Long-term Follow-up Of Participants Research Articles

Long-term follow-up of participants in ketamine clinical trials for mood disorders

BackgroundParticipants who received ketamine at the NIMH were among the first to receive ketamine for depression in controlled clinical trials, providing a unique opportunity to assess long-term outcomes. This analysis evaluated the relationship between participating in a ketamine clinical trial and subsequent ketamine/esketamine use after leaving the research setting. MethodsParticipants seen within the NIMH Experimental Therapeutics and Pathophysiology Branch from 2002 to 2022 (n = 1000) were contacted for follow-up assessment. Participants reported whether they had used ketamine/esketamine, sought non-prescribed ketamine, attempted suicide, or been psychiatrically hospitalized since discharge. Information regarding their recent depressive symptoms, dissociative symptoms, and hallucinations was also collected. ResultsOf the 203 participants in follow-up assessments (55 % female, average time since leaving NIMH = 9.04 years), 52 (25.6 %) had originally received ketamine at the NIMH, and the rest had participated in non-ketamine studies. Individuals who had received ketamine at the NIMH were more likely to have received ketamine/esketamine post-discharge than those who did not receive ketamine at the NIMH (OR = 0.25, p < .001). Participants who reported using ketamine/esketamine post-discharge reported more depressive symptoms than those who had not (p < .001). Receiving ketamine at the NIMH was not associated with differences in suicide attempts, psychiatric hospitalizations, dissociation, hallucinations, or attempt to obtain non-prescribed ketamine. LimitationsLow follow-up study participation rate; varying time since discharge. ConclusionsParticipants who received ketamine in an NIMH clinical trial were more likely to receive ketamine/esketamine post-discharge, but none reported symptoms indicating abuse. Results underscore the critical need for long-term follow-up of individuals receiving these and other rapid-acting antidepressants. Clinical Trials identifierNCT04877977.

Neuropathic Pain With and Without Diabetic Peripheral Neuropathy in Type 1 Diabetes.

Diabetic peripheral neuropathy (DPN) is common; however, the features and burden of neuropathic pain (NP) in type 1 diabetes (T1D) are poorly understood. We evaluated the incidence of first occurrence, annual prevalence, remission, and risk factors for NP during long-term follow-up of participants with T1D. The Michigan Neuropathy Screening Instrument (MNSI) was administered annually (1994-2020) for 1,324 participants in the Epidemiology of Diabetes Interventions and Complications (EDIC) study. NP with clinical signs of DPN (NP DPN+) was defined according to self-reported NP plus an examination score >2, while NP without clinical signs of DPN (NP DPN-) was defined according to self-reported NP and an examination score ≤2. At EDIC year 1, median age for participants was 36 years (interquartile range 30, 41), diabetes duration 13 years (10, 18), and HbA1c 7.9% (7.2, 8.9). At year 26 (median diabetes duration 39 years), cumulative incidence of NP was 57%, regardless of concomitant clinical signs of DPN (36% NP DPN+ vs. 46% NP DPN-). NP prevalence was 20% at 26 years (11% NP DPN+ and 9% NP DPN-), suggesting frequent remission. Annualized remission rates were similar regardless of pain medication use. In addition to HbA1c, female sex was associated with NP DPN-. NP incidence in T1D was high and frequently occurred in the absence of clinical signs of neuropathy, as assessed with the MNSI. Pain remission was not explained by pain medication use. Effective clinical strategies for identification and management are needed.

Efficacy and Safety of Avatrombopag in Combination with Immunosuppressive Therapy in Treatment-Naïve and Relapsed/Refractory Severe Aplastic Anaemia - the Diaamond-Ava-First and Diaamond-Ava-Next Bayesian Optimal Phase II Trials

Background: Improving treatment for patients with severe aplastic anemia (sAA) is a priority. Immunosuppressive therapy (IST) with antithymocyte globulin (ATG) and ciclosporin is standard of care for patients with sAA not eligible or suitable for allogeneic stem cell transplant. While 50-75% of patients respond to IST, few achieve complete responses and a significant proportion are refractory or relapse. The addition of eltrombopag, a thrombopoietin-receptor agonist (TPO-A), to IST has been shown to improve hematological responses in sAA. Avatrombopag is a second-generation TPO-A, and like eltrombopag, lacks competitive binding with endogenous TPO, suggesting it may also be effective in AA. Avatrombopag has potential advantages over eltrombopag, including dosing, toxicity profile and pharmacokinetics. It has also been shown to have greater in vitro and in vivo pharmacological potency than eltrombopag. However, to date avatrombopag has not been studied in sAA. Methods: The DIAAMOND Ava-FIRST and DIAAMOND Ava-NEXT trials are investigator-initiated, non-randomised, single-arm registry-based Bayesian Optimal Phase II (BOP2) trials. The FIRST trial is evaluating avatrombopag in addition to IST in patients with untreated sAA. Patients receive IST (equine ATG and ciclosporin) plus avatrombopag from day 1 until day 180 at 60 mg oral daily and dose adjusted according to platelet count. Two primary endpoints, complete response (CR) rate and acquired clonal evolution (ACE) at 6 months are monitored at each interim analysis where a go/no-go decision is made by evaluating the posterior probability of the events of interest. The maximum sample size is 50 evaluable patients. The stopping boundaries were calculated with a target false positive rate of 10% under the global null as recommended in phase II studies. The performance of the trial and operating characteristics were assessed with 10,000 simulations. Other trial endpoints which are collected until 24 months following enrolment include rate and time to first hematological response, survival, cytogenetic evolution, progression to hematological malignancy, safety and quality of life. Exploratory assessments of interest include changes in iron studies and marrow iron stores, longitudinal cell free DNA somatic mutation analysis and T-cell receptor repertoire studies. In the NEXT trial, patients with relapsed or refractory sAA, six or more months following at least one course of horse or rabbit ATG are eligible. All patients receive avatrombopag at 60 mg oral daily from day 1 until day 180, further additional IST is at the discretion of the treating clinician. Two primary endpoints, hematological response (HR) rate and ACE are monitored at each interim analysis following which a go/no-go decision is made as described in the FIRST trial. The trials are embedded within the Australian Aplastic Anaemia and Other Bone Marrow Failure Syndromes Registry, which will allow long-term follow-up of participants after completion of the trial (at 24 months). Progress: The FIRST trial has enrolled 40 patients and the NEXT trial 16 patients. The dosing of avatrombopag was changed after the initial eleven patients were enrolled, when the starting dose was 20 mg daily and increased to a maximum of 60 mg daily over 8 weeks based on hematological response. This change was made based on observed tolerability of the maximum (60 mg) dose and timing of response rates. Interim analyses have been performed for both trials and stopping boundaries for efficacy or safety have not been met.

Comprehensive Behavioral Treatment of an Older Adult Man with Trichotillomania

The Comprehensive Behavioral (ComB) model of treatment for trichotillomania (TTM) and other body-focused repetitive behaviors offers a framework for individualized, flexible intervention based on functional analysis. This case report focuses on the treatment of a patient who enrolled in the first randomized clinical trial of ComB for TTM (Carlson et al., 2021) as well as a long-term follow-up of participants from that trial conducted during the COVID-19 pandemic (Flannery et al., in press). Walter (pseudonym) entered the treatment trial at 69, having had TTM since age 17 but not received treatment for it. Walter showed clinically significant improvement in treatment, ultimately abstaining from hair pulling for two years. A single case from a parallel-groups trial cannot support strong conclusions about why his results were favorable, but qualitative review of Walter’s experience in therapy suggested that allowing him a good deal of collaborative input on the specific methods of implementation of ComB principles was helpful. Along with the general literature on patient age as a predictor of therapy outcome, Walter’s case serves as a reminder that older adults, even those with highly chronic clinical conditions, can benefit greatly from psychotherapy.

A Cree Indian Treatment for Psoriasis: A Longitudinal Study

This article reports on the treatment of 10 non-native patients with psoriasis by a Cree Indian healer. The traditional treatment ceremony is described, and the changes in the course of the disease over a six-month period are documented using the patient’s subjective reports of symptoms, outline tracings of selected lesions, videotapes and photographs. The study is unique in two ways: (1) it included a variety of documentary procedures seldom allowed by native healers and it was conducted under conditions that facilitated evaluation; and (2) to the researchers’ knowledge, it is the first study of traditional native medicine with long-term follow-up of participants. Initially, all patients responded to the treatment, but by the sixth month improvement remained in only six patients. Difficulties encountered when conducting research on traditional healing are discussed and future research directions are indicated.

Baseline Differences in Long-term Survivors and Nonsurvivors of the Colorado/Columbia Fetal Implant Trial.

This study is based on long-term follow-up of participants in a randomized double-blind sham surgery-controlled trial (1995-1999) designed to determine the effectiveness of implantation of human embryonic mesencephalic tissue containing dopamine neuron precursors into the brains of patients with advanced Parkinson's disease (PD). We investigated differences between long-term survivors and nonsurvivors at baseline in order to contribute to information regarding optimal patient selection for upcoming stem cell trials. Forty participants were randomly assigned to receive either neural implantation or sham surgery. Thirty-four patients who ultimately received the implant were followed periodically with the most recent assessment occurring in 2015-2016. Demographic information, neurological measures, positron emission tomography (PET) imaging, neuropsychological assessments, and a personality assessment were included in the current analyses. T-tests were used to compare survivors and nonsurvivors. Logistic regression analyses examined predictors of survivorship. Five of six survivors were female. They were younger than nonsurvivors (p = .03) and more neuropsychologically "intact" across a broad range of cognitive areas (significance levels ranged from <.001 to .045). There were no differences between survivors and nonsurvivors off medications at baseline on neurological or PET assessments. Survivors reported more "Openness to Experience" (p = .004) than nonsurvivors. Using empirically derived predictor variables, results of logistic regression analyses indicated that Animal Naming (cognitive task) and Openness to Experience (personality variable) were the strongest predictors of survivorship. Variables to consider when selecting participants for future cell-based therapies include being "intact" neuropsychologically, level of Openness to Experience, younger age, and inclusion of women.

Follow-Up Phone Interviews and Attendance Motivation From A Free Head and Neck Cancer Screening.

Head and Neck Cancer Awareness and Screening Programs (HNCASP) are popular community outreach events hosted by academic and community otolaryngology departments. However, long-term follow-up of participants is lacking. Participants of a HNCASP held at an academic cancer center prospectively filled out demographic and risk factor surveys followed by HNC screening examination. A phone interview was conducted for participants between 2012 and 2016 with suspicious findings to assess outcomes. Participants were largely Caucasian, female, and had health insurance, reflecting the setting at an academic medical center. Despite this, there were 156 (16.8%) positive screenings; 47 of these completed follow up interviews. Twelve (1.1% of all participants) cancer cases were confirmed. A significant proportion of HNCASP participants benefited from this screening opportunity. Education regarding HNC is the primary benefit and motivational factor for attendance of HNCASPs, although a significant subset of patients was identified that needed follow-up, and several cancers were detected.

Employability pathways for young adults: lived experiences of learners and practitioners in Youth Guarantee programmes

ABSTRACT Until today, thousands of young adults still dropout of school with no or low qualifications and experience difficulties in entering the labour market. The European Commission offers funding and opportunities for young adults to enter employability enhancing training, often organised under its flagship initiative ‘The Youth Guarantee’. The aim of these programmes is to make young adults a work, training or educational offer within four months of their start into this initiative. In this paper, we critically explore the concept of employability and focus on the roles of both the young adults undergoing training interventions, but also of practitioners whose work is ideally embedded within the local context of the labour market and the economy. We were interested in the participation experiences by both groups to analyse the strengths and weaknesses of these programmes. Evidence from interviews demonstrated that learners and practitioners were generally satisfied with the interventions, although individualised support was preferred over group-based activities. Working with stakeholders was strongly recommended for this target group who tends to experience cumulative disadvantages. Long-term follow-up of participants’ destinations will provide better evidence on the effectiveness of these programmes.

Long-term stroke incidence in proximal thoracic aorta aneurysm survivors.

Aneurysm of proximal thoracic aorta (pTAA) is an often indolent, yet fatal disease. Although advancements in aneurysmal repair techniques have increased long-term survival rates, studies have proven that there are increases in perioperative risk for stroke incidence after pTAA surgery. Conversely, there is little evidence regarding the long-term stroke incidence in pTAA individuals, which strongly influences the morbidity, mortality, and usage of antithrombotic agents. Using the Taiwan National Health Insurance Research Database, a nationwide population-based cohort, we recruited 3013 pTAA survivors hospitalized from 1 January 2000 to 31 December 2012. To ensure study cohort quality, only patients aged 20 years and above who underwent aneurysmal repair surgery are included. The control cohort is identified by matching background features (comorbidities, age, gender) at a 1:4 ratio through the use of frequency matching. The primary outcomes include incidence of ischemic stroke and intracranial hemorrhage one month after aneurysmal repair surgery. The mortality of pTAA survivors is nearly twice of the matched controls despite aneurysmal repair (28.5 % vs. 15.2%, p < 0.001). Long-term follow-up of participants indicated that pTAA survivors had a higher risk for hemorrhage stroke (adjusted hazard ratio (aHR): 1.93; 95% confidence interval (CI): 1.47-2.53), but no significant increase in risk for ischemic stroke (aHR: 1.07; 95% CI: 0.92-1.25). Hemorrhagic stroke occurrence was found to be associated with age and diabetes mellitus. Comparison on hemorrhagic stroke subtypes between study and matched cohorts showed no statistical differences in intracerebral hemorrhage and subarachnoid hemorrhage. Despite the advancement of aneurysmal repair surgery, this study suggests that pTAA patients may still face an increased risk of hemorrhage stroke. Further investigation is warranted to provide better long-term care for the pTAA population.

Is improvement in comorbid major depression associated with longer survival in people with cancer? A long-term follow-up of participants in the SMaRT Oncology-2 and 3 trials

ObjectiveThere is evidence that patients with cancer have worse survival if they have comorbid major depression, but uncertainty whether a reduction in depression severity improves survival. We aimed to address this question. MethodsWe did a secondary analysis of data from participants in the SMaRT Oncology-2 and 3 trials of depression treatment in patients with cancer and comorbid major depression (total n = 642). Participants' data were analysed as cohorts, defined by treatment (usual care or Depression Care for People with Cancer, an intensive treatment programme, in both trials) and cancer prognosis (good or poor, in SMaRT Oncology-2 and 3 respectively). We measured change in depression severity from randomisation to 12 weeks using Symptom Checklist Depression Scale (SCL-20) scores and assessed survival by linked mortality data. We used Cox regression to estimate the effect of a one-unit decrease in SCL-20 score on survival, controlling for measured confounders. ResultsWe found no evidence for an association between improvement in depression and survival in any of the four cohorts, after adjusting for age, sex, primary cancer, baseline cancer severity and baseline depression severity. Pooling the cohorts in a fixed-effects meta-analysis yielded an estimated 7% reduction in the hazard of death per one-unit decrease in SCL-20 score. This finding was not statistically significant; the 95% confidence interval extended from a 26% decrease to an 18% increase in hazard of death. ConclusionWe found no evidence that reduction in severity of comorbid major depression is associated with longer survival in patients with cancer.

Does depression treatment improve the survival of depressed patients with cancer? A long-term follow-up of participants in the SMaRT Oncology-2 and 3 trials

Comorbid major depression has been associated with worse survival in patients with cancer. However, we do not know if treating depression improves survival. In the SMaRT Oncology-2 (good prognosis cancers) and SMaRT Oncology-3 (lung cancer, a poor prognosis cancer) trials, we found that a depression treatment programme, Depression Care for People with Cancer (DCPC), was effective in reducing comorbid major depression. In this analysis, we aimed to identify whether DCPC also had an effect on survival. The trials were conducted in three cancer centres and their associated clinics in Scotland, UK. In SMaRT Oncology-2, outpatients with good prognosis cancers and major depression were randomly assigned in a 1:1 ratio to DCPC or usual care, with stratification (by trial centre) and minimisation (by age, primary cancer, and sex) with allocation concealment. In SMaRT Oncology-3, outpatients with lung cancer and major depression were randomly assigned (1:1 ratio) to DCPC or usual care with stratification (by trial centre) and minimisation (by age, sex, and cancer type) with allocation concealment. For this analysis, we obtained long-term data on deaths (all causes) in the SMaRT Oncology-2 and 3 trial participants, censored at July 31, 2015, and analysed survival as a trial outcome. We estimated unadjusted hazard ratios (HRs) for each trial using Cox regression, and pooled the log HRs in a fixed-effects meta-analysis. We recruited 642 participants; between May 12, 2008, and May 13, 2011, 500 participants were recruited to the SMaRT Oncology-2 trial and between Jan 5, 2009, and Sept 9, 2011, 142 participants were recruited to the SMaRT Oncology-3 trial. We followed up SMaRT Oncology-2 and SMaRT Oncology-3 participants for a median of 5 years and 1 year, respectively. 135 (27%) of 500 SMaRT Oncology-2 participants and 114 (80%) of 142 SMaRT Oncology-3 participants died within this period. We found no significant effect of DCPC on survival in the total follow-up period for either SMaRT Oncology 2 (HR 1·02, 95% CI 0·72-1·42, p=0·93) or SMaRT Oncology-3 (HR 0·82, 95% CI 0·56-1·18, p=0·28; pooled HR 0·92, 95% CI 0·72-1·18, p=0·51). DCPC is highly effective in improving depression and quality of life in depressed patients with cancer, but there was no evidence for a significant effect on survival. Despite the absence of an effect on length of life, the management of depression remains important for its beneficial effect on quality of life. NIHR CLAHRC Oxford, Cancer Research UK, and the Chief Scientist Office of the Scottish Government.

Physical activity levels in adults and older adults 3-4 years after pedometer-based walking interventions: Long-term follow-up of participants from two randomised controlled trials in UK primary care.

BackgroundPhysical inactivity is an important cause of noncommunicable diseases. Interventions can increase short-term physical activity (PA), but health benefits require maintenance. Few interventions have evaluated PA objectively beyond 12 months. We followed up two pedometer interventions with positive 12-month effects to examine objective PA levels at 3–4 years.Methods and findingsLong-term follow-up of two completed trials: Pedometer And Consultation Evaluation-UP (PACE-UP) 3-arm (postal, nurse support, control) at 3 years and Pedometer Accelerometer Consultation Evaluation-Lift (PACE-Lift) 2-arm (nurse support, control) at 4 years post-baseline. Randomly selected patients from 10 United Kingdom primary care practices were recruited (PACE-UP: 45–75 years, PACE-Lift: 60–75 years). Intervention arms received 12-week walking programmes (pedometer, handbooks, PA diaries) postally (PACE-UP) or with nurse support (PACE-UP, PACE-Lift). Main outcomes were changes in 7-day accelerometer average daily step counts and weekly time in moderate-to-vigorous PA (MVPA) in ≥10-minute bouts in intervention versus control groups, between baseline and 3 years (PACE-UP) and 4 years (PACE-Lift). PACE-UP 3-year follow-up was 67% (681/1,023) (mean age: 59, 64% female), and PACE-Lift 4-year follow-up was 76% (225/298) (mean age: 67, 53% female). PACE-UP 3-year intervention versus control comparisons were as follows: additional steps/day postal +627 (95% CI: 198–1,056), p = 0.004, nurse +670 (95% CI: 237–1,102), p = 0.002; total weekly MVPA in bouts (minutes/week) postal +28 (95% CI: 7–49), p = 0.009, nurse +24 (95% CI: 3–45), p = 0.03. PACE-Lift 4-year intervention versus control comparisons were: +407 (95% CI: −177–992), p = 0.17 steps/day, and +32 (95% CI: 5–60), p = 0.02 minutes/week MVPA in bouts. Neither trial showed sedentary or wear-time differences. Main study limitation was incomplete follow-up; however, results were robust to missing data sensitivity analyses.ConclusionsIntervention participants followed up from both trials demonstrated higher levels of objectively measured PA at 3–4 years than controls, similar to previously reported 12-month trial effects. Pedometer interventions, delivered by post or with nurse support, can help address the public health physical inactivity challenge.Trial registrationsPACE-UP isrctn.com ISRCTN98538934; PACE-Lift isrctn.com ISRCTN42122561.

Gender-informed psycho-educational programme to promote respectful relationships and reduce postpartum common mental disorders among primiparous women: long-term follow-up of participants in a community-based cluster randomised controlled trial.

What Were We Thinking (WWWT) is a gender-informed, psychoeducational programme to promote respectful relationships and skilled management of unsettled infant behaviours and thereby reduce postpartum common mental disorders. It comprises a highly structured seminar for couples and babies, usual primary care from a WWWT-trained nurse and take-home print materials. The aim was to assess long-term outcomes after a cluster randomised controlled trial of WWWT. Trial participants who consented completed a computer-assisted telephone interview 18 months postpartum. Depressive symptoms were assessed with the Patient Health Questionnaire (PHQ-9) and anxiety symptoms with the Generalised Anxiety Disorder Scale (GAD-7). Impacts of baseline characteristics and trial arm on changes in scores from baseline to follow-up were calculated using Conditional Latent Growth Curve Models adjusting for prognostic indicators and controlling for clustering effects. Overall, 314/400 (78.5%) women contributed data at baseline (6 weeks postpartum), trial endline (26 weeks postpartum) and follow-up (12 months after trial endline). In intention-to-treat analyses, there was a significantly greater improvement in adjusted GAD-7 scores [regression coefficient (RC) -0.55; 95% confidence interval (CI) -0.94 to -0.17] and non-significant improvement (RC -0.27; 95% CI -0.63 to 0.08) in PHQ-9 scores from baseline to follow-up in the intervention than the control arm. In a per-protocol analysis, the proportion with GAD-7 scores ⩽4 (asymptomatic) improved 24.1% (55.7% baseline to 79.8% follow-up, p = 0.043) among women who received the full WWWT programme, which included the seminar, compared with 2.4% (77.1-79.5%, p = 0.706) among those who received the partial intervention (usual care from WWWT-trained nurse and print materials). The WWWT programme has a significant sustained beneficial impact on postnatal generalised anxiety among primiparous women compared with usual care. The in-person seminar is the most influential component of the intervention. Psycho-educational programmes integrated into primary care appear promising as a strategy to reduce postpartum common mental disorders.

Can routine data be used to support cancer clinical trials? A historical baseline on which to build: retrospective linkage of data from the TACT (CRUK 01/001) breast cancer trial and the National Cancer Data Repository

BackgroundRandomised clinical trials (RCTs) are the gold standard for evaluating new cancer treatments. They are, however, expensive to conduct, particularly where long-term follow-up of participants is required. Tracking participants via routine datasets could provide a cost-effective alternative for ascertaining follow-up information required to evaluate disease outcomes. This project explores the potential for routine data to inform cancer trials, using, the historical National Cancer Data Repository (NCDR) for English NHS sites and, for validation, mature data available from the TACT trial.MethodsDatasets were matched using patients’ NHS number, date of birth (dob) and name/initials. Demographics, clinical characteristics and outcomes were assessed for agreement and completeness. Overall survival was compared between NCDR and TACT.ResultsA total of 3151 patients underwent linkage; 3047 (96.7%) of which had matched records. Extensive cleaning was required for some registry data fields, e.g. cause of death, whilst others had large amounts of missing data, e.g. tumour size (22.1%). Other data had high levels of matching such as dob (99.6%) and date of death (89.6%). There was no evidence of differential survival rates (8-year survival: TACT = 75% (95% CI 73, 76); NCDR = 76% (95% CI 74, 77)).ConclusionsData quality and completeness requires improvement before routine data could be used for RCTs. Introduction of new routine datasets, including COSD, is welcomed although reporting of disease-recurrence events remains a concern. Prospective validation of such datasets is required before RCTs can confidently switch patient follow-up to utilise routinely collected NHS-based data.TACT Trial registrationClinicaltrials.gov NCT00033683, registered on 9 April 2002; ISRCTN79718493, registered on 1 July 2001.

Patient Reported Pain and Disability Following a Distal Radius Fracture: A Prospective Study.

Background:Fractures of the distal radius are common. Few studies investigating the extended long term outcomes of participants following a distal radius fracture (especially beyond 2 years) and they have relied on subjective measures or single objective tests to measure participant’s final outcome.Objectives:The objective of this study was to describe the pain and disability in long-term follow-up of participants after a distal radius fracture. Participants who had previously participated in a prospective study, where baseline and standardized one-year follow-up were performed, were contacted to volunteer to participate in this follow-up (FU) study. Sixty-five participants (17 males, 48 females) with an average age of 57 (SD 13) years at the time of injury and 67 (SD 13 years) at follow-up were evaluated at an average of 11(SD 6) years (range 2-20 years).Results:The majority of patients (85%) participants reported no change or had less pain and disability (PRWE) (<5 point difference) at their long-term follow-up compared to their one year PRWE scores. One year PRWE scores were found to be predictive (19.1%) of the variability in long term PRWE score (p=0.02). Age, gender, and mechanism of fall were not significant predictors of worsened outcome.Conclusion:The majority of people that are experiencing no or low patient reported pain and disability one year following a DRF can expect to retain their positive outcome 10-20 years later. This study did not identify how to predict worsened outcome.

Protocol for a scoping review of post-trial extensions of randomised controlled trials using individually linked administrative and registry data

IntroductionWell-conducted randomised controlled trials (RCTs) provide the least biased estimates of intervention effects. However, RCTs are costly and time-consuming to perform and long-term follow-up of participants may be hampered by...

Twin birth - planned vaginal delivery still standard of care.

Commentary on: Barrett JF, Hannah ME, Hutton EK, Willan AR, Allen AC, Armson BA, Gafni A, Joseph KS, Mason D, Ohlsson A, Ross S, Sanchez JJ, Asztalos EV. Twin Birth Study Collaborative Group. A randomized trial of planned cesarean or vaginal delivery for twin pregnancy. N Engl J Med 2013; 369: 1295–305. In this unique international effort to find evidence for the optimal mode of delivery for twins, planned Caesarean section did not reduce the risk for perinatal death or serious neonatal morbidity as compared to vaginal delivery 1. As pointed out by the authors, this finding may in part be explained by the high rate of Caesarean section (>40) in the planned-vaginal-delivery group, with most of these deliveries occurring during labour. Nevertheless, the design, the size of the study and high follow-up rate suggest that the findings are robust. Why is this knowledge important to neonatologists? Mainly, because the neonatologist is an important participant in counselling of women (and their partners) having twins, as well as in discussions with the obstetricians responsible for the delivery. With expectations of being the expert advisor acting in ‘the best interest of the baby’, the professional role of the neonatologist is to provide and discuss the safest mode of delivery. In this context, the study by Barrett et al. is central. The Twin Birth Study is also reassuring for those who try to challenge the ongoing increase in Caesarean section rates, not only for twin births 2 but also in general 3. Today, Caesarean section is the most common surgical procedure in women of reproductive ages and in many large countries and hospitals, Caesarean section rates exceed 50% by far. Besides the Twin Birth Study and the Term Breech Trial 4, there is a very weak evidence base for Caesarean section outside the emergency situation. For example, there is no randomized controlled trial testing Caesarean section for preterm birth; still, Caesarean section is often recommended for deliveries occurring before term. Given that half of the infants in the Twin Birth Study were born at 32–36 weeks of gestation, there seems to be little evidence for improved outcome after planned Caesarean section in moderately preterm infants. On the contrary, the opposite may be the case as suggested by observational data 5, 6. In this study, only short-term maternal and infant outcomes were compared. Epidemiological studies have reported associations between birth by Caesarean section and later health problems, such as increased risk for chronic immune disorders 7. While the underlying pathways for these associations are still obscure 8, it seems important that further long-term follow-up of participants in the Twin Birth Study will take place. https://ebneo.org/2015/04/twin-birth-planned-vaginal-delivery-still-standard-of-care/ None. None.

Landmark estimation of survival and treatment effects in observational studies.

Clinical studies aimed at identifying effective treatments to reduce the risk of disease or death often require long term follow-up of participants in order to observe a sufficient number of events to precisely estimate the treatment effect. In such studies, observing the outcome of interest during follow-up may be difficult and high rates of censoring may be observed which often leads to reduced power when applying straightforward statistical methods developed for time-to-event data. Alternative methods have been proposed to take advantage of auxiliary information that may potentially improve efficiency when estimating marginal survival and improve power when testing for a treatment effect. Recently, Parast et al. (J Am Stat Assoc 109(505):384-394, 2014) proposed a landmark estimation procedure for the estimation of survival and treatment effects in a randomized clinical trial setting and demonstrated that significant gains in efficiency and power could be obtained by incorporating intermediate event information as well as baseline covariates. However, the procedure requires the assumption that the potential outcomes for each individual under treatment and control are independent of treatment group assignment which is unlikely to hold in an observational study setting. In this paper we develop the landmark estimation procedure for use in an observational setting. In particular, we incorporate inverse probability of treatment weights (IPTW) in the landmark estimation procedure to account for selection bias on observed baseline (pretreatment) covariates. We demonstrate that consistent estimates of survival and treatment effects can be obtained by using IPTW and that there is improved efficiency by using auxiliary intermediate event and baseline information. We compare our proposed estimates to those obtained using the Kaplan-Meier estimator, the original landmark estimation procedure, and the IPTW Kaplan-Meier estimator. We illustrate our resulting reduction in bias and gains in efficiency through a simulation study and apply our procedure to an AIDS dataset to examine the effect of previous antiretroviral therapy on survival.

Capsule commentary on Piller et al., Characteristics and long-term follow-up of participants with peripheral vascular disease during ALLHAT.

More than a decade ago, the ALLHAT trial1 influenced the Joint National Committee (JNC) 7 to recommend diuretics for initial anti-hypertensive therapy in patients without “compelling indications.”2 JNC 8 does not comment on specific high-risk conditions considered compelling indications, other than chronic kidney disease (CKD).3 However, there are other conditions generally considered compelling indications to start a specific anti-hypertensive class, including: heart failure, postmyocardial infarction status, high coronary heart disease risk, diabetes and prior stroke.2 In this issue, a sub-study of the ALLHAT trial asks the question of whether peripheral artery disease (PAD) could be another compelling indication for choosing a specific anti-hypertensive class; namely, calcium channel blockers.4 In the original ALLHAT publication,1 analysis of the individual components of the secondary outcome revealed an intriguing trend for a lesser incidence of PAD among participants started on amlodipine, in comparison to chlorthalidone (Table 5). In the current follow-up paper, using a stricter definition for PAD, an almost identical trend for a lower incidence of PAD was found for amlodipine, though the finding remained not quite statistically significant. Based on the results of this analysis, PAD continues to stand alone as a major high-risk cardiovascular condition without compelling evidence to use a specific antihypertensive agent in order to improve outcomes. The authors conclude that there is a compelling need for comparative outcome trials examining treatment of PAD in high-risk patients. Unfortunately, this is no easy proposal, since monotherapy is rarely sufficient to adequately control hypertension in this complicated population. For example, most ALLHAT participants ended up needing a second line anti-hypertensive agent to achieve goal blood pressure levels. Therefore, we still need to figure out how to adequately account for the confounding that occurs in these multiple agent trials. In the interim, it should be appreciated that patients with PAD generally would be noted to have other comorbidities that are considered compelling indications for use of certain anti-hypertensive classes. We should use these comorbidities to guide our therapy of these high-risk patients.

Are we ready to recommend aspirin for cancer prevention?

Rothwell and colleagues report additional data supporting the hope that daily aspirin can ward off a panoply of cancers (1). Aspirin’s role in reducing risk of vascular events is well-established, although which risk factor profiles derive net benefit remain controversial (2). The strongest proof of aspirin’s anti-neoplastic effect has been in colorectal tumors. Several epidemiological studies (3), randomised controlled trials (RCTs) of colon polyp recurrence (4), and RCTs in patients with hereditary colorectal cancer (CRC) syndromes (5, 6), have shown that aspirin reduces incidence of colorectal neoplasia. By long-term follow-up of participants in five cardiovascular-prevention RCTs, Rothwell and colleagues previously observed that daily aspirin at any dose reduced risk of CRC by 24% and of CRC-associated mortality by 35% after a delay of 8–10 years (7).