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Background: High-impact surgery imposes a significant physiological and functional burden and is associated with substantial postoperative morbidity. Multimodal prehabilitation has demonstrated a reduction in postoperative complications and enhanced functional recovery, mainly in abdominal cancer surgery. Common preoperative risk factors shared among patients undergoing high-impact surgery, extending beyond abdominal cancer surgery procedures, suggest the relevance of multimodal prehabilitation to a broader patient population. This stepped wedge trial primarily aims to examine the hospital-wide effect of multimodal prehabilitation, compared to standard preoperative care, on the occurrence and severity of postoperative complications. Secondary and tertiary endpoints include length of hospital stay, physical fitness, nutritional status, mental health, intoxications, and cost-effectiveness of the intervention. Methods: The Fit4Surgery (F4S) PREHAB trial is a monocenter stepped wedge trial in an academic hospital. Adult patients, divided into 20 health clusters based on specific diagnoses, will be assessed for eligibility and receive usual preoperative care or multimodal prehabilitation. Patient enrollment commenced in March 2021 and continues up to and including April 2024. The intervention consists of a high-intensity exercise program, a nutritional intervention, psychological support, and smoking and alcohol cessation. The primary outcome will be measured by the Clavien-Dindo classification (grade II or higher) and the Comprehensive Complication Index (CCI). Discussion: Multimodal prehabilitation potentially reduces postoperative complications and enhances functional recovery. This is the first study to determine the hospital-wide effect and cost-effectiveness of multimodal prehabilitation in patients across various surgical specialties. [ABSTRACT FROM AUTHOR]

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-1β, 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). [ABSTRACT FROM AUTHOR]

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‐1β, 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. [ABSTRACT FROM AUTHOR]

Background: Delirium is a pathobiological brain process that is frequently observed in Intensive Care Unit (ICU) patients, and is associated with longer hospitalization as well as long-term cognitive impairment. In neurological ICU patients, delirium may be more treatment-resistant due to the initial brain injury. This study examined the effects of a multicomponent non-pharmacological nursing intervention program on delirium in neurological ICU patients. Methods: A single-center interrupted time series trial was conducted in adult neurological ICU patients at high risk for developing delirium who were non-delirious at admission. A multicomponent nursing intervention program focusing on modifiable risk factors for delirium, including the optimalization of vision, hearing, orientation and cognition, sleep and mobilization, was implemented as the standard of care, and its effects were studied. The primary outcome was the number of delirium-free and coma-free days alive at 28 days after ICU admission. The secondary outcomes included delirium incidence and duration, ICU and hospital length-of-stay and duration of mechanical ventilation. Results: Of 289 eligible patients admitted to the ICU, 130 patients were included, with a mean age of 68 ± 11 years, a mean APACHE-IV score of 79 ± 25 and a median predicted delirium risk (E-PRE-DELIRIC) score of 42 [IQR 38–50]). Of these, 73 were included in the intervention period and 57 in the control period. The median delirium- and coma-free days alive were 15 days [IQR 0–26] in the intervention group and 10 days [IQR 0–24] in the control group (level change −0.48 days, 95% confidence interval (95%CI) −7 to 6 days, p = 0.87; slope change −0.95 days, 95%CI −2.41 to 0.52 days, p = 0.18). Conclusions: In neurological ICU patients, our multicomponent non-pharmacological nursing intervention program did not change the number of delirium-free and coma-free days alive after 28 days. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective The purpose of this study was to assess whether the superior cost-effectiveness of a personalized physical therapy approach (Coach2Move)—which was demonstrated in a previous trial compared with usual care physical therapy (UCP)—can be replicated in daily clinical practice. Methods A multicenter, cluster-randomized, stepped wedge trial with 4 clusters consisting of 4 physical therapist practices in the Netherlands was used to compare a personalized physical therapy approach to elicit physical activity (Coach2Move) versus care as usual. Multilevel analyses for effectiveness were conducted for the amount of physical activity (Longitudinal Aging Study Amsterdam Physical Activity Questionnaire) and functional mobility (Timed "Up & Go" Test) at 3, 6 (primary outcome), and 12 months' follow-up. Secondary outcomes were level of frailty (Evaluative Frailty Index for Physical Activity), perceived effect (Global Perceived Effect and Patient-Specific Complaints Questionnaires), quality of life (Euro Quality of Life-5 Dimensions-5 Levels [EQ-5D-5L]), and health care expenditures. Results The 292 community-dwelling older adults with mobility problems visiting physical therapists were included in either the Coach2Move (n = 112; mean [SD] age = 82 [5] years; 60% female) or UCP (n = 180; mean [SD] age = 81 (6) years; 62% female) section of the trial. At baseline, Coach2Move participants were less physically active compared with UCP participants (mean difference = −198; 95% CI = −90 to −306 active minutes). At 6 months, between-group mean differences [95% CI] favored Coach2Move participants on physical activity levels (297 [83 to 512] active minutes), functional mobility (−14.2 [−21 to −8]) seconds), and frailty levels (−5 [−8 to −1] points). At 12 months, the physical activity levels of Coach2Move participants further increased, and frailty levels and secondary outcomes remained stable, whereas outcomes of UCP participants decreased. After the Coach2Move implementation strategy, physical therapists utilized significantly fewer treatment sessions compared with before the implementation (15 vs 22). Anticipated cost savings were not observed. Conclusion This study replicated the results of an earlier trial and shows that Coach2Move leads to better mid- and long-term outcomes (physical activity, functional mobility, level of frailty) in fewer therapy sessions compared with UCP. Based on these and earlier findings, the implementation of Coach2Move in physical therapist practice is recommended. Impact This article describes the implementation of the Coach2Move approach, a treatment strategy that has proven to be cost-effective in a previously conducted randomized controlled trial. Implementation of Coach2Move in a real-life setting allowed an evaluation of the effects in a clinically relevant population. Coach2Move has been shown to increase physical activity, improve functional mobility, and reduce frailty more effectively compared with UCP therapy and therefore has application for physical therapists working with older adults in daily clinical practice. Lay summary Coach2Move is a new physical therapy approach for older adults. Implementation of Coach2Move in daily clinical practice can help people better outcomes over a longer period of time against similar costs compared with regular physical therapy. [ABSTRACT FROM AUTHOR]

Iatrogenic hypoglycemia activates the immune system and is associated with an increased risk for atherosclerotic disease. We determined acute and long-term effects of insulin-induced hypoglycemia on inflammatory markers in humans with or without type 2 diabetes. A total of 15 adults with type 2 diabetes and 16 matched control subjects (17 men and 14 women, age 59.6 ± 7.1 years, BMI 28.5 ± 4.3 kg/m2) underwent a hyperinsulinemic-euglycemic (5.31 ± 0.32 mmol/L) hypoglycemic (2.80 ± 0.12 mmol/L) glucose clamp. Blood was drawn during euglycemia and hypoglycemia and 1, 3, and 7 days later to determine circulating immune cell composition, function, and inflammatory proteins. In response to hypoglycemia, absolute numbers of circulating lymphocytes and monocytes significantly increased and remained elevated for 1 week. The proportion of CD16+ monocytes increased, and the proportion of CD14+ monocytes decreased, which was sustained for 1 week in people without diabetes. During hypoglycemia, ex vivo stimulated monocytes released more tumor necrosis factor-α and interleukin 1β, and less interleukin 10, particularly in people with diabetes. hs-CRP and 25 circulating inflammatory proteins increased, remaining significantly elevated 1 week after hypoglycemia. While levels at euglycemia differed, responses to hypoglycemia were broadly similar in people with or without type 2 diabetes. We conclude that hypoglycemia induces a proinflammatory response at the cellular and protein level that is sustained for 1 week in people with type 2 diabetes and control subjects. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective: Hypoglycemia poses an immediate threat for cognitive function. Due to its association with acute cognitive impairment, the International Hypoglycemia Study Group (IHSG) defines a blood glucose level <3.0 mmol/L as "level 2 hypoglycemia." In the current study we investigated whether having diabetes, type of diabetes, or hypoglycemia awareness moderates this association.Research Design and Methods: Adults with type 1 diabetes with normal (n = 26) or impaired (n = 21) hypoglycemic awareness or with insulin-treated type 2 diabetes (n = 15) and age-matched control subjects without diabetes (n = 32) underwent a hyperinsulinemic-euglycemic-hypoglycemic glucose clamp (2.80 ± 0.13 mmol/L [50.2 ± 2.3 mg/dL]). At baseline and during hypoglycemia, calculation ability, attention, working memory and cognitive flexibility were measured with the Paced Auditory Serial Addition Test (PASAT) and the Test of Attentional Performance (TAP).Results: For the whole group, hypoglycemia decreased the mean ± SD proportion of correct answers on the PASAT by 8.4 ± 12.8%, increased reaction time on the TAP Alertness task by 32.1 ± 66.6 ms, and increased the sum of errors and omissions on the TAP Working Memory task by 2.0 ± 5.5 (all P < 0.001). Hypoglycemia-induced cognitive declines were largely irrespective of the presence or type of diabetes, level of symptomatic awareness, diabetes duration, or HbA1c.Conclusions: IHSG level 2 hypoglycemia impairs cognitive function in people with and without diabetes, irrespective of type of diabetes or hypoglycemia awareness status. These findings support the cutoff value of hypoglycemia <3.0 mmol/L (<54 mg/dL) as being clinically relevant for most people with diabetes. [ABSTRACT FROM AUTHOR]

A study published in the journal Diabetes, Obesity & Metabolism examined the impact of sedentary behavior on glucose concentration in individuals with type 1 diabetes. The study found that increased sitting time and long sedentary bouts were positively associated with higher same-day mean glucose levels. However, sedentary breaks did not show a significant association with glucose levels. The study suggests that reducing sitting time may be an effective strategy for improving glucose control in individuals with type 1 diabetes. The findings highlight the importance of physical activity in managing diabetes, although further research is needed to confirm these results. [Extracted from the article]

Repeated sessions of cerebellar anodal transcranial direct current stimulation (tDCS) have been suggested to modulate cerebellar-motor cortex (M1) connectivity and decrease ataxia severity. However, therapeutic trials involving etiologically homogeneous groups of ataxia patients are lacking. The objective of this study was to investigate if a two-week regimen of daily cerebellar tDCS sessions diminishes ataxia and non-motor symptom severity and alters cerebellar-M1 connectivity in individuals with spinocerebellar ataxia type 3 (SCA3). We conducted a randomized, double-blind, sham-controlled trial in which twenty mildly to moderately affected SCA3 patients received ten sessions of real or sham cerebellar tDCS (i.e., five days per week for two consecutive weeks). Effects were evaluated after two weeks, three months, six months, and twelve months. Change in Scale for the Assessment and Rating of Ataxia (SARA) score after two weeks was defined as the primary endpoint. Static posturography, SCA Functional Index tests, various patient-reported outcome measures, the cerebellar cognitive affective syndrome scale, and paired-pulse transcranial magnetic stimulation to examine cerebellar brain inhibition (CBI) served as secondary endpoints. Absolute change in SARA score did not differ between both trial arms at any of the time points. We observed significant short-term improvements in several motor, cognitive, and patient-reported outcomes after the last stimulation session in both groups but no treatment effects in favor of real tDCS. Nonetheless, some of the patients in the intervention arm showed a sustained reduction in SARA score lasting six or even twelve months, indicating interindividual variability in treatment response. CBI, which reflects the functional integrity of the cerebellothalamocortical tract, remained unchanged after ten tDCS sessions. Albeit exploratory, there was some indication for between-group differences in SARA speech score after six and twelve months and in the number of extracerebellar signs after three and six months. Taken together, our study does not provide evidence that a two-week treatment with daily cerebellar tDCS sessions reduces ataxia severity or restores cerebellar-M1 connectivity in early-to-middle-stage SCA3 patients at the group level. In order to potentially increase therapeutic efficacy, further research is warranted to identify individual predictors of symptomatic improvement. [ABSTRACT FROM AUTHOR]

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). [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

* OBJECTIVE: To (1) classify patients who are recovering from total knee arthroplasty (TKA) based on walking speed during an early physical therapy program, and (2) assess whether walking-speed trajectory predicts performance on the timed up- and-go (TUG) test. * DESIGN: Cohort study. * METHODS: We included 218 patients from a 10-day physical therapy program after TKA. A latent class mixed model was used to classify patients according to their walking-speed trajectory during the program. We assessed the change in TUG test score from pre-TKA to 6 weeks and 1 year after TKA. The association between change in TUG test score and walking-speed trajectory was assessed using multivariable regression. * RESULTS: There were 2 groups with distinct walking-speed trajectories: a high-gain group (46%) and a low-gain group (54%). There was no significant association between change in TUG test score and walking-speed trajectory after TKA and physical therapy. Function (based on TUG test performance) improved for all patients 1 year after TKA, irrespective of walking-speed trajectory (ie, high or low gain) early in postoperative physical therapy. CONCLUSION: Although we distinguished different groups based on functional outcomes during physical therapy, the clinical relevance of classifying patients based on walking speed remains unclear, as it did not predict short- and long-term functional outcomes. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objective The aim was to study the effect of non-mandatory transitioning from etanercept originator to etanercept biosimilar on retention rates in a setting promoting shared decision-making. Methods In 2016, all patients treated with etanercept originator and stable disease at the Rheumatology department in Bernhoven were offered transitioning to etanercept biosimilar by an opt-in approach. A historical cohort of patients treated with etanercept originator in 2015 was identified as the control group. Etanercept discontinuation was compared between the cohorts using Cox regression. To study the nocebo effect, reasons for discontinuation were categorized into objective reasons (e.g. laboratory abnormalities, increase in swollen joint count, allergic reaction) and subjective health complaints (symptoms perceptible only to the patient, e.g. tiredness, arthralgia). An adjusted Kaplan–Meier curve for retention of the etanercept biosimilar was made, censoring subjective health complaints as the reason for discontinuation. Results Seventy of the 79 patients eligible for transitioning agreed to transition (89%). The 1-year crude retention rate of etanercept in the transition cohort was 73% (95% CI: 0.62, 0.83), compared with a retention rate of 89% (95% CI: 0.81, 0.95) in the historical cohort (P  = 0.013). This resulted in a higher risk of treatment discontinuation in the transition cohort (adjusted hazard ratio = 2.73; 95% CI: 1.23, 6.05, P  = 0.01). After adjusting for the nocebo effect, the cohorts had comparable retention rates (86 vs 89%, P  = 0.51). Conclusion Non-mandatory transition from etanercept originator to its biosimilar using an opt-in approach in a setting promoting shared decision-making resulted in a higher discontinuation of etanercept compared with the historical cohort. This could be attributed largely to the nocebo effect. [ABSTRACT FROM AUTHOR]

Introduction With the widespread use of electronic health records and handheld electronic devices in hospitals, informatics-based antimicrobial stewardship interventions hold great promise as tools to promote appropriate antimicrobial drug prescribing. However, more research is needed to evaluate their optimal design and impact on quantity and quality of antimicrobial prescribing. Methods and analysis Use of smartphone-based digital stewardship applications (apps) with local guideline directed empirical antimicrobial use by physicians will be compared with antimicrobial prescription as per usual as primary outcome in three hospitals in the Netherlands, Sweden and Switzerland. Secondary outcomes will include antimicrobial use metrics, clinical and process outcomes. A multicentre stepped-wedge cluster randomised trial will randomise entities defined as wards or specialty regarding time of introduction of the intervention. We will include 36 hospital entities with seven measurement periods in which the primary outcome will be measured in 15 participating patients per time period per cluster. At participating wards, patients of at least 18 years of age using antimicrobials will be included. After a baseline period of 2-week measurements, six periods of 4 weeks will follow in which the intervention is introduced in 6 wards (in three hospitals) until all 36 wards have implemented the intervention. Thereafter, we allow use of the app by everyone, and evaluate the sustainability of the app use 6 months later. Ethics and dissemination This protocol has been approved by the institutional review board of each participating centre. Results will be disseminated via media, to healthcare professionals via professional training and meetings and to researchers via conferences and publications. [ABSTRACT FROM AUTHOR]

Background Coach2Move is a personalized treatment strategy by physical therapists to elicit physical activity in community-dwelling older adults with mobility problems. Objective The primary objective of this study is to assess the effectiveness and cost-effectiveness of the implementation of Coach2Move compared with regular care physical therapy in daily clinical practice. Design, Setting, Participants, and Intervention A multicenter cluster-randomized stepped wedge trial is being implemented in 16 physical therapist practices (4 clusters of 4 practices in 4 steps) in the Netherlands. The study aims to include 400 older adults (≥70 years) living independently with mobility problems and/or physically inactive lifestyles. The intervention group receives physical therapy conforming to the Coach2Move strategy; the usual care group receives typical physical therapist care. Measurements Measurements are taken at baseline and 3, 6, and 12 months after the start of treatment. The primary outcomes for effectiveness are the amount of physical activity (LASA Physical Activity Questionnaire) and functional mobility (Timed Up and Go test). Trial success can be declared if at least 1 parameter improves while another does not deteriorate. Secondary outcomes are level of frailty (Evaluative Frailty Index for Physical Activity), perceived effect (Global Perceived Effect and Patient Specific Complaints questionnaire), quality of life (EQ-5D-5 L), and health care expenditures. Multilevel linear regression analyses are used to compare the outcomes between treatment groups according to an intention-to-treat approach. Alongside the trial, a mixed-methods process evaluation is performed to understand the outcomes, evaluate therapist fidelity to the strategy, and detect barriers and facilitators in implementation. Limitations An important limitation of the study design is the inability to blind treating therapists to study allocation. Discussion The trial provides insight into the effectiveness and cost-effectiveness of the Coach2Move strategy compared with usual care. The process evaluation provides insight into influencing factors related to outcomes and implementation. [ABSTRACT FROM AUTHOR]

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®). [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effectiveness of internal auditing in hospital care focussed on improving patient safety.Design, Setting and Participants: A before-and-after mixed-method evaluation study was carried out in eight departments of a university medical center in the Netherlands.Intervention(s): Internal auditing and feedback focussed on improving patient safety.Main Outcome Measure(s): The effect of internal auditing was assessed 15 months after the audit, using linear mixed models, on the patient, professional, team and departmental levels. The measurement methods were patient record review on adverse events (AEs), surveys regarding patient experiences, safety culture and team climate, analysis of administrative hospital data (standardized mortality rate, SMR) and safety walk rounds (SWRs) to observe frontline care processes on safety.Results: The AE rate decreased from 36.1% to 31.3% and the preventable AE rate from 5.5% to 3.6%; however, the differences before and after auditing were not statistically significant. The patient-reported experience measures regarding patient safety improved slightly over time (P < 0.001). The SMR, patient safety culture and team climate remained unchanged after the internal audit. The SWRs showed that medication safety and information security were improved (P < 0.05).Conclusions: Internal auditing was associated with improved patient experiences and observed safety on wards. No effects were found on adverse outcomes, safety culture and team climate 15 months after the internal audit. [ABSTRACT FROM AUTHOR]

Subgroup analyses are an essential part of fully understanding the complete results from confirmatory clinical trials. However, they come with substantial methodological challenges. In case no statistically significant overall treatment effect is found in a clinical trial, this does not necessarily indicate that no patients will benefit from treatment. Subgroup analyses could be conducted to investigate whether a treatment might still be beneficial for particular subgroups of patients. Assessment of the level of evidence associated with such subgroup findings is primordial as it may form the basis for performing a new clinical trial or even drawing the conclusion that a specific patient group could benefit from a new therapy. Previous research addressed the overall type I error and the power associated with a single subgroup finding for continuous outcomes and suitable replication strategies. The current study aims at investigating two scenarios as part of a nonconfirmatory strategy in a trial with dichotomous outcomes: (a) when a covariate of interest is represented by ordered subgroups, eg, in case of biomarkers, and thus, a trend can be studied that may reflect an underlying mechanism, and (b) when multiple covariates, and thus multiple subgroups, are investigated at the same time. Based on simulation studies, this paper assesses the credibility of subgroup findings in overall nonsignificant trials and provides practical recommendations for evaluating the strength of evidence of subgroup findings in these settings. [ABSTRACT FROM AUTHOR]

Background/Aims: Power and sample size calculation formulas for stepped-wedge trials with two levels (subjects within clusters) are available. However, stepped-wedge trials with more than two levels are possible. An example is the CHANGE trial which randomizes nursing homes (level 4) consisting of nursing home wards (level 3) in which nurses (level 2) are observed with respect to their hand hygiene compliance during hand hygiene opportunities (level 1) in the care of patients. We provide power and sample size methods for such trials and illustrate these in the setting of the CHANGE trial. Methods: We extend the original sample size methodology derived for stepped-wedge trials based on a random intercepts model, to accommodate more than two levels of clustering. We derive expressions that can be used to determine power and sample size for p levels of clustering in terms of the variances at each level or, alternatively, in terms of intracluster correlation coefficients. We consider different scenarios, depending on whether the same units in a particular level are repeatedly measured as a cohort sample or whether different units are measured cross-sectionally. Results: A simple variance inflation factor is obtained that can be used to calculate power and sample size for continuous and by approximation for binary and rate outcomes. It is the product of (1) variance inflation due to the multilevel structure and (2) variance inflation due to the stepped-wedge manner of assigning interventions over time. Standard and non-standard designs (i.e. so-called "hybrid designs" and designs with more, less, or no data collection when the clusters are all in the control or are all in the intervention condition) are covered. Conclusions: The formulas derived enable power and sample size calculations for multilevel stepped-wedge trials. For the two-, three-, and four-level case of the standard stepped wedge, we provide programs to facilitate these calculations. [ABSTRACT FROM AUTHOR]

Patient-reported outcome measures (PROMs) are increasingly used in the assessment of patients with rheumatoid arthritis (RA). The aim of this study was to assess the construct validity and reproducibility of four types of PROMs (numerical rating scale (NRS), visual analogue scale (VAS), verbal rating scale (VRS), and Likert scale). In addition, patients’ preference for one of these PROMs was measured. Patients with stable RA and no change in pain medication or steroid medication (n = 211) were asked to complete a questionnaire directly following, and 5 days after their outpatient visit. The questionnaire measured the validity of the PROMs in four domains (pain, fatigue, experienced disease activity, and general well-being). To assess construct validity, Pearson correlation coefficients were calculated using the Disease Activity Score-3. To assess reproducibility, intraclass correlation coefficients (ICCs) were calculated. Correlation coefficients between the different PROMs within each domain were compared. There were no differences regarding construct validity between the different PROM scale types. Regarding reproducibility, VAS and NRS scored better in the domains pain and experienced disease activity. Patients chose NRS as preferred measurement method, with the VAS in second place. The four scale types of PROMs appeared to be equally valid to assess pain, fatigue, experienced disease activity, and general well-being. VAS and NRS appeared to be more reliable for measuring pain and experienced disease activity. The patients favoured NRS. In combination with other practical advantages of NRS over VAS, we do advise the NRS as the preferred scale type for PROMs. [ABSTRACT FROM AUTHOR]

Objectives: To determine psychotropic drug prescription rates in nursing home residents with dementia and to identify associations with the so far understudied psychosocial non-resident-related factors. Method: A cross-sectional, observational, exploratory design as part of PROPER I (PRescription Optimization of Psychotropic drugs in Elderly nuRsing home patients with dementia). Participants were 559 nursing home residents with dementia, 25 physicians, and 112 nurses in the Netherlands. Psychotropic drug prescription, non-resident-related and known resident-related variables were measured to operationalize the themes of our previous qualitative analysis. Results: Fifty-six percent of residents were prescribed any psychotropic drug, 25% antipsychotics, 29% antidepressants, 15% anxiolytics, and 13% hypnotics, with large differences between the units. Multivariate multilevel regression analyses revealed that antipsychotic prescription was less likely with higher physicians’ availability (odds ratio 0.96, 95% confidence interval 0.93-1.00) and that antidepressant prescription was more likely with higher satisfaction of nurses on resident contact (odds ratio 1.50, 95% confidence interval 1.00-2.25). Resident-related factors explained 6%-15% of the variance, resident- and non-resident-related factors together 8%-17%. Conclusion: Prescription rates for antipsychotics are similar compared to other countries, and relatively low for antidepressants, anxiolytics, and hypnotics. Our findings indicate that improvement of prescribing could provisionally best be targeted at resident-related factors. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the effects of non‐mandatory transitioning from the originator biologic drug etanercept (ETN) to its biosimilar, SB4, on drug survival and effectiveness in a controlled cohort study of patients with an inflammatory rheumatic disease. Methods: In 2016, 642 patients were asked to transition their treatment from originator ETN to biosimilar SB4 by a structured communication strategy with opt‐out option. Patients who consented to switch to SB4 were considered eligible for inclusion in the transition cohort, while patients being treated with originator ETN in 2014 were recruited as the historical cohort. Drug survival was compared between the 2 cohorts using Cox regression analyses, which were adjusted for age, sex, diagnosis, ETN treatment duration, ETN dose interval, conventional synthetic disease‐modifying antirheumatic drug usage, and C‐reactive protein (CRP) level, with a robust variance estimator applied to account for repeated subjects (i.e., patients who were included in both the transition cohort and the historical cohort). Adjusted differences in the 6‐month change in CRP level, Disease Activity Score in 28 joints using CRP level (DAS28‐CRP), and Bath Ankylosing Spondylitis Disease Activity Index were also assessed. Results: Of the 642 ETN‐treated patients, 635 (99%) agreed to transition from originator ETN to biosimilar SB4, of whom 625 patients (433 with rheumatoid arthritis, 128 with psoriatic arthritis, and 64 with ankylosing spondylitis) were included in the transition cohort, and 600 ETN‐treated patients from 2014 were included in the historical cohort. The crude treatment persistence rate for biosimilar SB4 over 6 months was 90% (95% confidence interval [95% CI] 88–93%), compared to a 6‐month treatment persistence rate of 92% (95% CI 90–94%) for originator ETN. Patients in the transition cohort, compared to the historical cohort, had a statistically significantly higher relative risk of treatment discontinuation (adjusted hazard ratio 1.57, 95% CI 1.05–2.36) and showed smaller decreases in the CRP level (adjusted difference 1.8, 95% CI 0.3–3.2) and DAS28‐CRP (adjusted difference 0.15, 95% CI 0.05–0.25) over 6 months. Conclusion: Non‐mandatory transitioning from originator ETN to biosimilar SB4 using a specifically designed communication strategy resulted in a slightly lower 6‐month treatment persistence rate and smaller decreases in disease activity in the transition cohort compared to the historical cohort, but these differences were not considered clinically relevant. [ABSTRACT FROM AUTHOR]

Objective: We studied the efficacy of biannual structured medication reviews to improve the appropriateness of psychotropic drug (PD) prescriptions for neuropsychiatric symptoms (NPS) in nursing home patients with dementia. Study Design and Setting: In this randomised controlled trial, the intervention encompassed a structured multidisciplinary medication review by physician, pharmacist and nurse. During this 18-month study, the patient's medical files were assessed every 6 months. The primary outcome was the appropriateness of PD prescriptions defined by the Appropriate Psychotropic drug use In Dementia (APID) index sum score, lower scores indicating more appropriate use. Results: At baseline, 380 patients were included, of which 222 were randomised to the intervention group. Compared to the control group, the APID index sum score in the intervention group improved significantly for all PD prescriptions (-5.28, P = 0.005). Conclusion: We advise the implementation of a structured, repeated medication review with the essential roles of pharmacist, physician and nurse, into daily practice. This work was supported and funded by the Netherlands Organisation for Health Research and Development (ZonMw). Netherlands Trial Register (NTR3569). [ABSTRACT FROM AUTHOR]

ABSTRACTBackground:We studied the patient and non-patients factors of inappropriate psychotropic drug (PD) prescription for neuropsychiatric symptoms (NPS) in nursing home patients with severe dementia.Methods: In a cross-sectional study, the appropriateness of prescriptions was explored using the Appropriate Psychotropic drug use In Dementia (APID) index sum score. This index assesses information from medical records on indication, evaluation, dosage, drug-drug interactions, drug-disease interactions, duplications, and therapy duration. Various measurements were carried out to identify the possible patient and non-patient factors. Linear multilevel regression analysis was used to identify factors that are associated with APID index sum scores. Analyses were performed for groups of PDs separately, i.e. antipsychotics, antidepressants, anxiolytics, and hypnotics.Results: The sample consisted of 338 patients with a PD prescription that used 147 antipsychotics, 167 antidepressants, 85 anxiolytics, and 76 hypnotics. It was found that older patients and more severe aggression, agitation, apathy, and depression were associated with more appropriate prescriptions. Additionally, less appropriate prescriptions were found to be associated with more severe anxiety, dementia diagnoses other than Alzheimer dementia, more physician time available per patient, more patients per physician, more years of experience of the physician, and higher nurse's workload.Conclusions: The association of more pronounced NPS with more appropriate PD prescriptions implies that physicians should pay more attention to the appropriateness of PD prescriptions when NPS are less manifest. Non-patient-related factors are also associated with the appropriateness of PD prescriptions. However, especially considering that some of these findings are counter-intuitive, more research on the topic is recommended. [ABSTRACT FROM AUTHOR]

Objective To evaluate the effectiveness of a nurse-supported self-management programme to improve social participation of dual sensory impaired older adults in long-term care homes. Design Cluster randomised controlled trial. Setting Thirty long-term care homes across the Netherlands. Participants Long-term care homes were randomised into intervention clusters (n=17) and control clusters (n=13), involving 89 dual sensory impaired older adults and 56 licensed practical nurses. Intervention Nurse-supported self-management programme. Measurements Effectiveness was evaluated by the primary outcome social participation using a participation scale adapted for visually impaired older adults distinguishing four domains: instrumental activities of daily living, social-cultural activities, high-physical- demand and low-physical-demand leisure activities. A questionnaire assessing hearing-related participation problems was added as supportive outcome. Secondary outcomes were autonomy, control, mood and quality of life and nurses’ job satisfaction. For effectiveness analyses, linear mixed models were used. Sampling and intervention quality were analysed using descriptive statistics. Results Self-management did not affect all four domains of social participation; however. the domain ‘instrumental activities of daily living’ had a significant effect in favour of the intervention group (P=0.04; 95% CI 0.12 to 8.5). Sampling and intervention quality was adequate. Conclusions A nurse-supported self-management programme was effective in empowering the dual sensory impaired older adults to address the domain ‘instrumental activities of daily living’, but no differences were found in addressing the other three participation domains. Self-management showed to be beneficial for managing practical problems, but not for those problems requiring behavioural adaptations of other persons. [ABSTRACT FROM AUTHOR]

Objective. Ultrasonography (US) can be used for treatment decisions in RA patients. This study investigated the added value of US to clinical variables in predicting flare in RA patients with longstanding low disease activity when stopping TNF inhibitors (TNFi). Methods. Cox models with and without using US added to clinical variables were developed in the Potential Optimization of Expediency of TNFi-UltraSonography study. RA patients (n = 259), using >1 year TNFi and csDMARD with DAS28<3.2 for 6months prior to inclusion, were followed for 52 weeks after stopping TNFi. The added value of US was assessed in two ways: first, by the extent to which individual predictions for flare at 52 weeks with and without US differed; and second, by comparing how US information improved the prediction to classify patients at 52 weeks in the low risk (<33% flare), intermediate risk (33-50%) and high risk (50-100%) groups. Results. Although US was predictive of flare at group level (multivariate hazard ratio = 1.7; 95% CI: 1.1, 2.5), individual predictions for flare at 52 weeks with and without US differed little (median difference 3.7%; interquartile range: -7.8 to 6.5%). With US, 15.9% of patients were designated low risk; without US, 14.6%. In fact, 12.0% of patients were US-classified as low risk with/without knowing US. Conclusion. In RA patients with longstanding low disease activity, at time of stopping TNFi, US is a predictor for flare at group level, but at the patient level, US has limited added value when common clinical parameters are used already, though the predictive value of clinical predictors is modest as well. [ABSTRACT FROM AUTHOR]

Background: A standard low-dosing schedule of rituximab (RTX; 2 × 500 mg or 1 × 1000 mg) is as effective for active rheumatoid arthritis (RA) as the registered dose (2 × 1000 mg). Moreover, several small uncontrolled studies suggest that even lower-dosed treatment with RTX also leads to good treatment response in patients with RA. Retreatment with such an 'ultra-low' dose RTX in patients who responded well to RTX induction treatment is of special interest, as long-term use of lower RTX doses may lead to shorter infusion duration, lower risk of adverse events and lower costs. However, the effect of ultra-low dose of RTX has not been investigated using a controlled trial of proper design and dimensions.Methods/design: REDO is an investigator driven six-month pragmatic, double-blind, randomised controlled non-inferiority trial on the effects of ultra-low-dose RTX (1 × 500 or 1 × 200 mg) compared to standard low dose (1 × 1000 mg) in RA patients who are being retreated with RTX. A total of 140 RA patients, having reached low disease activity (DAS28CRP < 2.9) after the previous RTX infusion and DAS28CRP < 3.5 at moment of retreatment, are randomised in a ratio of 1:2:2 to 1 × 1000 mg, 1 × 500 mg or 1 × 200 mg. The primary objective is testing non-inferiority of the ultra-low-dose vs. standard low-dose RTX, by comparing mean change in DAS28CRP from baseline to six months to the non-inferiority margin of 0.6. Secondary outcomes over the same period are: function; quality of life; safety; costs; and pharmacokinetics and dynamics as process measures.Discussion: This study protocol shares characteristics of both early dose finding trials as well as late pragmatic clinical studies. Several choices in the design of this trial are described and possible consequences for RA treatment and expected biosimilar introduction are discussed.Trial Registration: Dutch Trial Register, NTR6117 . Registered on 15 November 2016 (CMO NL57520.091.16 , 8 November 2016). [ABSTRACT FROM AUTHOR]

In drug development, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population but appears to be beneficial in a relevant subgroup. In case the subgroup of interest was not part of a confirmatory testing strategy, the inflation of the overall type I error is substantial and therefore such a subgroup analysis finding can only be seen as exploratory at best. To support such exploratory findings, an appropriate replication of the subgroup finding should be undertaken in a new trial. We should, however, be reasonably confident in the observed treatment effect size to be able to use this estimate in a replication trial in the subpopulation of interest. We were therefore interested in evaluating the bias of the estimate of the subgroup treatment effect, after selection based on significance for the subgroup in an overall 'failed' trial. Different scenarios, involving continuous as well as dichotomous outcomes, were investigated via simulation studies. It is shown that the bias associated with subgroup findings in overall nonsignificant clinical trials is on average large and varies substantially across plausible scenarios. This renders the subgroup treatment estimate from the original trial of limited value to design the replication trial. An empirical Bayesian shrinkage method is suggested to minimize this overestimation. The proposed estimator appears to offer either a good or a conservative correction to the observed subgroup treatment effect hence provides a more reliable subgroup treatment effect estimate for adequate planning of future studies. [ABSTRACT FROM AUTHOR]

Background People with intellectual disabilities are vulnerable to develop psychopathology (in particular anxiety) and related challenging behaviour. A diagnostic guideline was developed to support professionals to better diagnose and thus treat psychopathology and related CB. This study examined preliminary outcomes from the application of this guideline. Method A comparative multiple case study with an experimental and a control condition. Results The application of the guideline showed a trend of decreases of internalizing problems ( P = 0.07) and anxiety/depressed problems ( P = 0.09). We found no statistically significant decreases of externalizing problems and no increases in perceived quality of life as compared with care as usual. Clients were not more satisfied with the support they received for coping with their emotional and behaviour problems. Conclusion The application of the Diagnostic Guideline for Anxiety and Challenging Behaviour did not show statistically significant changes in externalizing problems and Quality of Life. Despite the small sample size of n = 59, we did find a trend in decreasing internalizing problems and anxiety/depressed problems. Further research into either or not confirming these trends is recommended. [ABSTRACT FROM AUTHOR]

The sample size required for a cluster randomised trial is inflated compared with an individually randomised trial because outcomes of participants from the same cluster are correlated. Sample size calculations for longitudinal cluster randomised trials (including stepped wedge trials) need to take account of at least two levels of clustering: the clusters themselves and times within clusters. We derive formulae for sample size for repeated cross-section and closed cohort cluster randomised trials with normally distributed outcome measures, under a multilevel model allowing for variation between clusters and between times within clusters. Our formulae agree with those previously described for special cases such as crossover and analysis of covariance designs, although simulation suggests that the formulae could underestimate required sample size when the number of clusters is small. Whether using a formula or simulation, a sample size calculation requires estimates of nuisance parameters, which in our model include the intracluster correlation, cluster autocorrelation, and individual autocorrelation. A cluster autocorrelation less than 1 reflects a situation where individuals sampled from the same cluster at different times have less correlated outcomes than individuals sampled from the same cluster at the same time. Nuisance parameters could be estimated from time series obtained in similarly clustered settings with the same outcome measure, using analysis of variance to estimate variance components. Copyright © 2016 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

In drug development and drug licensing, it sometimes occurs that a new drug does not demonstrate effectiveness for the full study population, but there appears to be benefit in a relevant, pre-defined subgroup. This raises the question, how strong the evidence from such a subgroup is, and which confirmatory testing strategies are the most appropriate ones. Hence, we considered the type I error and the power of a subgroup result in a trial with non-significant overall results and of suitable replication strategies. In the case of a single trial, the inflation of the overall type I error is substantial and can be up to twice as large, especially in relatively small subgroups. This also increases to the risk of starting a replication trial that should not be done, if such a second trial is not already available. The overall type I error is almost controlled by using an appropriate replication strategy. This confirms the required cautious interpretation of promising subgroups, even in the case that overall trial results were perceived to be close to significance. [ABSTRACT FROM AUTHOR]

Background: It is often unclear which approach to fit, assess and adjust a model will yield the most accurate prediction model. We present an extension of an approach for comparing modelling strategies in linear regression to the setting of logistic regression and demonstrate its application in clinical prediction research.Methods: A framework for comparing logistic regression modelling strategies by their likelihoods was formulated using a wrapper approach. Five different strategies for modelling, including simple shrinkage methods, were compared in four empirical data sets to illustrate the concept of a priori strategy comparison. Simulations were performed in both randomly generated data and empirical data to investigate the influence of data characteristics on strategy performance. We applied the comparison framework in a case study setting. Optimal strategies were selected based on the results of a priori comparisons in a clinical data set and the performance of models built according to each strategy was assessed using the Brier score and calibration plots.Results: The performance of modelling strategies was highly dependent on the characteristics of the development data in both linear and logistic regression settings. A priori comparisons in four empirical data sets found that no strategy consistently outperformed the others. The percentage of times that a model adjustment strategy outperformed a logistic model ranged from 3.9 to 94.9 %, depending on the strategy and data set. However, in our case study setting the a priori selection of optimal methods did not result in detectable improvement in model performance when assessed in an external data set.Conclusion: The performance of prediction modelling strategies is a data-dependent process and can be highly variable between data sets within the same clinical domain. A priori strategy comparison can be used to determine an optimal logistic regression modelling strategy for a given data set before selecting a final modelling approach. [ABSTRACT FROM AUTHOR]

Given the growing attention to quality improvement, comparative effectiveness research, and pragmatic trials embedded within learning health systems, the use of the cluster randomization design is bound to increase. The number of clusters available for randomization is often limited in such trials. Designs that incorporate pre-intervention measurements (e.g. cluster cross-over, repeated parallel arm, and stepped wedge designs) can substantially reduce the required numbers of clusters by decreasing between-cluster sources of variation. However, there are substantial risks associated with few clusters, including increased probability of chance imbalances and type I and type II error, limited perceived or actual generalizability, and fewer options for statistical analysis. Furthermore, current sample size methods for the stepped wedge design make a strong underlying assumption with respect to the correlation structure—in particular, that the intracluster and inter-period correlations are equal. This is in contrast with methods for the cluster cross-over design that explicitly allow for a smaller inter-period correlation. Failing to similarly allow for the inter-period correlation in the design of a stepped wedge trial may yield perilously low sample sizes. Further methodological and empirical work is required to inform sample size methods and guidance for the stepped wedge trial and to provide minimum thresholds for this design. [ABSTRACT FROM AUTHOR]