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Longitudinal experiments often involve multiple outcomes measured repeatedly within a set of study participants. While many questions can be answered by modeling the various outcomes separately, some questions can only be answered in a joint analysis of all of them. In this article, we will present a review of the many approaches proposed in the statistical literature. Four main model families will be presented, discussed and compared. Focus will be on presenting advantages and disadvantages of the different models rather than on the mathematical or computational details.

Background The medicines’ pathway in nursing homes (NHs) is complex and challenging, resulting in processes that are prone to medication errors and lack person-centredness. There is a clear need for quality improvement initiatives, for which a systems approach - rather than isolated interventions - is considered more effective. In this context, the Process Optimization Of the Medicines’ pAthway in nursing Homes (POOMAH) study was established. The study aims to evaluate the effectiveness of different formats and intensities of support provided to NHs to improve the quality of the medicines’ pathway. Methods The intervention includes four arms, each offering a different level of support: access to toolbox, intervision meetings, external coaching and integration of a coordinating pharmacist. In total, 100 NHs participate in this study, with stratified randomization used to allocate them to the intervention arms. The primary outcome is the overall quality of the medicines’ pathway, through the calculation of performance scores. The key secondary outcome is the number of (psychoactive) medications used by NHRs. Other secondary outcomes include the quality of specific processes and KAs of the medicines’ pathway, represented by process-specific and activity-specific performance scores, and the number of falls and hospitalizations of NHRs. A comprehensive process evaluation will also be conducted. Both quantitative and qualitative data will be collected and analyzed using (generalised) linear mixed models and content/thematic analysis, respectively. Discussion The POOMAH study will assess and compare the effectiveness of four support levels aimed at improving the quality of the medicines’ pathway in NHs. The findings will contribute to the evidence base on quality improvement in this context and inform future strategies, including the role of pharmacists in optimizing medication management. Clinical trial number Not applicable. Although this study was not classified as a clinical trial by the ethics committee, it was retrospectively registered in the ISRCTN registry (ISRCTN17231220) on 07 May 2025 ( https://www.isrctn.com/ISRCTN17231220 ).

Randomized controlled trials evaluating real-time continuous glucose monitoring (RT-CGM) patients with type 1 diabetes (T1D) show improved glycemic control, but limited data are available on real-world use. To assess impact of RT-CGM in real-world settings on glycemic control, hospital admissions, work absenteeism, and quality of life (QOL). Prospective, observational, multicenter, cohort study. A total of 515 adults with T1D on continuous subcutaneous insulin infusion (CSII) therapy starting in the Belgian RT-CGM reimbursement program. Initiation of RT-CGM reimbursement. Hemoglobin A1c (HbA1c) evolution from baseline to 12 months. Between September 1, 2014, and December 31, 2016, 515 adults entered the reimbursement system. Over this period, 417 (81%) patients used RT-CGM for at least 12 months. Baseline HbA1c was 7.7 ± 0.9% (61 ± 9.8 mmol/mol) and decreased to 7.4 ± 0.8% (57 ± 8.7 mmol/mol) at 12 months (P < 0.0001). Subjects who started RT-CGM because of insufficient glycemic control showed stronger decrease in HbA1c at 4, 8, and 12 months compared with patients who started because of hypoglycemia or pregnancy. In the year preceding reimbursement, 16% of patients were hospitalized for severe hypoglycemia or ketoacidosis in contrast to 4% (P < 0.0005) the following year, with decrease in admission days from 54 to 18 per 100 patient years (P < 0.0005). In the same period, work absenteeism decreased and QOL improved significantly, with strong decline in fear of hypoglycemia. Sensor-augmented pump therapy in patients with T1D followed in specialized centers improves HbA1c, fear of hypoglycemia, and QOL, whereas work absenteeism and admissions for acute diabetes complications decreased.

Postoperative pancreatic fistula is the leading cause of death and morbidity after pancreaticoduodenectomy. However, the best reconstruction method to reduce occurrence of fistula is debated. We did a multicentre, randomised superiority trial to compare the outcomes of different reconstructive techniques in patients undergoing pancreaticoduodenectomy for pancreatic or periampullary tumours. Patients aged 18–85 years with confirmed or suspected neoplasms of the pancreas, distal bile duct, ampulla vateri, duodenum, or periampullary tumours were eligible for inclusion. An internet-based platform was used to randomly assign patients to either pancreaticojejunostomy or pancreaticogastrostomy as reconstruction after pancreaticoduodenectomy, using permuted blocks with six patients per block. Within each centre the randomisation was stratified on the pancreatic duct diameter (≤3 mm vs >3 mm) measured at the time of surgery. The primary endpoint was the occurrence of clinical postoperative pancreatic fistula (grade B or C) as defined by the International Study Group on Pancreatic Fistula. The study was not masked and analyses were done by intention to treat. Patient follow-up was closed 2 months after discharge from the hospital. This study is registered with ClinicalTrials.gov, number NCT00830778. Between June, 2009, and August, 2012, we randomly allocated 167 patients to receive pancreaticojejunostomy and 162 to receive pancreaticogastrostomy. 33 (19·8%) patients in the pancreaticojejunostomy group and 13 (8·0%) in the pancreaticogastrostomy group had clinical postoperative pancreatic fistula (OR 2·86, 95% CI 1·38–6·17; p=0·002). The overall incidence of postoperative complications did not differ significantly between the groups (99 in the pancreaticojejunostomy group vs 100 in the pancreaticogastrostomy group), although more events in the pancreaticojejunostomy group were of grade ≥3a than in the pancreaticogastrostomy group (39 vs 35). In patients undergoing pancreaticoduodenectomy for pancreatic head or periampullary tumours, pancreaticogastrostomy is more efficient than pancreaticojejunostomy in reducing the incidence of postoperative pancreatic fistula. Funding Johnson & Johnson Medical Devices, Belgium.

To investigate if an erector spinae plane (ESP) block decreases postoperative opioid consumption, pain and postoperative nausea and vomiting in patients undergoing robotically-assisted minimally invasive direct coronary artery bypass surgery (RAMIDCAB). A single-center, double-blind, prospective, randomized, placebo-controlled trial. Postoperative period; operating room, post-anesthesia care unit (PACU) and hospital ward in a university hospital. Sixty-four patients undergoing RAMIDCAB surgery via left-sided mini-thoracotomy and enrolled in the institutional enhanced recovery after cardiac surgery program. At the end of surgery, patients received an ESP catheter at vertebra T5 under ultrasound guidance and were randomized to the administration of either ropivacaine 0.5% (loading dose of 30 ml and three additional doses of 20 ml each, interspersed with a 6 h interval) or normal saline 0.9% (with an identical administration scheme). In addition, patients received multimodal analgesia including acetaminophen, dexamethasone and patient-controlled analgesia with morphine. Following the final ESP bolus and before catheter removal, the position of the catheter was re-evaluated by ultrasound. Patients, investigators and medical personnel were blinded for the group allocation during the entire trial. Primary outcome was cumulative morphine consumption during the first 24 h after extubation. Secondary outcomes included location and severity of pain, presence/extent of sensory block, duration of postoperative ventilation and hospital length of stay. Safety outcomes comprised the incidence of adverse events. Median (IQR) 24-h morphine consumption was not different between the intervention- and control-groups, 67 mg (35–84) versus 71 mg (52–90) (p = 0.25), respectively. Likewise, no differences were detected in secondary and safety endpoints. Following RAMIDCAB surgery, adding an ESP block to a standard multimodal analgesia regimen did not reduce opioid consumption and pain scores. •Randomized and placebo-controlled trial for unilateral ESP block in cardiac surgery.•Further research into dosing regimens for unilateral ESP block is required.•Postoperative pain following MIDCAB surgery is not reduced with ESP block.•ESP block did not reduce opioid consumption following MIDCAB surgery.•Multimodal analgesia without ESP was sufficient following MIDCAB surgery.

To investigate if an erector spinae plane (ESP) block decreases postoperative opioid consumption, pain and postoperative nausea and vomiting in patients undergoing minimally invasive mitral valve surgery (MIMVS). A single-center, double-blind, prospective, randomized, placebo-controlled trial. Postoperative period; operating room, post-anesthesia care unit (PACU) and hospital ward in a university hospital. Seventy-two patients undergoing video-assisted thoracoscopic MIMVS via right-sided mini-thoracotomy and enrolled in the institutional enhanced recovery after cardiac surgery program. At the end of surgery, all patients received an ESP catheter at vertebra T5 under ultrasound guidance and were randomized to the administration of either ropivacaine 0.5% (loading of dose 30 ml and three additional doses of 20 ml with a 6 h interval) or normal saline 0.9% (with an identical administration scheme). In addition, patients received multimodal postoperative analgesia including dexamethasone, acetaminophen and patient-controlled intravenous analgesia with morphine. Following the final ESP bolus and before catheter removal, the position of the catheter was re-evaluated by ultrasound. Patients, investigators and medical personnel were blinded for the group allocation during the entire trial. Primary outcome was cumulative morphine consumption during the first 24 h after extubation. Secondary outcomes included severity of pain, presence/extent of sensory block, duration of postoperative ventilation and hospital length of stay. Safety outcomes comprised the incidence of adverse events. Median (IQR) 24-h morphine consumption was not different between the intervention- and control-group, 41 mg (30–55) versus 37 mg (29–50) (p = 0.70), respectively. Likewise, no differences were detected for secondary and safety endpoints. Following MIMVS, adding an ESP block to a standard multimodal analgesia regimen did not reduce opioid consumption and pain scores. •Continuous ESP block did not reduce opioid consumption in mitral valve surgery.•Randomized placebo-controlled trial for unilateral ESP block in cardiac surgery.•Postoperative pain following MIMVS is not reduced with ESP block.•Multimodal analgesia without ESP provided sufficient pain relief after MIMVS.•Additional research is required into dosing regimens for unilateral ESP blocks.

The surgical management of endometrioma(s) remains challenging. Although laparoscopic surgery is a well-established treatment of endometrioma(s), caution is required to minimize ovarian damage. Several surgical techniques have been described to treat endometrioma(s): classical cystectomy, ablative techniques, or a combination of both. As cystectomy is strongly associated with a reduction in ovarian reserve, this randomized controlled trial (RCT) aims to determine to what extent the two other surgical procedures may affect ovarian reserve by comparing changes in serum anti-Müllerian hormone (AMH) levels concentrations after each type of surgery. This is a multicenter, non-blinded, RCT with parallel groups (group 1 (combined technique) versus group 2 (CO2 laser vaporization only)) and allocation 1:1. Four Belgian centers will be involved. Main inclusion criteria are symptomatic patients (pain and/or infertility), 18-40 years (both inclusive) with an endometriotic cyst (mean diameter of ≥ 2.5 cm and ≤ 8 cm) and AMH level ≥ 0.7 ng/mL. Suspicion of malignancy, a contralateral endometrioma of > 2 cm, use of gonadotrophin-releasing hormone (GnRH) analogues around timing of surgery or previous oophorectomy are exclusion criteria. The primary aim is the evaluation of the difference in serum AMH levels between baseline and 3 months postoperatively (or delta AMH). The secondary outcomes include differences in AMH levels at 6 and 12 months postoperatively, cyst recurrence rate, evolution of pain pattern and fertility outcomes. The present study will help us to answer the question on which surgical technique for endometrioma(s) has the most favorable outcome in patients wishing to preserve their reproductive potential. ClinicalTrials.gov: NCT04151433. Registered on November 5th, 2019.

Objectives: Pulmonary metastasectomy is not a standardised procedure, with no consensus regarding the optimal extent of lung resection. This international multicentre study aimed at comparing short and long-term outcomes of anatomical versus non-anatomical pulmonary metastasectomy. Methods: Retrospective database including 1647 patients aged ≥18 years, who underwent curative intent pulmonary metastasectomy between January 2010 and December 2018 at 15 European centres. Patients who underwent pneumonectomy, previous metastasectomies, and/or suffered from extrapulmonary recurrence at the time of lung surgery were excluded. Primary endpoint was overall survival. Secondary endpoints were recurrence-free survival and 30-day morbidity. Differences between the two groups were analysed using 3:1 matching. Results: In the matched cohort, 324 patients underwent anatomical resection, and 830 patients underwent non-anatomical resection. Five-year overall survival was 62.0%. Averaged over the entire follow-up, there was no significant difference in overall survival between the two groups (HR = 1.122, 95% CI = 0.909–1.385, p = 0.283). In the early period following pulmonary metastasectomy, anatomical resections were associated with worse overall survival (HR = 1.549, 95% CI = 1.135–2.114, p = 0.006). The difference in any-site recurrence-free survival between the two groups was not significant (HR = 0.832, 95% CI = 0.690–1.002, p = 0.053). Locoregional recurrence-free survival was significantly longer after anatomical resection (HR = 0.651, 95% CI = 0.520–0.817, p < 0.001). Thirty-day morbidity was significantly higher after anatomical resection (22.2% versus 13.7% for non-anatomical resections, p = 0.001). Conclusions: In a highly selected cohort, non-anatomical resection showed comparable survival and lower morbidity compared to anatomical resections, supporting the surgical strategy of favouring limited resections whenever technically and oncologically feasible. Anatomical resections remain a valid option in selected cases with acceptable outcomes.

A mixed model is a flexible tool for joint modeling purposes, especially when the gathered data are unbalanced. However, computational problems due to the dimension of the joint covariance matrix of the random effects arise as soon as the number of outcomes and/or the number of used random effects per outcome increases. We propose a pairwise approach in which all possible bivariate models are fitted, and where inference follows from pseudo‐likelihood arguments. The approach is applicable for linear, generalized linear, and nonlinear mixed models, or for combinations of these. The methodology will be illustrated for linear mixed models in the analysis of 22‐dimensional, highly unbalanced, longitudinal profiles of hearing thresholds.