects, at the time, and within seven days of intervention.ResultsFour randomised controlled trials (RCTs) met inclusion criteria. When compared to active placebo, intervention groups taking 75mg (MD -46.90; 95% CI -58.78, -35.02), 125mg (MD -20.98; 95% CI -34.35, -7.61) but not 100mg (MD -12.90; 95% CI -36.09, 10.29) of MDMA with psychotherapy, had significant decreases in CAPS-IV scores, as did the inactive placebo arm (MD -33.20; 95% CI -40.53, -25.87). A significant decrease in BDI when compared to active placebo (MD -10.80; 95% CI -20.39, -1.21) was only observed at 75mg. Compared to placebo, participants reported significantly more episodes of low mood, nausea and jaw-clenching during sessions and lack of appetite after seven days.ConclusionsThese results demonstrate potential therapeutic benefit with minimal physical and neurocognitive risk for the use of MDMA-assisted psychotherapy in TR-PTSD, despite little effect on Beck’s Depression Inventory. Better powered RCTs are required to investigate further.DisclosureJames Rucker has attended trial related meetings paid for by Compass Pathways Ltd.