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Traditional methods of reporting adverse events in clinical trials are inadequate for modern cancer treatments with chronic administration. Conventional analysis and display of maximum grade adverse events do not capture toxicity profiles that evolve over time or longer lasting, lower grade toxic effects; we aimed to address this shortcoming in this study. We developed an analytic approach and standardised, comprehensive format, the Toxicity over Time (ToxT) approach, which combines graphs and adverse event tabular displays with multiple longitudinal statistical techniques into a readily applicable method to study toxic effects. Plots visualising summary statistics or individual patient data over discrete timepoints were combined with statistical methods including the following longitudinal techniques: repeated measures models that describe the changes in adverse events across all cycles of treatment; time-to-event analyses of first and worst grade toxicity; and area under the curve (AUC) analyses summarising adverse event profiles over the entire course of a study, including chronic low-grade events. We applied ToxT analysis to adverse event data from two completed North Central Cancer Treatment Group (NCCTG/Alliance) trials: N9741 (NCT00003594), in which different combinations of oxaliplatin, 5-fluorouracil, and irinotecan were investigated for metastatic colorectal cancer, and 979254, in which survivors of breast cancer were given venlafaxine or placebo for control of hot flashes. In trial NCCTG 979254 there was a higher incidence of late-occurring dry mouth in patients who were given venlafaxine than in those given placebo (week 1 [baseline]: 13% [six incidence in 48 patients, SD 5] vs 22% [11/49, SD 6]; p=0·20; week 5: 49% [24/49, 7] vs 2% [1/46, 2]; p<0·0001). In trial NCCTG N9741 there was an increased incidence of early nausea for patients given irinotecan plus oxaliplatin (IROX) compared with those given 5-fluorouracil plus oxaliplatin (FOLFOX; cycle 1 mean grade nausea 1·1 [SD 1·0] vs 0·6 [0·7]; p<0·0001). Event charts showed earlier occurrences of higher grades of diarrhoea for patients given IROX compared with those given FOLFOX, and the AUC analysis shows a higher magnitude of diarrhoea consistently over time throughout the study in patients given IROX versus those given FOLFOX (mean AUC 4·2 [SD 5·2] vs 2·9 [4·2]; p<0·0001). The ToxT analytical approach incorporates the dimension of time into adverse event assessment and offers a more comprehensive depiction of toxic effects than present methods. With new, continuously administered targeted agents, immunotherapy, and maintenance regimens, these improved longitudinal analyses are directly relevant to patients and are crucial in cancer clinical trials. National Cancer Institute of the National Institutes of Health and the Mayo Comprehensive Cancer Center.

We aimed to compare differences in risk and timing of recurrent ischemic events among patients with stable ischemic heart disease (SIHD), non–ST-segment elevation acute coronary syndrome (NSTE-ACS), and ST-segment elevation myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). We performed an individual data pooled analysis of 5 randomized controlled all-comer trials including a total of 8,859 patients and investigated the risk and timing of recurrent ischemic events among patients with SIHD (n = 3,543), NSTE-ACS (n = 3,364), and STEMI (n = 1,952) throughout 2 years of follow-up. At 2 years, all-cause mortality was higher among patients with STEMI (6.4%) and NSTE-ACS (6.1%) compared with those with SIHD (4.2%) (STEMI vs SIHD: hazard ratio [HR] 1.40, 95% CI 1.09-1.78, P = .007; NSTE-ACS vs SIHD: 1.40, 95% CI 1.13-1.73, P = .002). In a landmark analysis, the risk of mortality among patients with STEMI compared with those with SIHD was confined to the first 30 days after PCI (HR 6.19, 95% CI 3.15-12.16, P < .001) but was similar between 30 days and 2 years (HR 1.00, 95% CI 0.76-1.33, P = .974) (Pinteraction < .001). Conversely, patients with NSTE-ACS had a higher risk of mortality compared with those with SIHD both within the first 30 days (HR 2.19, 95% CI 1.08-4.47, P = .031) and beyond (HR 1.34, 95% CI 1.07-1.67, P = .012) (Pinteraction < .001). A similar pattern in the differential timing of events was observed for cardiac death. Beyond 30 days, the risk of myocardial infarction was comparable in patients with STEMI and SIHD, whereas the risk in patients with NSTE-ACS was increased (HR 1.65, 95% CI 1.23-2.21, P = .001). Whereas patients with NSTE-ACS are at increased risk for death at any time after PCI, the mortality of STEMI patients is higher during the first 30 days after PCI but not thereafter compared with patients with SIHD.

Objective To determine whether being upright in the second stage of labour in nulliparous women with a low dose epidural increases the chance of spontaneous vaginal birth compared with lying down.Design Multicentre pragmatic individually randomised controlled trial.Setting 41 UK hospital labour wards.Participants 3093 nulliparous women aged 16 or older, at term with a singleton cephalic presentation and in the second stage of labour with epidural analgesia.Interventions Women were allocated to an upright or lying down position, using a secure web based randomisation service, stratified by centre, with no masking of participants or clinicians to the trial interventions.Main outcome measures The primary outcome was spontaneous vaginal birth. Women were analysed in the groups into which they were randomly allocated, regardless of position recorded at any time during the second stage of labour (excluding women with no valid consent, who withdrew, or who did not reach second stage before delivery). Secondary outcomes included mode of birth, perineal trauma, infant Apgar score <4 at five minutes, admission to a neonatal unit, and longer term included maternal physical and psychological health, incontinence, and infant gross developmental delay. Results Between 4 October 2010 and 31 January 2014, 3236 women were randomised and 3093 (95.6%) included in the primary analysis (1556 in the upright group and 1537 in the lying down group). Significantly fewer spontaneous vaginal births occurred in women in the upright group: 35.2% (548/1556) compared with 41.1% (632/1537) in the lying down group (adjusted risk ratio 0.86, 95% confidence interval 0.78 to 0.94). This represents a 5.9% absolute increase in the chance of spontaneous vaginal birth in the lying down group (number needed to treat 17, 95% confidence interval 11 to 40). No evidence of differences was found for most of the secondary maternal, neonatal, or longer term outcomes including instrumental vaginal delivery (adjusted risk ratio 1.08, 99% confidence interval 0.99 to 1.18), obstetric anal sphincter injury (1.27, 0.88 to 1.84), infant Apgar score <4 at five minutes (0.66, 0.06 to 6.88), and maternal faecal incontinence at one year (1.18, 0.61 to 2.28).Conclusions Evidence shows that lying down in the second stage of labour results in more spontaneous vaginal births in nulliparous women with epidural analgesia, with no apparent disadvantages in relation to short or longer term outcomes for mother or baby.Trial registration Current Controlled Trials ISRCTN35706297.

This secondary analysis of a randomized clinical trial examines the effect of androgen deprivation therapy (ADT) during radiotherapy in patients who were classified as having either favorable intermediate-risk or unfavorable intermediate-risk prostate cancer.

Background The catabolic state that follows hip fracture contributes to loss of muscle mass and strength, that is sarcopenia, which impacts functional ability and health-related quality of life. Measures to prevent such long-term postoperative consequences are of important concern. The aim of this study was to evaluate the combined effects of protein-rich nutritional supplementation and bisphosphonate on body composition, handgrip strength and health-related quality of life following hip fracture. Methods The study included 79 men and women with hip fracture, mean age 79 years (SD 9), without severe cognitive impairment, who were ambulatory and living independently before fracture. Patients were randomized postoperatively to receive liquid supplementation that provided 40 g of protein and 600 kcal daily for six months after the fracture, in addition to bisphosphonates once weekly for 12 months (group N, n  = 26), or bisphosphonates alone once weekly for 12 months (group B, n  = 28). All patients, including the controls (group C, n  = 25) received calcium 1 g and vitamin D3 800 IU daily. Body composition as measured by dual-energy X-ray absorptiometry (DXA), handgrip strength (HGS) and health-related quality of life (HRQoL) were registered at baseline, six and 12 months postoperatively. Results There were no differences among the groups regarding change in fat-free mass index (FFMI), HGS, or HRQoL during the study year. Intra-group analyses showed improvement of HGS between baseline and six months in the N group ( P  = 0.04). HRQoL decreased during the first year in the C and B groups ( P  = 0.03 and P  = 0.01, respectively) but not in the nutritional supplementation N group ( P  = 0.22). Conclusions Protein-rich nutritional supplementation was unable to preserve FFMI more effectively than vitamin D and calcium alone, or combined with bisphosphonate, in this relatively healthy group of hip fracture patients. However, trends toward positive effects on both HGS and HRQoL were observed following nutritional supplementation. Trial registration Clinicaltrials.gov NCT01950169 (Date of registration 23 Sept 2013).

ObjectiveThis study compared the clinical features, cardiac structure and function evaluated by echocardiography, cardiopulmonary response to exercise and long-term clinical outcomes between patients with heart failure (HF) induced by cancer therapy (CTHF) and heart failure not induced by cancer therapy (NCTHF).MethodsWe evaluated 75 patients with CTHF and 894 with NCTHF who underwent clinically indicated cardiopulmonary exercise testing, and followed these individuals for a median of 4.5 (3.0–5.8) years, during which 187 deaths and 256 composite events (death, heart transplantation and left ventricular (LV) assistant device implantation) occurred.ResultsCompared with NCTHF, patients with CTHF were younger, with lower prevalence of cardiovascular comorbidities, higher LV ejection fraction (LVEF), but similar global longitudinal strain. LV diastolic function (higher E/e′ ratio) and compliance (higher end-diastolic pressure/LV end-diastolic volume index ratio) were worse in CTHF and were both associated with adverse outcomes. Despite a favourable clinical profile, peak VO2 and VE/VCO2 slope were similarly impaired in CTHF and NCTHF. In multivariable Cox regression analysis including clinical characteristics, cardiopulmonary exercise testing variables and LVEF, CTHF was associated with a significantly higher risk of death (HR 2.64; 95% CI 1.53 to 4.55; p=0.001) and composite events (HR 1.79; 95% CI 1.10 to 2.91; p=0.019) compared with NCTHF.ConclusionsCTHF is characterised by a distinct clinical profile, better LVEF but worse LV diastolic properties, and similarly impaired global longitudinal strain, functional capacity and ventilatory efficiency. Accounting for differences in clinical characteristics, CTHF was associated with worse long-term prognosis than NCTHF.

Correspondence to: T Greenhalgh trish.greenhalgh@phc.ox.ac.uk What you need to know Management of covid-19 after the first three weeks is currently based on limited evidence Approximately 10% of people experience prolonged illness after covid-19 Many such patients recover spontaneously (if slowly) with holistic support, rest, symptomatic treatment, and gradual increase in activity Home pulse oximetry can be helpful in monitoring breathlessness Indications for specialist assessment include clinical concern along with respiratory, cardiac, or neurological symptoms that are new, persistent, or progressive Post-acute covid-19 (“long covid”) seems to be a multisystem disease, sometimes occurring after a relatively mild acute illness.1 Clinical management requires a whole-patient perspective.2 This article, intended for primary care clinicians, relates to the patient who has a delayed recovery from an episode of covid-19 that was managed in the community or in a standard hospital ward. The specialist rehabilitation needs of a third group, covid-19 patients whose acute illness required intensive care, have been covered elsewhere.3 Defining post-acute covid-19 In the absence of agreed definitions, for the purposes of this article we define post-acute covid-19 as extending beyond three weeks from the onset of first symptoms and chronic covid-19 as extending beyond 12 weeks. Since many people were not tested, and false negative tests are common,4 we suggest that a positive test for covid-19 is not a prerequisite for diagnosis. [...]called mild covid-19 may be associated with long term symptoms, most commonly cough, low grade fever, and fatigue, all of which may relapse and remit.47 Other reported symptoms include shortness of breath, chest pain, headaches, neurocognitive difficulties, muscle pains and weakness, gastrointestinal upset, rashes, metabolic disruption (such as poor control of diabetes), thromboembolic conditions, and depression and other mental health conditions.424 Skin rashes can take many forms including vesicular, maculopapular, urticarial, or chilblain-like lesions on the extremities (so called covid toe).25 There seems to be no need to refer or investigate these if the patient is otherwise well. Box 5 links to patient resources, including a comprehensive patient guide from Homerton University Hospital.28 Respiratory symptoms and support Cough The British Thoracic Society defines chronic cough as one that persists beyond eight weeks.26 Up to that time, and unless there are signs of super-infection or other complications such as painful pleural inflammation, cough seems to be best managed with simple breathing control exercises28 (see box 2) and medication where indicated (such as proton pump inhibitors if reflux is suspected).

Premise of the Study The stem of Vitis vinifera, a climbing vine of global economic importance, is characterized by both wide and narrow vessels and high specific hydraulic conductivity. While the effect of drought stress has been studied in 1‐ and 2‐yr‐old stems, there are few data documenting effects of drought stress on the anatomical structure of the mature, woody stem near the base of the vine. Here we describe mature wood anatomical responses to two irrigation regimes on wood anatomy and specific hydraulic conductivity in Vitis vinifera Merlot vines. Methods For 4 years, irrigation was applied constantly at low, medium, or high levels, or at alternating levels at two different periods during the growing season, either early spring or late summer, resulting in late season or early spring deficits, respectively. The following variables were measured: trunk diameter, annual ring width and area, vessel diameter, specific hydraulic conductivity and stem water potential. Key Results High water availability early in the season (late deficit) resulted in vigorous vegetative growth (greater trunk diameter, ring width and area), wider vessels and increased specific hydraulic conductivity. High water availability early in the season caused a shift of the vessel population towards the wider frequency classes. These late deficit vines showed more negative water potential values late in the season than vines that received low but relatively constant irrigation. Conclusions We concluded that high water availability during vegetative growth period of Vitis increases vessels diameter and hydraulic conductivity and causes the vines to be more vulnerable to drought stress late in the season.

Purpose To assess the long-term patient-reported outcomes following TO-TVT as a secondary continence procedure in women with recurrent stress urinary incontinence (R-SUI). Methods A secondary analysis of the 9-year follow-up of the E-TOT study was performed: 341 women with predominant SUI symptoms were randomised to undergo either Inside-out or Outside-in TO-TVT between April 2005 and April 2007. Forty-six women had R-SUI following previously failed continence surgery at time of randomisation and are the basis of this analysis as a one single cohort. Primary outcome was the patient-reported success rate defined as very/much improved on Patient’s Global Impression of Improvement (PGI-I). Secondary outcomes included late adverse events and impact on women’s quality of life and sexual function. Statistical analysis was performed using SPSS version 23. Results Sixty-three per cent completed the 9-year follow-up. The success based on the PGI-I was 62.1% with no significant difference between groups (OR 5.33; 95% CI 1.03, 27.76; p  = 0.094). Clinically significant improvement in QoL was found in 84.2%. Adverse events included vaginal erosions ( n  = 3) and groin pain ( n  = 2). The small sample size is a limitation in this study; nevertheless, this is one of the largest cohorts reported for women with R-SUI and the first to report the long-term outcomes of TO-TVT as a secondary continence procedure. Conclusions TO-TVT operations are associated with good patient-reported success rates (62%) in women with previous failed continence surgery with up to 9-years follow-up. There is a non-significant trend towards better outcomes with the inside-out TO-TVT.

Purpose of Review The current review aims to summarize the state of research on cannabis and sleep up to 2014 and to review in detail the literature on cannabis and specific sleep disorders from 2014 to the time of publication. Recent Findings Preliminary research into cannabis and insomnia suggests that cannabidiol (CBD) may have therapeutic potential for the treatment of insomnia. Delta-9 tetrahydrocannabinol (THC) may decrease sleep latency but could impair sleep quality long-term. Novel studies investigating cannabinoids and obstructive sleep apnea suggest that synthetic cannabinoids such as nabilone and dronabinol may have short-term benefit for sleep apnea due to their modulatory effects on serotonin-mediated apneas. CBD may hold promise for REM sleep behavior disorder and excessive daytime sleepiness, while nabilone may reduce nightmares associated with PTSD and may improve sleep among patients with chronic pain. Summary Research on cannabis and sleep is in its infancy and has yielded mixed results. Additional controlled and longitudinal research is critical to advance our understanding of research and clinical implications.