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Background Commonly in surgical randomised controlled trials (RCT) the experimental treatment is a relatively new technique which the surgeons may still be learning, while the control is a well-established standard. This can lead to biased comparisons between treatments. In this paper we discuss the implementation of approaches for addressing this issue in the ROLARR trial, and points of consideration for future surgical trials. Methods ROLARR was an international, randomised, parallel-group trial comparing robotic vs. laparoscopic surgery for the curative treatment of rectal cancer. The primary endpoint was conversion to open surgery (binary). A surgeon inclusion criterion mandating a minimum level of experience in each technique was incorporated. Additionally, surgeon self-reported data were collected periodically throughout the trial to capture the level of experience of every participating surgeon. Multi-level logistic regression adjusting for operating surgeon as a random effect is used to estimate the odds ratio for conversion to open surgery between the treatment groups. We present and contrast the results from the primary analysis, which did not account for learning effects, and a sensitivity analysis which did. Results The primary analysis yields an estimated odds ratio (robotic/laparoscopic) of 0.614 (95% CI 0.311, 1.211; p  = 0.16), providing insufficient evidence to conclude superiority of robotic surgery compared to laparoscopic in terms of the risk of conversion to open. The sensitivity analysis reveals that while participating surgeons in ROLARR were expert at laparoscopic surgery, some, if not all, were still learning robotic surgery. The treatment-effect odds ratio decreases by a factor of 0.341 (95% CI 0.121, 0.960; p  = 0.042) per unit increase in log-number of previous robotic operations performed by the operating surgeon. The odds ratio for a patient whose operating surgeon has the mean experience level in ROLARR – 152.46 previous laparoscopic, 67.93 previous robotic operations – is 0.40 (95% CI 0.168, 0.953; p  = 0.039). Conclusions In this paper we have demonstrated the implementation of approaches for accounting for learning in a practical example of a surgery RCT analysis. The results demonstrate the value of implementing such approaches, since we have shown that without them the ROLARR analysis would indeed have been confounded by the learning effects. Trial registration International Standard Randomised Controlled Trial Number (ISRCTN) registry, ID: ISRCTN80500123. Registered on 27 May 2010.

IntroductionThe incidence of anal carcinoma is increasing, with the current gold standard treatment being chemoradiotherapy. There is currently a wide range in the radiotherapy dose used internationally which may lead to overtreatment of early-stage disease and potential undertreatment of locally advanced disease.PLATO is an integrated umbrella trial protocol which consists of three trials focused on assessing risk-adapted use of adjuvant low-dose chemoradiotherapy in anal margin tumours (ACT3), reduced-dose chemoradiotherapy in early anal carcinoma (ACT4) and dose-escalated chemoradiotherapy in locally advanced anal carcinoma (ACT5), given with standard concurrent chemotherapy.Methods and analysisThe primary endpoints of PLATO are locoregional failure (LRF)-free rate for ACT3 and ACT4 and LRF-free survival for ACT5. Secondary objectives include acute and late toxicities, colostomy-free survival and patient-reported outcome measures. ACT3 will recruit 90 participants: participants with removed anal tumours with margins ≤1 mm will receive lower dose chemoradiotherapy, while participants with anal tumours with margins >1 mm will be observed. ACT4 will recruit 162 participants, randomised on a 1:2 basis to receive either standard-dose intensity modulated radiotherapy (IMRT) in combination with chemotherapy or reduced-dose IMRT in combination with chemotherapy. ACT5 will recruit 459 participants, randomised on a 1:1:1 basis to receive either standard-dose IMRT in combination with chemotherapy, or one of two increased-dose experimental arms of IMRT with synchronous integrated boost in combination with chemotherapy.Ethics and disseminationThis study has been approved by Yorkshire & The Humber – Bradford Leeds Research Ethics Committee (ref: 16/YH/0157, IRAS: 204585), July 2016. Results will be disseminated via national and international conferences, peer-reviewed journal articles and social media. A plain English report will be shared with the study participants, patients’ organisations and media.Trial registration numberISRCTN88455282.

Localised squamous cell carcinoma of the anus is treated with radical chemoradiotherapy. Cure rates are high, but treatment can result in substantial acute and long-term morbidity. We aimed to assess whether lower dose chemoradiotherapy maintains high local control rates in patients with early-stage disease, with the secondary aim of reducing toxicity. ACT4 is a phase 2, prospective, multicentre, open-label, two-arm non-comparative, randomised, controlled trial, investigating reduced-dose intensity-modulated radiotherapy (rd-IMRT: 41·4 Gy in 23 fractions) in patients with early-stage anal cancer; T1–2 (≤4 cm) N0–NxM0. Eligible patients were at least 16 years of age, with an Eastern Cooperative Oncology Group performance status of 0–1. The primary outcome is 3-year loco-regional failure rates. Patients were randomly assigned 1:2 (with stratification by T stage, N stage, gender, HIV status, and randomising site) to standard-dose IMRT (sd-IMRT: 50·4 Gy in 28 fractions) or rd-IMRT with concurrent mitomycin and capecitabine chemotherapy. Here, we report the pre-planned, modified intention-to-treat analysis of secondary endpoints 6 months after treatment end—complete clinical response, compliance, patient-reported outcomes (EORTC QLQ-C30 and ANL27), and safety data. The trial is registered at the ISRCTN registry (ISRCTN88455282) and is ongoing but no longer recruiting. 163 patients were recruited from 28 UK tertiary centres between April 24, 2017, and Dec 1, 2020. 160 patients were included in the primary analysis (sd-IMRT n=55; dr-IMRT n=105). Data on ethnicity were not collected. The median patient age was 66 years (IQR 58–72 years); 117 (73%) were female and 43 (27%) male; and 129 (94%) of 138 evaluable samples were p16 positive. Complete clinical responses at 6 months were 87% (46 of 53) for sd-IMRT and 92% (89 of 97) for rd-IMRT. Radiotherapy interruptions of 3 days or more occurred in 14 (26%) of 55 patients in sd-IMRT and 16 (15%) of 105 patients in rd-IMRT. Chemotherapy modifications occurred in 27 (49%) of 55 patients in sd-IMRT and 39 (37%) of 105 patients in rd-IMRT. Grade 3 or worse acute toxicity was reported in 25 (46%) of 55 patients in sd-IMRT and 37 (35%) of 105 patients in rd-IMRT. The most common grade 3 or worse adverse events were radiation dermatitis (seven [13%] of 55 in sd-IMRT and ten [10%] of 105 in rd-IMRT), and diarrhoea (four [7%] of 55 in sd-IMRT and nine [9%] of 105 in rd-IMRT). Serious adverse events occurred in eight (15%) of 55 patients in sd-IMRT and ten (10%) of 105 patients in rd-IMRT. Patient-reported outcomes for most issues deteriorated at the end of treatment and resolved to baseline by 6 weeks in both groups. Poorer sexual function for men and women was observed at 6 months following sd-IMRT. Good 6-month complete clinical responses rates were seen in both groups. Early results suggest rd-IMRT is well tolerated with oncological outcomes maintained. 3-year locoregional failure rates are awaited. Cancer Research UK and Stand Up to Cancer.

It has long been an accepted belief that serum cholesterol significantly falls after myocardial infarction and that a return to pre-event levels takes approximately 3 months. The magnitude and clinical significance of this fall has recently been challenged. In the Secondary Prevention of Acute Coronary Events-Reduction Of Cholesterol to Key European Targets (SPACE ROCKET) trial, we measured serum lipids of individuals on day 1 and between days 2 and 4 after acute myocardial infarction (AMI). Second, we performed a thorough literature review and compared all studies reporting data on absolute changes in lipids immediately after AMI, using weighted means. Of 1263 SPACE ROCKET participants, 128 had paired lipid measurements where both samples had been measured using identical methods at baseline and on days 2-4 after AMI. The mean lowering in total cholesterol between day 1 and day 2-4 was 0.71 mmol/L (95% CI 0.58-0.84; P < 0.0001) and in triglycerides was 0.10 mmol/L (-0.14-0.33; P = 0.405). A total of 25 papers showing absolute lipid changes post-AMI were identified. The combined data demonstrated a mean fall in total cholesterol of 9% to 11% from baseline over days 3-14 post-AMI, whereas for triglycerides, there was a rise of 18% from baseline to between day 9 and 12 weeks. After a secondary analysis of SPACE ROCKET data and a comparison of previously published data, we report a 10% fall in total cholesterol after AMI-a difference that is of high clinical significance. Consequently, measurement of serum lipids in patients with AMI should be performed within the first hours after presentation.

Children need safe, supervised places to learn how to jump, land, roll, climb, swing, etc. If these safe spaces are not given to the children in their early years how are they going to learn how to be safe on climbing equipment when not supervised. The staff at Tender Beginnings is excellent. Their concern for the children's well being and their enjoyment of their work is evident. Above all the children are always properly supervised. I absolutely trust their judgement and their abilities to keep my child safe whilst she climbs, jumps and slides.

Chemical probes are powerful reagents with increasing impacts on biomedical research. However, probes of poor quality or that are used incorrectly generate misleading results. To help address these shortcomings, we will create a community-driven wiki resource to improve quality and convey current best practice.

Depression contributes to persistent opioid analgesic use (OAU). Treating depression may increase opioid cessation. Aims To determine if adherence to antidepressant medications (ADMs) v. non-adherence was associated with opioid cessation in patients with a new depression episode after >90 days of OAU. Patients with non-cancer, non-HIV pain (n = 2821), with a new episode of depression following >90 days of OAU, were eligible if they received ≥1 ADM prescription from 2002 to 2012. ADM adherence was defined as >80% of days covered. Opioid cessation was defined as ≥182 days without a prescription refill. Confounding was controlled by inverse probability of treatment weighting. In weighted data, the incidence rate of opioid cessation was significantly (P = 0.007) greater in patients who adhered v. did not adhered to taking antidepressants (57.2/1000 v. 45.0/1000 person-years). ADM adherence was significantly associated with opioid cessation (odds ratio (OR) = 1.24, 95% CI 1.05-1.46). ADM adherence, compared with non-adherence, is associated with opioid cessation in non-cancer pain. Opioid taper and cessation may be more successful when depression is treated to remission. Declaration of interest None.

Defective primary ciliogenesis or cilium stability forms the basis of human ciliopathies, including Joubert syndrome (JS), with defective cerebellar vermis development. We performed a high-content genome-wide small interfering RNA (siRNA) screen to identify genes regulating ciliogenesis as candidates for JS. We analyzed results with a supervised-learning approach, using SYSCILIA gold standard, Cildb3.0, a centriole siRNA screen and the GTex project, identifying 591 likely candidates. Intersection of this data with whole exome results from 145 individuals with unexplained JS identified six families with predominantly compound heterozygous mutations in KIAA0586 . A c.428del base deletion in 0.1% of the general population was found in trans with a second mutation in an additional set of 9 of 163 unexplained JS patients. KIAA0586 is an orthologue of chick Talpid3 , required for ciliogenesis and Sonic hedgehog signaling. Our results uncover a relatively high frequency cause for JS and contribute a list of candidates for future gene discoveries in ciliopathies. Joubert syndrome is a rare disorder that affects the brain and causes physical, mental, and sometimes visual impairments. In individuals with this condition, two parts of the brain called the cerebellar vermis and the brainstem do not develop properly. This is thought to be due to defects in the development and maintenance of tiny hair-like structures called cilia, which are found on the surface of cells. Currently, mutations in 25 different genes are known to be able to cause Joubert syndrome. However, these mutations only account for around 50% of the cases that have been studied, and the ‘unexplained’ cases suggest that mutations in other genes may also cause the disease. Here, Roosing et al. used a technique called a ‘genome-wide siRNA screen’ to identify other genes regulating the formation of cilia that might also be connected with Joubert syndrome. This approach identified almost 600 candidate genes. The data from the screen were combined with gene sequence data from 145 individuals with unexplained Joubert syndrome. Roosing et al. found that individuals with Joubert syndrome from 15 different families had mutations in a gene called KIAA0586 . In chickens and mice, this gene—known as Talpid3 —is required for the formation of cilia. Roosing et al.'s findings reveal a new gene that is involved in Joubert syndrome and also provides a list of candidate genes for future studies of other conditions caused by defects in the formation of cilia. The next challenges are to find out what causes the remaining unexplained cases of the disease and to understand what roles the genes identified in this study play in cilia.

An innovative method for discharge medication reconciliation was developed by nurses to ensure safe transition of care and improved patient outcomes. The discharge time-out process has empowered nurses to take a more active role in discharging their patients, and has fostered a more collaborative relationship between nurses and physicians.

An innovative method for discharge medication reconciliation was developed by nurses to ensure safe transition of care and improved patient outcomes. The discharge time-out process has empowered nurses to take a more active role in discharging their patients, and has fostered a more collaborative relationship between nurses and physicians.