Effect of a Standardized Family Participation Program in the ICU: A Multicenter Stepped-Wedge Cluster Randomized Controlled Trial.

OBJECTIVES: To determine the effect of a standardized program for family participation in essential care activities in the ICU on symptoms of anxiety, depression, posttraumatic stress and satisfaction among relatives, and perceptions and experiences of ICU healthcare providers (HCPs). DESIGN: Multicenter stepped-wedge cluster randomized controlled trial. SETTING: Seven adult ICUs, one university, and six general teaching hospitals. PARTICIPANTS: Three hundred six relatives and 235 ICU HCPs. INTERVENTIONS: A standardized program to facilitate family participation inpatient communication, amusement/distraction, comfort, personal care, breathing, mobilization, and nutrition. MEASUREMENTS AND MAIN RESULTS: Data were collected through surveys among relatives and ICU HCPs. There were no significant differences in symptoms of anxiety in relatives in the intervention period compared with the control period (median Hospital Anxiety and Depression Scale [HADS] 5 [interquartile range (IQR) 2-10] vs 6 [IQR 3-9]; median ratio [MR] 0.72; 95% CI, 0.46-1.13; p = 0.15), depression (median HADS 4 [IQR 2-6] vs 3 [IQR 1-6]; MR 0.85; 95% CI, 0.55-1.32; p = 0.47) or posttraumatic stress (median Impact of Event Scale-Revised score 0.45 [IQR 0.27-0.82] vs 0.41 [IQR 0.14-1]; MR 0.94; 95% CI, 0.78-1.14; p = 0.54). Reported satisfaction was slightly lower in the intervention period (mean 8.90 [ sd 1.10] vs mean 9.06 [ sd 1.10], difference -0.60; 95% CI, -1.07 to -0.12; p = 0.01). ICU HCPs perceived that more relatives knew how to participate: 47% in the intervention period versus 22% in the control period (odds ratio [OR] 3.15; 95% CI, 1.64-6.05; p < 0.01). They also reported relatives having sufficient knowledge (41% vs 16%; OR 3.56; 95% CI, 1.75-7.25; p < 0.01) and skills (44% vs 25%; OR 2.38; 95% CI, 1.22-4.63; p = 0.01) to apply family participation. CONCLUSIONS: Application of a standardized program to facilitate family participation did not change mental health symptoms in relatives of ICU patients 3 months after discharge. ICU HCPs reported increased clarity, knowledge, and skills among relatives and ICU HCPs.

The impact of prior exposure to hypoglycaemia on the inflammatory response to a subsequent hypoglycaemic episode.

BACKGROUND: Hypoglycaemia has been shown to induce a systemic pro-inflammatory response, which may be driven, in part, by the adrenaline response. Prior exposure to hypoglycaemia attenuates counterregulatory hormone responses to subsequent hypoglycaemia, but whether this effect can be extrapolated to the pro-inflammatory response is unclear. Therefore, we investigated the effect of antecedent hypoglycaemia on inflammatory responses to subsequent hypoglycaemia in humans. METHODS: Healthy participants (n = 32) were recruited and randomised to two 2-h episodes of either hypoglycaemia or normoglycaemia on day 1, followed by a hyperinsulinaemic hypoglycaemic (2.8 ± 0.1 mmol/L) glucose clamp on day 2. During normoglycaemia and hypoglycaemia, and after 24 h, 72 h and 1 week, blood was drawn to determine circulating immune cell composition, phenotype and function, and 93 circulating inflammatory proteins including hs-CRP. RESULTS: In the group undergoing antecedent hypoglycaemia, the adrenaline response to next-day hypoglycaemia was lower compared to the control group (1.45 ± 1.24 vs 2.68 ± 1.41 nmol/l). In both groups, day 2 hypoglycaemia increased absolute numbers of circulating immune cells, of which lymphocytes and monocytes remained elevated for the whole week. Also, the proportion of pro-inflammatory CD16+-monocytes increased during hypoglycaemia. After ex vivo stimulation, monocytes released more TNF-α and IL-1ß, and less IL-10 in response to hypoglycaemia, whereas levels of 19 circulating inflammatory proteins, including hs-CRP, increased for up to 1 week after the hypoglycaemic event. Most of the inflammatory responses were similar in the two groups, except the persistent pro-inflammatory protein changes were partly blunted in the group exposed to antecedent hypoglycaemia. We did not find a correlation between the adrenaline response and the inflammatory responses during hypoglycaemia. CONCLUSION: Hypoglycaemia induces an acute and persistent pro-inflammatory response at multiple levels that occurs largely, but not completely, independent of prior exposure to hypoglycaemia. Clinical Trial information Clinicaltrials.gov no. NCT03976271 (registered 5 June 2019).

Rectal Culture-Based Versus Empirical Antibiotic Prophylaxis to Prevent Infectious Complications in Men Undergoing Transrectal Prostate Biopsy: A Randomized, Nonblinded Multicenter Trial.

BACKGROUND: An increase in infections after transrectal prostate biopsy (PB), related to an increasing number of patients with ciprofloxacin-resistant rectal flora, necessitates the exploration of alternatives for the traditionally used empirical prophylaxis of ciprofloxacin. We compared infectious complication rates after transrectal PB using empirical ciprofloxacin prophylaxis versus culture-based prophylaxis. METHODS: In this nonblinded, randomized trial, between 4 April 2018 and 30 July 2021, we enrolled 1538 patients from 11 Dutch hospitals undergoing transrectal PB. After rectal swab collection, patients were randomized 1:1 to receive empirical prophylaxis with oral ciprofloxacin (control group [CG]) or culture-based prophylaxis (intervention group [IG]). Primary outcome was any infectious complication within 7 days after biopsy. Secondary outcomes were infectious complications within 30 days, and bacteremia and bacteriuria within 7 and 30 days postbiopsy. For primary outcome analysis, the χ2 test stratified for hospitals was used. Trial registration number: NCT03228108. RESULTS: Data from 1288 patients (83.7%) were available for analysis (CG, 652; IG, 636). Infection rates within 7 days postbiopsy were 4.3% (n = 28) (CG) and 2.5% (n = 16) (IG) (P value = .08; reduction: -1.8%; 95% confidence interval, -.004 to .040). Ciprofloxacin-resistant bacteria were detected in 15.2% (n = 1288). In the CG, the presence of ciprofloxacin-resistant rectal flora resulted in a 6.2-fold higher risk of early postbiopsy infection. CONCLUSIONS: Our study supports the use of culture-based prophylaxis to reduce infectious complications after transrectal PB. Despite adequate prophylaxis, postbiopsy infections can still occur. Therefore, culture-based prophylaxis must be weighed against other strategies that could reduce postbiopsy infections. Clinical Trials Registration. NCT03228108.

Effect of Structural Moral Case Deliberation on Burnout Symptoms, Moral Distress, and Team Climate in ICU Professionals: A Parallel Cluster Randomized Trial.

OBJECTIVES: Moral case deliberation (MCD) is a team-based and facilitator-led, structured moral dialogue about ethical difficulties encountered in practice. This study assessed whether offering structural MCD in ICUs reduces burnout symptoms and moral distress and strengthens the team climate among ICU professionals. DESIGN: This is a parallel cluster randomized trial. SETTING: Six ICUs in two hospitals located in Nijmegen, between January 2020 and September 2021. SUBJECTS: Four hundred thirty-five ICU professionals. INTERVENTIONS: Three of the ICUs organized structural MCD. In three other units, there was no structural MCD or other structural discussions of moral problems. MEASUREMENTS AND MAIN RESULTS: The primary outcomes investigated were the three burnout symptoms-emotional exhaustion, depersonalization, and a low sense of personal accomplishment-among ICU professionals measured using the Maslach Burnout Inventory on a 0-6 scale. Secondary outcomes were moral distress (Moral Distress Scale) on a 0-336 scale and team climate (Safety Attitude Questionnaire) on a 0-4 scale. Organizational culture was an explorative outcome (culture of care barometer) and was measured on a 0-4 scale. Outcomes were measured at baseline and in 6-, 12-, and 21-month follow-ups. Intention-to-treat analyses were conducted using linear mixed models for longitudinal nested data. Structural MCD did not affect emotional exhaustion or depersonalization, or the team climate. It reduced professionals' personal accomplishment (-0.15; p < 0.05) but also reduced moral distress (-5.48; p < 0.01). Perceptions of organizational support (0.15; p < 0.01), leadership (0.19; p < 0.001), and participation opportunities (0.13; p < 0.05) improved. CONCLUSIONS: Although structural MCD did not mitigate emotional exhaustion or depersonalization, and reduced personal accomplishment in ICU professionals, it did reduce moral distress. Moreover, it did not improve team climate, but improved the organizational culture.

Towards patient-led follow-up after curative surgical resection of stage I, II and III colorectal cancer (DISTANCE-trial): a study protocol for a stepped-wedge cluster-randomised trial.

BACKGROUND: Colorectal cancer (CRC) is among the most frequently diagnosed cancers. Approximately 20-30% of stage I-III CRC patients develop a recurrent tumour or metastases after curative surgical resection. Post-operative follow-up is indicated for the first five years after curative surgical resection. As intensified follow-up after curative surgical resection has shown no effect on survival, patient organisations and policy makers have advocated for a more patient-centred approach to follow-up. The objective of this study is to successfully implement patient-led, home-based follow-up (PHFU) in six hospitals in The Netherlands, with as ultimate aim to come to a recommendation for a patient-centred follow-up schedule for stage I-III CRC patients treated with surgical resection with curative intent. METHODS: This study is designed as a stepped-wedge cluster-randomised trial (SW-CRT) in six participating centres. During the trial, three centres will implement PHFU after six months; the other three centres will implement PHFU after 12 months of inclusion in the control group. Eligible patients are those with pT2-4N0M0 or pT1-4N1-2M0 CRC, who are 18 years or older and have been free of disease for 12 months after curative surgical resection. The studied intervention is PHFU, starting 12 months after curative resection. The in-hospital, standard-of-care follow-up currently implemented in the participating centres functions as the comparator. The proportion of patients who had contact with the hospital regarding CRC follow-up between 12-24 months after curative surgical resection is the primary endpoint of this study. Quality of life, fear of cancer recurrence, patient satisfaction, cost-effectiveness and survival are the secondary endpoints. DISCUSSION: The results of this study will provide evidence on whether nationwide implementation of PHFU for CRC in The Netherlands will be successful in reducing contact between patient and health care provider. Comparison of PROMs between in-hospital follow-up and PHFU will be provided. Moreover, the cost-effectiveness of PHFU will be assessed. TRIAL REGISTRATION: Dutch Trail Register (NTR): NL9266 (Registered on January 1st, 2021).

Hypoglycaemia induces a sustained pro-inflammatory response in people with type 1 diabetes and healthy controls.

AIM: To determine the duration and the extension of the pro-inflammatory response to hypoglycaemia both in people with type 1 diabetes and healthy controls. MATERIALS AND METHODS: Adults with type 1 diabetes (n = 47) and matched controls (n = 16) underwent a hyperinsulinaemic-euglycaemic hypoglycaemic (2.8 ± 0.1 mmoL/L [49.9 ± 2.3 mg/dL]) glucose clamp. During euglycaemia, hypoglycaemia, and 1, 3 and 7 days later, blood was drawn to determine immune cell phenotype, monocyte function and circulating inflammatory markers. RESULTS: Hypoglycaemia increased lymphocyte and monocyte counts, which remained elevated for 1 week. The proportion of CD16+ monocytes increased and the proportion of CD14+ monocytes decreased. During hypoglycaemia, monocytes released more tumour necrosis factor-α and interleukin-1ß, and less interleukin-10, after ex vivo stimulation. Hypoglycaemia increased the levels of 19 circulating inflammatory proteins, including high sensitive C-reactive protein, most of which remained elevated for 1 week. The epinephrine peak in response to hypoglycaemia was positively correlated with immune cell number and phenotype, but not with the proteomic response. CONCLUSIONS: Overall, despite differences in prior exposure to hypoglycaemia, the pattern of the inflammatory responses to hypoglycaemia did not differ between people with type 1 diabetes and healthy controls. In conclusion, hypoglycaemia induces a range of pro-inflammatory responses that are sustained for at least 1 week in people with type 1 diabetes and healthy controls.

Sample size for partially nested designs and other nested or crossed designs with a continuous outcome when adjusted for baseline.

In a randomized controlled trial, outcomes of different subjects may be independent at baseline, but correlated at a follow-up measurement due to treatment. This treatment-related clustering at follow-up can arise for instance because the treatment is given in a group or because subjects are treated individually but by the same therapist (therapist effect). There is substantial literature on the design and analysis of such trials when estimation of the intervention effect is based on a follow-up measurement (eg, directly after treatment or at a later time point). However, often the baseline measurement of the outcome is highly correlated with the follow-up measurement, and this information can be used in the analysis. For a randomized design with a baseline and a follow-up measurement, we compare sample size requirements for analyses with and without adjustment for this baseline measure. We show that adjusting for baseline reduces required sample size. This reduction depends on the variance of the difference between arms at baseline, the variance of this difference at follow-up, and the correlation between the two. From this, we derive sample size formulas for partially or fully nested designs, and cluster randomized trials with treatment as a partially or fully cross-classified factor. Also, we discuss situations where clusters are already present at baseline or where treatment by cluster interaction is present. For the partially nested design, we work out practical design considerations (eg, use of content-matter input, design factors and optimal allocation ratio) and investigate small sample properties of the sample size formula.

Glycaemic thresholds for counterregulatory hormone and symptom responses to hypoglycaemia in people with and without type 1 diabetes: a systematic review.

AIM/HYPOTHESIS: The physiological counterregulatory response to hypoglycaemia is reported to be organised hierarchically, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To compare thresholds for activation of these responses more accurately between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic-hypoglycaemic glucose clamps. METHODS: A literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Key exclusion criteria were as follows: data were previously published; other patient population; a clamp not the primary intervention; and an inadequate clamp description. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using generalised logrank test for interval-censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% CI of the mean baseline measurement or euglycaemic control clamp. Because of the use of interval-censored data, we described thresholds using median and IQR. RESULTS: A total of 63 articles were included, whereof 37 papers included participants with type 1 diabetes (n=559; 67.4% male sex, aged 32.7±10.2 years, BMI 23.8±1.4 kg/m2) and 51 papers included participants without diabetes (n=733; 72.4% male sex, aged 31.1±9.2 years, BMI 23.6±1.1 kg/m2). Compared with non-diabetic control individuals, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 [3.2-4.2] vs 3.4 [2.8-3.9 mmol/l]), noradrenaline (3.2 [3.2-3.7] vs 3.0 [2.8-3.1] mmol/l), cortisol (3.5 [3.2-4.2]) vs 2.8 [2.8-3.4] mmol/l) and growth hormone (3.8 [3.3-3.8] vs. 3.2 [3.0-3.3] mmol/l) all occurred at lower glucose levels in people with diabetes than in those without diabetes (all p≤0.01). Similarly, although both autonomic (median [IQR] 3.4 [3.4-3.4] vs 3.0 [2.8-3.4] mmol/l) and neuroglycopenic (median [IQR] 3.4 [2.8-N/A] vs 3.0 [3.0-3.1] mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup. CONCLUSIONS/INTERPRETATION: People with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia. There was a considerable variation in the methodology of the articles and the high insulin doses in most of the clamps may affect the counterregulatory responses. FUNDING: This article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460. REGISTRATION: This systematic review is registered in PROSPERO (CRD42019120083).

Treat-to-target dose reduction and withdrawal strategy of TNF inhibitors in psoriatic arthritis and axial spondyloarthritis: a randomised controlled non-inferiority trial.

OBJECTIVES: Tumour necrosis factor inhibitors (TNFi) are effective in psoriatic arthritis (PsA) and axial spondyloarthritis (axSpA), but are associated with a small (0.6%) increase in serious infection risk, patient burden due to need for self-injection and high costs. Treat-to-target (T2T) tapering might ameliorate these drawbacks, but high-quality evidence on T2T tapering strategies is lacking in PsA and axSpA. METHODS: We performed a pragmatic open-label, monocentre, randomised controlled non-inferiority (NI) trial on T2T tapering of TNFi. Patients with PsA and axSpA using a TNFi with ≥6 months stable low disease activity (LDA) were included. Patients were randomised 2:1 to disease activity-guided T2T with or without tapering until withdrawal and followed-up to 12 months. Primary endpoint was the difference in proportion of patients having LDA at 12 months between groups, compared with a prespecified NI margin of 20%, estimated using a Bayesian prior. RESULTS: 122 patients (64 PsA and 58 axSpA) were randomised to a T2T strategy with (N=81) or without tapering (N=41). The proportion of patients in LDA at 12 months was 69% for the tapering and 73% for the no-tapering group: adjusted difference 5% (Bayesian 95% credible interval: -10% to 19%) which confirms NI considering the NI margin of 20%. The mean percentage of daily defined dose was 53% for the tapering and 91% for the no-tapering group at month 12. CONCLUSIONS: A T2T TNFi strategy with tapering attempt is non-inferior to a T2T strategy without tapering with regard to the proportion of patients still in LDA at 12 months, and results in a substantial reduction of TNFi use. TRIAL REGISTRATION NUMBER: NL 6771.

Differential Temporal Dynamics of Axial and Appendicular Ataxia in SCA3.

BACKGROUND: Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items. OBJECTIVES: To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluate if clinical and demographic factors are differentially associated with evolution of axial and appendicular ataxia. METHODS: In a prospective, multinational cohort study involving 11 European and 2 US sites, SARA scores were determined longitudinally in 223 SCA3 patients with a follow-up assessment after 1 year. RESULTS: An increase in SARA score from 10 to 20 points was mainly driven by axial and speech items, with a markedly smaller contribution of appendicular items. Finger chase and nose-finger test scores not only showed the lowest variability at baseline, but also the least deterioration at follow-up. Compared with the full set of SARA items, omission of both tests would result in lower sample size requirements for therapeutic trials. Sex was associated with change in SARA sum score and appendicular, but not axial, subscore, with a significantly faster progression in men. Despite considerable interindividual variability, the average annual progression rate of SARA score was approximately three times higher in subjects with a disease duration over 10 years than in those within 10 years from onset. CONCLUSION: Our findings provide evidence for a difference in temporal dynamics between axial and appendicular ataxia in SCA3 patients, which will help inform the design of clinical trials and development of new (etiology-specific) outcome measures. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Increased adherence to perioperative safety guidelines associated with improved patient safety outcomes: a stepped-wedge, cluster-randomised multicentre trial.

BACKGROUND: National Dutch guidelines have been introduced to improve suboptimal perioperative care. A multifaceted implementation programme (IMPlementatie Richtlijnen Operatieve VEiligheid [IMPROVE]) has been developed to support hospitals in applying these guidelines. This study evaluated the effectiveness of IMPROVE on guideline adherence and the association between guideline adherence and patient safety. METHODS: Nine hospitals participated in this unblinded, superiority, stepped-wedge, cluster RCT in patients with major noncardiac surgery (mortality risk ≥1%). IMPROVE consisted of educational activities, audit and feedback, reminders, organisational, team-directed, and patient-mediated activities. The primary outcome of the study was guideline adherence measured by nine patient safety indicators on the process (stop moments from the composite STOP bundle, and timely administration of antibiotics) and on the structure of perioperative care. Secondary safety outcomes included in-hospital complications, postoperative wound infections, mortality, length of hospital stay, and unplanned care. RESULTS: Data were analysed for 1934 patients. The IMPROVE programme improved one stop moment: 'discharge from recovery room' (+16%; 95% confidence interval [CI], 9-23%). This stop moment was related to decreased mortality (-3%; 95% CI, -4% to -1%), fewer complications (-8%; 95% CI, -13% to -3%), and fewer unscheduled transfers to the ICU (-6%; 95% CI, -9% to -3%). IMPROVE negatively affected one other stop moment - 'discharge from the hospital' - possibly because of the limited resources of hospitals to improve all stop moments together. CONCLUSIONS: Mixed implementation effects of IMPROVE were found. We found some positive associations between guideline adherence and patient safety (i.e. mortality, complications, and unscheduled transfers to the ICU) except for the timely administration of antibiotics. CLINICAL TRIAL REGISTRATION: NTR3568 (Dutch Trial Registry).

The Impact of Nursing Delirium Preventive Interventions in the ICU: A Multicenter Cluster-randomized Controlled Clinical Trial.

Rationale: Delirium is common in critically ill patients and is associated with deleterious outcomes. Nonpharmacological interventions are recommended in current delirium guidelines, but their effects have not been unequivocally established. Objectives: To determine the effects of a multicomponent nursing intervention program on delirium in the ICU. Methods: A stepped-wedge cluster-randomized controlled trial was conducted in ICUs of 10 centers. Adult critically ill surgical, medical, or trauma patients at high risk of developing delirium were included. A multicomponent nursing intervention program focusing on modifiable risk factors was implemented as standard of care. The primary outcome was the number of delirium-free and coma-free days alive in 28 days after ICU admission. Measurements and Main Results: A total of 1,749 patients were included. Time spent on interventions per 8-hour shift was median (interquartile range) 38 (14-116) minutes in the intervention period and median 32 (13-73) minutes in the control period (P = 0.44). Patients in the intervention period had a median of 23 (4-27) delirium-free and coma-free days alive compared with a median of 23 (5-27) days for patients in the control group (mean difference, -1.21 days; 95% confidence interval, -2.84 to 0.42 d; P = 0.15). In addition, the number of delirium days was similar: median 2 (1-4) days (ratio of medians, 0.90; 95% confidence interval, 0.75 to 1.09; P = 0.27). Conclusions: In this large randomized controlled trial in adult ICU patients, a limited increase in the use of nursing interventions was achieved, and no change in the number of delirium-free and coma-free days alive in 28 days could be determined. Clinical trial registered with www.clinicaltrials.gov (NCT03002701).

Estimation of treatment effects in short-term depression studies. An evaluation based on the ICH E9(R1) estimands framework.

Estimands aim to incorporate intercurrent events in design, data collection and estimation of treatment effects in clinical trials. Our aim was to understand what estimands may correspond to efficacy analyses commonly employed in clinical trials conducted before publication of ICH E9(R1). We re-analysed six clinical trials evaluating a new anti-depression treatment. We selected the following analysis methods-ANCOVA on complete cases, following last observation carried forward (LOCF) imputation and following multiple imputation; mixed-models for repeated measurements without imputation (MMRM), MMRM following LOCF imputation and following jump-to-reference imputation; and pattern-mixture mixed models. We included a principal stratum analysis based on the predicted subset of the study population who would not discontinue due to adverse events or lack of efficacy. We translated each analysis into the implicitly targeted estimand, and formulated corresponding clinical questions. We could map six estimands to analysis methods. The same analysis method could be mapped to more than one estimand. The major difference between estimands was the strategy for intercurrent events, with other attributes mostly the same across mapped estimands. The quantitative differences in MADRS10 population-level summaries between the estimands were 4-8 points. Not all six estimands had a clinically meaningful interpretation. Only a few analyses would target the same estimand, hence only few could be used as sensitivity analyses. The fact that an analysis could estimate different estimands emphasises the importance of prospectively defining the estimands targeting the primary objective of a trial. The fact that an estimand can be targeted by different analyses emphasises the importance of prespecifying precisely the estimator for the targeted estimand.

Coronavirus Disease 2019 Immediately Increases Burnout Symptoms in ICU Professionals: A Longitudinal Cohort Study.

OBJECTIVES: ICU professionals are at risk of developing burnout due to coronavirus disease 2019. This study assesses the prevalence and incidence of burnout symptoms and moral distress in ICU professionals before and during the coronavirus disease 2019 crisis. DESIGN: This is a longitudinal open cohort study. SETTING: Five ICUs based in a single university medical center plus another adult ICU based on a separate teaching hospital in the Netherlands. SUBJECTS: All ICU professionals were sent a baseline survey in October-December 2019 (252 respondents, response rate: 53%), and a follow-up survey was sent in May-June 2020 (233 respondents, response rate: 50%). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Burnout symptoms and moral distress measured with the Maslach Burnout Inventory and the Moral Distress Scale, respectively. The prevalence of burnout symptoms was 23.0% before coronavirus disease 2019 and 36.1% at postpeak time, with higher rates in nurses (38.0%) than in physicians (28.6%). Reversely, the incidence rate of new burnout cases among physicians was higher (26.7%) than nurses (21.9%). Higher prevalence of burnout symptoms was observed in the postpeak coronavirus disease 2019 period (odds ratio, 1.83; 95% CI, 1.32-2.53), for nurses (odds ratio, 1.77; 95% CI, 1.03-3.04), for professionals working overtime (odds ratio 2.11; 95% CI, 1.48-3.02), and for professionals directly engaged with care for coronavirus disease 2019 patients (odds ratio, 1.87; 95% CI, 1.35-2.60). Physicians were more likely than nurses to develop burnout symptoms due to coronavirus disease 2019 (odds ratio, 3.56; 95% CI, 1.06-12.21). CONCLUSIONS: This study shows that overburdening of ICU professionals during an extended period of time leads to symptoms of burnout. Working long hours and under conditions of scarcity of staff, time, and resources comes at the price of ICU professionals' mental health.

Identifying the minimal important difference in patient-reported outcome measures in the field of people with severe mental illness: a pre-post-analysis of the Illness Management and Recovery Programme.

PURPOSE: Complementary interventions for persons with severe mental illness (SMI) focus on both personal recovery and illness self-management. This paper aimed to identify the patient-reported outcome measures (PROMs) associated with the most relevant and meaningful change in persons with SMI who attended the Illness Management and Recovery Programme (IMR). METHODS: The effect of the IMR was measured with PROMs concerning recovery, illness self-management, burden of symptoms and quality of life (QoL). From the QoL measures, an anchor was chosen based on the most statistically significant correlations with the PROMs. Then, we estimated the minimal important difference (MID) for all PROMs using an anchor-based method supported by distribution-based methods. The PROM with the highest outcome for effect score divided by MID (the effect/MID index) was considered to be a measure of the most relevant and meaningful change. RESULTS: All PROMs showed significant pre-post-effects. The QoL measure 'General Health Perception (Rand-GHP)' was identified as the anchor. Based on the anchor method, the Mental Health Recovery Measure (MHRM) showed the highest effect/MID index, which was supported by the distribution-based methods. Because of the modifying gender covariate, we stratified the MID calculations. In most MIDs, the MHRM showed the highest effect/MID indexes. CONCLUSION: Taking into account the low sample size and the gender covariate, we conclude that the MHRM was capable of showing the most relevant and meaningful change as a result of the IMR in persons with SMI.

Effectiveness and cost effectiveness of interpersonal community psychiatric treatment (ICPT) for people with long-term severe non-psychotic mental disorders: a multi-Centre randomized controlled trial.

BACKGROUND: Long-term community mental health treatment for non-psychotic disorder patients with severe mental illness (SMI) who are perceived as difficult by clinicians, is poorly developed and lacks a structured, goal-centred approach. This study compares (cost-)effectiveness of Interpersonal Community Psychiatric Treatment (ICPT) with Care As Usual (CAU) on quality of life and clinician perceived difficulty in the care for non-psychotic disorder SMI-patients. A multi-centre cluster-randomized clinical tria was conducted in which Community Mental Health Nurses (Clinicians) in three large community mental health services in the Netherlands were randomly allocated to providing either ICPT or CAU to included patients. A total of 56 clinicians were randomized, who treated a total of 93 patients (59 in ICPT-group and 34 in CAU-group). METHODS: Primary outcome measure is patient-perceived quality of life as measured by the Manchester Short Assessment of Quality of Life (MANSA). Secondary outcome measures include clinician-perceived difficulty, general mental health, treatment outcomes, illness management and recovery, therapeutic relationship, care needs and social network. Patients were assessed at baseline, during treatment (6 months), after treatment (12 months) and at 6 months follow-up (18 months). Linear mixed-effects models for repeated measurements were used to compare mean changes in primary and secondary outcomes between intervention and control group of patients over time on an intention to treat basis. Potential efficiency was investigated from a societal perspective. Economic evaluation was based on general principles of a cost-effectiveness analysis. Outcome measures for health economic evaluation, were costs, and Quality Adjusted Life Years (QALYs). RESULTS: Half of the intended number of patients were recruited. There was no statistically significant treatment effect found in the MANSA (0.17, 95%-CI [- 0.058,0.431], p = 0.191). Treatment effects showed significant improvement in the Different Doctor-Patient Relationship Questionnaire-scores and a significant increase in the Illness Management and Recovery-scale Client-version scores). No effects of ICPT on societal and medical costs nor QALYs were found. CONCLUSIONS: This is the first RCT to investigate the (cost)-effectiveness of ICPT. Compared with CAU, ICPT did not improve quality of life, but significantly reduced clinician-perceived difficulty, and increased subjective illness management and recovery. No effects on costs or QALY's were found. TRIAL REGISTRATION: NTR 3988 , registered 13 May 2013.

Steroid treatment for the first episode of childhood nephrotic syndrome: comparison of the 8 and 12 weeks regimen using an individual patient data meta-analysis.

Steroids are the cornerstone of the treatment of childhood nephrotic syndrome. The optimal duration for the first episode remains a matter of debate. The aim of this study is to determine whether the 8 weeks International Study of Kidney Disease in Children (ISKDC) regimen is equally effective as the 12 weeks steroid regimen from the German society of pediatric nephrology (Arbeitsgemeinschaft für Pädiatrische Nephrologie [APN]). An individual patient data (IPD) meta-analysis of randomized controlled trials reporting on prednisolone treatment for a first episode of childhood nephrotic syndrome was conducted. European trials aimed at investigating the ISKDC and/or APN steroid regimen were selected. The lead investigators of the selected trials were requested to provide the IPD of the specific treatment groups. Four trials included European cohorts using dosing schedules according to the regimens studied. IPD of two trials were available. A significant difference was found in time to first relapse after cessation of steroid treatment between the 8 and 12 weeks treatment group with a median time to relapse of 29 and 63 days, respectively. Moreover, relapse rate ratios during total follow-up were 51% higher for the 8 weeks regimen. Finally, younger children have a significantly lower time to first relapse and frequently relapsing nephrotic syndrome.Conclusions: The results of this IPD meta-analysis suggest that the 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen. Moreover, this study highlights the importance of using uniform definitions to enable accurate comparison and interpretation of trial results.Trial registration: Registration number: CRD42020199244, date of registration 16-08-2020 What is Known: • Steroids are the cornerstone of the treatment of childhood nephrotic syndrome, however the optimal duration for the first episode remains a matter of debate. • Currently, the 8 weeks ISKDC protocol and 12 weeks APN protocol are among the most frequently used protocols in Europe. What is New: • The 8 weeks steroid regimen for a first episode of steroid-sensitive nephrotic syndrome may not be equally effective as the 12 weeks steroid regimen for the treatment of a first episode of nephrotic syndrome. • Younger children have a significantly shorter time to first relapse and time to frequent relapsing nephrotic syndrome.

Beyond "Intent-to-treat" and "Per protocol": Improving assessment of treatment effects in clinical trials through the specification of an estimand.

There is a key problem in randomised clinical trials as outcomes can be distorted due to informative post-randomisation events. This is inadequately addressed by the use of traditional intention-to-treat or per protocol analysis sets and often either ignored or wrongly labelled as missing data. As a consequence, the treatment effects of interest in a clinical trial are not well defined and their estimates might be misinterpreted. The estimand framework should help all those planning, conducting and analysing clinical trials as well as those interpreting the results to better define, estimate and understand the treatment effects of interest. This framework is described in the addendum to ICH E9 and addresses precisely this problem. It is relevant for regulatory drug trials and academic-run trials, as well as for trials of nonpharmacological interventions.

Diagnostic accuracy of a single-lead portable ECG device for measuring QTc prolongation.

BACKGROUND: To assess the diagnostic accuracy of a single-lead portable ECG device for measuring QTc-intervals in comparison with a standard 12-lead ECG. METHODS: Adult patients visiting the cardiology outpatient clinic for a 12-lead recording were also measured with a portable single-lead ECG recorder (HeartcheckTM). QTc-intervals were determined by two cardiologists. Perfect agreement was defined as a limit of ≤10 ms between the two measurement methods. RESULTS: Hundred one ECGs were recorded. QTc-interval mean differences between the two measurement methods was substantially outside our definition of perfect agreement (-31.9 [SD±41.3] ms). CONCLUSION: In conclusion, the Heartcheck single-lead ECG device is not accurate for measuring QTc-intervals.

A tutorial on dynamic risk prediction of a binary outcome based on a longitudinal biomarker.

Dynamic risk predictions based on all available information are useful in timely identification of high-risk patients. However, in contrast with time to event outcomes, there is still a lack of studies that clearly demonstrate how to obtain and update predictions for a future binary outcome using a repeatedly measured biomarker. The aim of this study is to give an illustrative overview of four approaches to obtain such predictions: likelihood based two-stage method (2SMLE), likelihood based joint model (JMMLE), Bayesian two-stage method (2SB), and Bayesian joint model (JMB). We applied the approaches to provide weekly updated predictions of post-molar gestational trophoblastic neoplasia (GTN) based on age and repeated measurements of human chorionic gonadotropin (hCG). Discrimination and calibration measures were used to compare the accuracy of the weekly predictions. Internal validation of the models was conducted using bootstrapping. The four approaches resulted in the same predictive and discriminative performance in predicting GTN. A simulation study showed that the joint models outperform the two-stage methods when we increase the within- and the between-patients variability of the biomarker. The applicability of these models to produce dynamic predictions has been illustrated through a comprehensive explanation and accompanying syntax (R and SAS® ).