Early Extracorporeal CPR for Refractory Out-of-Hospital Cardiac Arrest.

BACKGROUND: Extracorporeal cardiopulmonary resuscitation (CPR) restores perfusion and oxygenation in a patient who does not have spontaneous circulation. The evidence with regard to the effect of extracorporeal CPR on survival with a favorable neurologic outcome in refractory out-of-hospital cardiac arrest is inconclusive. METHODS: In this multicenter, randomized, controlled trial conducted in the Netherlands, we assigned patients with an out-of-hospital cardiac arrest to receive extracorporeal CPR or conventional CPR (standard advanced cardiac life support). Eligible patients were between 18 and 70 years of age, had received bystander CPR, had an initial ventricular arrhythmia, and did not have a return of spontaneous circulation within 15 minutes after CPR had been initiated. The primary outcome was survival with a favorable neurologic outcome, defined as a Cerebral Performance Category score of 1 or 2 (range, 1 to 5, with higher scores indicating more severe disability) at 30 days. Analyses were performed on an intention-to-treat basis. RESULTS: Of the 160 patients who underwent randomization, 70 were assigned to receive extracorporeal CPR and 64 to receive conventional CPR; 26 patients who did not meet the inclusion criteria at hospital admission were excluded. At 30 days, 14 patients (20%) in the extracorporeal-CPR group were alive with a favorable neurologic outcome, as compared with 10 patients (16%) in the conventional-CPR group (odds ratio, 1.4; 95% confidence interval, 0.5 to 3.5; P = 0.52). The number of serious adverse events per patient was similar in the two groups. CONCLUSIONS: In patients with refractory out-of-hospital cardiac arrest, extracorporeal CPR and conventional CPR had similar effects on survival with a favorable neurologic outcome. (Funded by the Netherlands Organization for Health Research and Development and Maquet Cardiopulmonary [Getinge]; INCEPTION ClinicalTrials.gov number, NCT03101787.).

Standardised training for endoscopic mucosal resection of large non-pedunculated colorectal polyps to reduce recurrence (*STAR-LNPCP study): a multicentre cluster randomised trial.

OBJECTIVE: Endoscopic mucosal resection (EMR) is the preferred treatment for non-invasive large (≥20 mm) non-pedunculated colorectal polyps (LNPCPs) but is associated with an early recurrence rate of up to 30%. We evaluated whether standardised EMR training could reduce recurrence rates in Dutch community hospitals. DESIGN: In this multicentre cluster randomised trial, 59 endoscopists from 30 hospitals were randomly assigned to the intervention group (e-learning and 2-day training including hands-on session) or control group. From April 2019 to August 2021, all consecutive EMR-treated LNPCPs were included. Primary endpoint was recurrence rate after 6 months. RESULTS: A total of 1412 LNPCPs were included; 699 in the intervention group and 713 in the control group (median size 30 mm vs 30 mm, 45% vs 52% size, morphology, site and access (SMSA) score IV, 64% vs 64% proximal location). Recurrence rates were lower in the intervention group compared with controls (13% vs 25%, OR 0.43; 95% CI 0.23 to 0.78; p=0.005) with similar complication rates (8% vs 9%, OR 0.93; 95% CI 0.64 to 1.36; p=0.720). Recurrences were more often unifocal in the intervention group (92% vs 76%; p=0.006). In sensitivity analysis, the benefit of the intervention on recurrence rate was only observed in the 20-40 mm LNPCPs (5% vs 20% in 20-29 mm, p=0.001; 10% vs 21% in 30-39 mm, p=0.013) but less evident in ≥40 mm LNPCPs (24% vs 31%; p=0.151). In a post hoc analysis, the training effect was maintained in the study group, while in the control group the recurrence rate remained high. CONCLUSION: A compact standardised EMR training for LNPCPs significantly reduced recurrences in community hospitals. This strongly argues for a national dedicated training programme for endoscopists performing EMR of ≥20 mm LNPCPs. Interestingly, in sensitivity analysis, this benefit was limited for LNPCPs ≥40 mm. TRIAL REGISTRATION NUMBER: NTR7477.

Safety, effectiveness, and cost-effectiveness of immediate versus delayed sequential bilateral cataract surgery in the Netherlands (BICAT-NL study): a multicentre, non-inferiority, randomised controlled trial.

BACKGROUND: In an ageing population, efficiency improvements are required to assure future accessibility of cataract care. We aim to address remaining knowledge gaps by evaluating the safety, effectiveness, and cost-effectiveness of immediate sequential bilateral cataract surgery (ISBCS) versus delayed sequential bilateral cataract surgery (DSBCS). We hypothesised that ISBCS is non-inferior to DSBCS, regarding safety and effectiveness, and being superior in cost-effectiveness. METHODS: We did a multicentre, non-inferiority, randomised controlled trial, which included participants from ten Dutch hospitals. Eligible participants were 18 years or older, underwent expected uncomplicated surgery, and had no increased risk of endophthalmitis or refractive surprise. Participants were randomly assigned (1:1) to either the ISBCS (intervention) group or DSBCS (conventional procedure) group, using a web-based system stratified by centre and axial length. Participants and outcome assessors were not masked to the treatment groups because of the nature of the intervention. The primary outcome was the proportion of second eyes with a target refractive outcome of 1·0 dioptre (D) or less 4 weeks postoperatively, with a non-inferiority margin of -5% for ISBCS versus DSBCS. For the trial-based economic evaluation, the primary endpoint was the incremental societal costs per quality-adjusted life-year. All analyses were done by a modified intention-to-treat principle. Costs were calculated by multiplying volumes of resource use with unit cost prices and converted to 2020 Euros (€) and US$. This study was registered with ClinicalTrials.gov, number NCT03400124, and is now closed for recruitment. FINDINGS: Between Sept 4, 2018, and July 10, 2020, a total of 865 patients were randomly assigned to either the ISBCS group (427 [49%] patients; 854 eyes) or DSBCS group (438 [51%] patients; 876 eyes). In the modified intention-to-treat analysis, the proportion of second eyes with a target refraction of 1·0 D or less was 97% (404 of 417 patients) in the ISBCS group versus 98% (407 of 417) in the DSBCS group. The percentage difference was -1% (90% CI -3 to 1; p=0·526), thereby establishing non-inferiority for ISBCS compared with DSBCS. Endophthalmitis was not observed or reported in either group. Adverse events were comparable between groups, with only a significant difference in disturbing anisometropia (p=0·0001). Societal costs were €403 (US$507) lower with ISBCS than with DSBCS. The cost-effectiveness probability of ISBCS versus DSBCS was 100% across the willingness-to-pay range of €2500-80 000 (US$3145-100 629) per quality-adjusted life-year. INTERPRETATION: Our results showed non-inferiority of ISBCS versus DSBCS regarding effectiveness outcomes, comparable safety, and superior cost-effectiveness of ISBCS. National cost savings could amount to €27·4 million (US$34·5 million) annually, advocating for ISBCS if strict inclusion criteria are applied. FUNDING: Research grant from The Netherlands Organization for Health Research and Development (ZonMw) and Dutch Ophthalmological Society.

Liver regeneration after portal and hepatic vein embolization improves overall survival compared with portal vein embolization alone: mid-term survival analysis of the multicentre DRAGON 0 cohort.

BACKGROUND: The purpose of this study was to compare 3-year overall survival after simultaneous portal (PVE) and hepatic vein (HVE) embolization versus PVE alone in patients undergoing liver resection for primary and secondary cancers of the liver. METHODS: In this multicentre retrospective study, all DRAGON 0 centres provided 3-year follow-up data for all patients who had PVE/HVE or PVE, and were included in DRAGON 0 between 2016 and 2019. Kaplan-Meier analysis was undertaken to assess 3-year overall and recurrence/progression-free survival. Factors affecting survival were evaluated using univariable and multivariable Cox regression analyses. RESULTS: In total, 199 patients were included from 7 centres, of whom 39 underwent PVE/HVE and 160 PVE alone. Groups differed in median age (P = 0.008). As reported previously, PVE/HVE resulted in a significantly higher resection rate than PVE alone (92 versus 68%; P = 0.007). Three-year overall survival was significantly higher in the PVE/HVE group (median survival not reached after 36 months versus 20 months after PVE; P = 0.004). Univariable and multivariable analyses identified PVE/HVE as an independent predictor of survival (univariable HR 0.46, 95% c.i. 0.27 to 0.76; P = 0.003). CONCLUSION: Overall survival after PVE/HVE is substantially longer than that after PVE alone in patients with primary and secondary liver tumours.

The value of C-reactive protein, leucocytes and vital signs in detecting major complications after oncological colorectal surgery.

PURPOSE: To assess the association of postoperative C-reactive protein (CRP), leucocytes and vital signs in the first three postoperative days (PODs) with major complications after oncological colorectal resections in a tertiary referral centre for colorectal cancer in The Netherlands. METHODS: A retrospective cohort study, including 594 consecutive patients who underwent an oncological colorectal resection at Maastricht University Medical Centre between January 2016 and December 2020. Descriptive analyses of patient characteristics were performed. Logistic regression models were used to assess associations of leucocytes, CRP and Modified Early Warning Score (MEWS) at PODs 1-3 with major complications. Receiver operating characteristic curve analyses were used to establish cut-off values for CRP. RESULTS: A total of 364 (61.3%) patients have recovered without any postoperative complications, 134 (22.6%) patients have encountered minor complications and 96 (16.2%) developed major complications. CRP levels reached their peak on POD 2, with a mean value of 155 mg/L. This peak was significantly higher in patients with more advanced stages of disease and patients undergoing open procedures, regardless of complications. A cut-off value of 170 mg/L was established for CRP on POD 2 and 152 mg/L on POD 3. Leucocytes and MEWS also demonstrated a peak on POD 2 for patients with major complications. CONCLUSIONS: Statistically significant associations were found for CRP, Δ CRP, Δ leucocytes and MEWS with major complications on POD 2. Patients with CRP levels ≥ 170 mg/L on POD 2 should be carefully evaluated, as this may indicate an increased risk of developing major complications.

How a 5-Day Stay in the Tobacco-Free Environment of the Stoptober House Supports Individuals to Quit Smoking: A Mixed Methods Pilot Study.

INTRODUCTION: The Stoptober House is part of the annual national Stoptober smoking cessation campaign in the Netherlands. During the first week of October, 48 volunteers resided in the tobacco-free Stoptober House for 5 days and received smoking cessation counseling. This pilot study explored how the Stoptober House may have facilitated smoking cessation among participants. METHODS: We included 48 individuals who were selected for the Stoptober House (intervention group) and 67 individuals who were not selected (control group). Surveys were conducted at baseline, immediately after 2 and 8 weeks of post-intervention. We compared self-reported abstinence, psychosocial mediators related to smoking cessation, and perceived active elements of the Stoptober House between the intervention and control groups using t/χ2 tests and linear mixed model (LMM) analysis. Sixteen semi-structured qualitative interviews were conducted to explore participants' perspectives on the elements contributing to their success in quitting smoking. RESULTS: At 8 weeks of follow-up, a higher proportion of participants in the intervention group (24/48 [50%]) reported being abstinent compared to the control group (5/67 [7%]; p < 0.001). Among participants who reported making a quit attempt, 22/38 (57.9%) in the intervention group remained abstinent compared to 4/17 (23.5%) in the control group (p = 0.022). The intervention group also exhibited higher self-efficacy to quit smoking throughout the follow-up period and higher social support immediately after the Stoptober House. No significant differences were observed in other psychosocial factors. The interviews highlighted several perceived elements of the Stoptober House that contributed to smoking cessation success, including restricted smoking opportunities, access to smoking cessation counselors, and peer support. CONCLUSION: This pilot study suggests that the Stoptober House provides support that can help people quit smoking. Further research is needed to confirm these findings and determine the cost-effectiveness of this intervention in promoting long-term abstinence among specific groups of smokers.

Satisfaction With Life in IBS Is Associated With Psychological Burden Rather than Gastrointestinal Symptom Severity.

INTRODUCTION: Irritable bowel syndrome (IBS) has a major impact on emotional, social, and professional life. This study aimed to evaluate general life satisfaction, a subjective measure of well-being, in IBS patients, and to determine which factors are associated with higher life satisfaction. METHODS: IBS patients (n = 195, mean age 51.4 ± 16.5 years, 73.8% female) recruited from primary and secondary/tertiary care completed questionnaires regarding gastrointestinal symptoms, quality of life, psychological factors, and life satisfaction (Satisfaction With Life Scale, 5 items, range 5-35). A finite mixture model analysis was performed to identify latent classes. Multivariable linear regression was used to identify variables associated with life satisfaction. RESULTS: Overall, 71.3% of the patients were satisfied about their life (Satisfaction With Life Scale-score ≥21). Three latent subgroups could be identified with significantly higher life satisfaction in the subgroup with higher mental quality of life, fewer anxiety and depressive symptoms, lower gastrointestinal specific anxiety, and lower gastrointestinal symptom severity, compared with the other 2 groups. Multivariable linear regression showed that higher physical quality of life (B0.168, P < 0.001) and higher mental quality of life (B0.199, P < 0.001) were associated with higher life satisfaction. Using multivariable regression, no significant association was found between gastrointestinal symptom severity and life satisfaction. DISCUSSION: Higher physical and mental quality of life, but not gastrointestinal symptom severity, were independently associated with higher general life satisfaction in IBS. These findings reinforce the clinical need in IBS treatment to focus on the full extent of the disorder and not merely on gastrointestinal symptom improvement. ClinicalTrials.gov Identifier: NCT00775060.

HLA-B27, axial spondyloarthritis and survival.

INTRODUCTION: Ankylosing spondylitis (AS), and carriage of HLA-B27 gene in otherwise healthy individuals, are reportedly associated with increased mortality. We evaluated this hypothesis, using data from both a 35-year AS follow-up study and UK Biobank data. METHODS: In 1985, 363 members of the Swiss AS Patient Society and 806 relatives were screened clinically and then radiographically for AS/axial spondyloarthritis (axSpA). Life expectancy was analysed in 377 axSpA patients having available pelvic radiographs and HLA-B27 status, comparing with matched Swiss population data. Survival in relation to HLA-B27 status in the general population was studied in UK Biobank European-ancestry participants (n=407 480, n=30 419 deaths). RESULTS: AS patients have increased standardised mortality rate (SMR) compared with the general population (1.37, 95% CI 1.11 to 1.62). This increase was significant for HLA-B27-positive AS (SMR 1.38, 95% CI 1.11 to 1.65). Shortened life expectancy was observed among both HLA-B27-positive AS women (SMR 1.77, 95% CI 1.09 to 2.70) and men (SMR 1.31, 95% CI 1.02 to 1.59). Patients with non-radiographic axSpA (nr-axSpA) had significantly lower SMR: 0.44 (95% CI 0.23 to 0.77), compared with the general population. In the UK Biobank European-ancestry population cohort, HLA-B27 carriage was not significantly associated with any change in mortality (HR 1, 95% CI 0.97 to 1.1, p=0.349, adjusted by sex), in either males (HR 1, 95% CI 0.98 to 1.1, p=0.281) or females (HR 0.96, 95% CI 0.9 to 1, p=0.232), and no increase in vascular disease mortality was observed. DISCUSSION: AS patients, but not nr-axSpA patients, have a significantly shortened life expectancy. Increased mortality is particularly significant among women with HLA-B27-positive AS. HLA-B27 carriage in the European-ancestry general population does not influence survival, or the risk of death due to vascular disease.

Ferric Carboxymaltose Versus Ferrous Fumarate in Anemic Children with Inflammatory Bowel Disease: The POPEYE Randomized Controlled Clinical Trial.

OBJECTIVE: To determine whether intravenous (IV) or oral iron suppletion is superior in improving physical fitness in anemic children with inflammatory bowel disease (IBD). STUDY DESIGN: We conducted a clinical trial at 11 centers. Children aged 8-18 with IBD and anemia (defined as hemoglobin [Hb] z-score < -2) were randomly assigned to a single IV dose of ferric carboxymaltose or 12 weeks of oral ferrous fumarate. Primary end point was the change in 6-minute walking distance (6MWD) from baseline, expressed as z-score. Secondary outcome was a change in Hb z-score from baseline. RESULTS: We randomized 64 patients (33 IV iron and 31 oral iron) and followed them for 6 months. One month after the start of iron therapy, the 6MWD z-score of patients in the IV group had increased by 0.71 compared with -0.11 in the oral group (P = .01). At 3- and 6-month follow-ups, no significant differences in 6MWD z-scores were observed. Hb z-scores gradually increased in both groups and the rate of increase was not different between groups at 1, 3, and 6 months after initiation of iron therapy (overall P = .97). CONCLUSION: In this trial involving anemic children with IBD, a single dose of IV ferric carboxymaltose was superior to oral ferrous fumarate with respect to quick improvement of physical fitness. At 3 and 6 months after initiation of therapy, no differences were discovered between oral and IV therapies. The increase of Hb over time was comparable in both treatment groups. TRIAL REGISTRATION: NTR4487 [Netherlands Trial Registry].

Validity and Reliability of the Assessment of Burden of Chronic Conditions Scale in the Netherlands.

PURPOSE: The Assessment of Burden of Chronic Conditions (ABCC) tool was developed to improve care by facilitating shared decision making and self-management. It assesses and visualizes the experienced burden of 1 or multiple chronic conditions and integrates it in daily care. The aim of this study is to evaluate whether the ABCC scale is valid and reliable in people with chronic obstructive pulmonary disease (COPD), asthma, or type 2 diabetes (T2D). METHODS: The Saint George Respiratory Questionnaire (SGRQ), the Standardized Asthma Quality of Life Questionnaire (AQLQ-S), and the Audit of Diabetes Dependent Quality of Life Questionnaire (ADDQoL19) were compared with the ABCC scale to assess convergent validity. The internal consistency was evaluated using Cronbach's α. Test-retest reliability was evaluated at a 2-week interval. RESULTS: A total of 65 people with COPD, 62 with asthma, and 60 with T2D were included. The ABCC scale correlated, in accordance with hypotheses, with the SGRQ (75% of correlations ≥0.7), AQLQ-S (100%), and ADDQoL19 (75%). The ABCC scale was internally consistent with a Cronbach's α of 0.90, 0.92, and 0.91 for the total score for people with COPD, asthma, and T2D, respectively. The ABCC scale had a good test-retest reliability with an intraclass correlation coefficient of 0.95, 0.93, and 0.95 for people with COPD, asthma, and T2D, respectively. CONCLUSIONS: The ABCC scale is a valid and reliable questionnaire that can be used within the ABCC tool for people with COPD, asthma, or T2D. Future research should indicate whether this applies to people with multimorbidity, and what the effects and experiences are upon clinical use.

Effects of the egg protein hydrolysate NWT-03 on cognitive function in men and women with the metabolic syndrome: a randomized, double-blind, placebo-controlled study.

Objectives: The metabolic syndrome is associated with cardiovascular diseases and cognitive decline. The egg protein hydrolysate NWT-03 has shown to improve cardiovascular risk factors in humans. This study investigated whether NWT-03 also has an effect on cognitive function.Methods: Men and women with the metabolic syndrome (n = 76) with a mean age of 60 ± 10 years participated in this randomized, double-blind, placebo-controlled, cross-over trial with an intervention (5 g/day NWT-03) and control period (5 g/day maltodextrin) of 4 weeks separated by a wash-out period of 2-8 weeks. Cognitive function was assessed with the anti-cue reaction time test (impulse control) and psychomotor vigilance test (sustained attention) at day 0, 2, and 27 of both periods. Serum brain-derived neurotrophic factor (BDNF) concentrations were measured at the start and end of both periods.Results: NWT-03 consumption significantly improved the change (day 27 - day 0) in response times of the anti-cue reaction time test compared with the control period (P < 0.001), but not of the psychomotor vigilance test (P = 0.487). Serum BDNF concentrations of all subjects did not significantly change (P = 0.241).Conclusion: NWT-03 has the ability to improve cognitive function within the executive function domain. The underlying mechanism warrants further research and could either be indirect via inhibition of dipeptidyl peptidase 4 (DPP4) or direct via passage of small peptides over the blood-brain barrier inducing local effects.Trial registration: ClinicalTrials.gov identifier: NCT02561663.

Effects of breaking up sitting with light-intensity physical activity on cognition and mood in university students.

BACKGROUND: University students often exhibit high levels of sedentary behavior that is negatively associated with cognition and mood. On the other hand, light-intensity physical activity (LIPA) may improve cognitive performance and mood. Therefore, this study investigated the acute effect of LIPA breaks during prolonged sitting on attention, executive functioning, and mood. METHODS: A randomized crossover design was used in this study. In total, 21 healthy adults (15 women, age = 24 ± 3 years, BMI = 23 ± 2 kg/m2 ) completed three prolonged sitting conditions: (1) without a demanding cognitive task (SIT), (2) with a demanding cognitive task (COGN), and (3) with every 25 min sitting interrupted by a 5-minute walk (INTERRUPT). Attention, executive function (response inhibition, task shifting, and working memory updating), and mood were assessed before and after each condition. RESULTS: Linear mixed models analyses showed that prolonged sitting frequently interrupted by LIPA (INTERRUPT) or with cognitively demanding activities (COGN) significantly improved task shifting compared to SIT. However, INTERRUPT did not significantly improve task shifting compared with COGN. No significant acute effects on attention, response inhibition, working memory updating, or mood were found. CONCLUSIONS: Frequent LIPA breaks or cognitively demanding activities have a selective, acute positive impact on one aspect of cognitive performance compared to idle sitting. No evidence was found that LIPA breaks have an acute improvement in attention, executive function, and mood compared to sitting with cognitive loading. To further investigate the effect of PA on cognitive performance, it is necessary to consider cognitive loading and control for the cognitive activity during sitting in the experimental design.

Efficacy of customized corneal crosslinking versus standard corneal crosslinking in patients with progressive keratoconus (C-CROSS study): study protocol for a randomized controlled trial.

BACKGROUND: Keratoconus is a degenerative disorder of the cornea leading to a protrusion and thinning with loss of visual acuity. The only treatment to halt the progression is corneal crosslinking (CXL), which uses riboflavin and UV-A light to stiffen the cornea. Recent ultra-structural examinations show that the disease is regional and does not affect the entire cornea. Treating only the affected zone with CXL could be as good as the standard CXL, that treats the entire cornea. METHODS: We set up a multicentre non-inferiority randomized controlled clinical trial comparing standard CXL (sCXL) and customized CXL (cCXL). Patients between 16 and 45 years old with progressive keratoconus were included. Progression is based on one or more of the following changes within 12 months: 1 dioptre (D) increase in keratometry (Kmax, K1, K2); or 10% decrease of corneal thickness; or 1 D increase in myopia or refractive astigmatism, requiring corneal crosslinking. DISCUSSION: The goal of this study is to evaluate whether the effectiveness of cCXL is non-inferior to sCXL in terms of flattening of the cornea and halting keratoconus progression. Treating only the affected zone could be beneficial for minimalizing the risk of damaging surrounding tissues and faster wound healing. Recent non-randomized studies suggest that a customized crosslinking protocol based on the tomography of the patient's cornea may stop the progression of keratoconus and result in flattening of the cornea. TRIAL REGISTRATION: This study was prospectively registered at ClinicalTrials.gov on August 31st, 2020, the identifier of the study is NCT04532788.

Effectiveness and cost-effectiveness of MicroShunt implantation versus standard trabeculectomy for open-angle glaucoma (a SIGHT study): study protocol of a multicentre randomised controlled trial.

BACKGROUND: Trabeculectomy is the "gold standard" initial surgical procedure for open-angle glaucoma worldwide. During the last decade, the introduction of less invasive procedures, including new bleb-forming surgery such as the MicroShunt, has altered the approach of glaucoma management. At present, there is insufficient evidence comparing the effectiveness between these procedures nor versus trabeculectomy. Furthermore, there is no data available on patient impact and cost-effectiveness. This study aims to address this gap in evidence and establish whether MicroShunt implantation is non-inferior compared to trabeculectomy with regard to effectiveness and whether it is cost-effective. METHODS: A multicentre, non-inferiority, randomised controlled trial (RCT) studying open-angle glaucoma with an indication for surgery will be conducted. Patients with previous ocular surgery except for phacoemulsification are excluded, as are patients with ocular comorbidity compromising the visual field or requiring a combined procedure. After informed consent is obtained, patients will be randomly allocated to the intervention, a PRESERFLO™ MicroShunt implantation, or the control group, trabeculectomy, using block randomisation (blocks of 2, 4 or 6 patients). In total, 124 patients will be randomised in a 1:1 ratio, stratified by centre. The primary endpoint will be intraocular pressure (IOP) one year after surgery. Secondary outcomes include IOP-lowering medication use, treatment failure, visual acuity, visual field progression, additional interventions, adverse events, patient-reported outcome measures (PROMs), and cost-effectiveness. Study outcomes will be measured up to 12 months postoperatively. DISCUSSION: This study protocol describes the design of a multicentre non-inferiority randomised controlled trial. To this date, cost-effectiveness studies evaluating the MicroShunt have not been undertaken. This multicentre RCT will provide more insight into whether MicroShunt implantation is non-inferior compared to standard trabeculectomy regarding postoperative IOP and whether MicroShunt implantation is cost-effective. TRIAL REGISTRATION: ClinicalTrials.gov, Identifier: NCT03931564 , Registered 30 April 2019.

Intra and interobserver agreement of the Dynamic Imaging Grade of Swallowing Toxicity Scale (DIGEST) in fiberoptic endoscopic evaluation of swallowing (FEES): the importance of observer-tailored training.

PURPOSE: The Dynamic Imaging Grade of Swallowing Toxicity (DIGEST) is a scale to quantify the severity of pharyngeal dysphagia in head and neck cancer (HNC) patients. This study (1) described the training process of the observers for DIGEST in fiberoptic endoscopic evaluation of swallowing (FEES), (2) determined observer agreement on the DIGEST in FEES, (3) explored the effect of bolus consistency on observer agreement, and 4) explored criterion validity of the DIGEST in FEES. METHODS: Twenty-seven dysphagic HNC patients were enrolled. Two observers completed a training program for DIGEST in FEES. Observer agreement on the Penetration-Aspiration Scale (PAS), percentage of pharyngeal residue (PPR), and DIGEST grades was determined using linearly weighted Cohen's kappa coefficient (κ). RESULTS: Due to insufficient observer agreement after the first measurement attempt, additional training was organized using an elaborated manual with descriptions of the visuoperceptual variables, thereby improving observer agreement. Intraobserver agreement was almost perfect on the PAS (κ = 0.86-0.88) and PPR (κ = 0.84-0.86). Interobserver agreement was substantial on the PAS (κ = 0.78), almost perfect on the PPR (κ = 0.82), substantial on the safety grade (κ = 0.64), almost perfect on the efficiency grade (κ = 0.85), and substantial on the summary grade (κ = 0.71). Bolus consistency had an effect on observer agreement. A significant correlation was found between DIGEST efficiency grade and EAT-10. CONCLUSION: The DIGEST showed to be a reproducible measurement for FEES in terms of observer agreement. However, agreement between novice observers on the DIGEST was only reached after specific observer-tailored training. Observer agreement should be analyzed by taking bolus consistency into account during training, as this might affect the interpretation of the outcome. A manual with well-defined descriptions can optimize the reproducibility of DIGEST measurements.

Molecular pathways in post-colonoscopy versus detected colorectal cancers: results from a nested case-control study.

BACKGROUND: Post-colonoscopy colorectal cancers (PCCRCs) pose challenges in clinical practice. PCCRCs occur due to a combination of procedural and biological causes. In a nested case-control study, we compared clinical and molecular features of PCCRCs and detected CRCs (DCRCs). METHODS: Whole-genome chromosomal copy number changes and mutation status of genes commonly affected in CRC were examined by low-coverage WGS and targeted sequencing, respectively. MSI and CIMP status was also determined. RESULTS: In total, 122 PCCRCs and 98 DCRCs with high-quality DNA were examined. PCCRCs were more often located proximally (P < 0.001), non-polypoid appearing (P = 0.004), early stage (P = 0.009) and poorly differentiated (P = 0.006). PCCRCs showed significantly less 18q loss (FDR < 0.2), compared to DCRCs. No significant differences in mutations were observed. PCCRCs were more commonly CIMP high (P = 0.014) and MSI (P = 0.029). After correction for tumour location, only less 18q loss remained significant (P = 0.005). CONCLUSION: Molecular features associated with the sessile serrated lesions (SSLs) and non-polypoid colorectal neoplasms (CRNs) are more commonly seen in PCCRCs than in DCRCs. These together with the clinical features observed support the hypothesis that SSLs and non-polypoid CRNs are contributors to the development of PCCRCs. The future focus should be directed at improving the detection and endoscopic removal of these non-polypoid CRN and SSLs. CLINICAL TRIAL REGISTRATION: NTR3093 in the Dutch trial register ( www.trialregister.nl ).

Predictive Algorithm for Thiopurine-Induced Hepatotoxicity in Inflammatory Bowel Disease Patients.

BACKGROUND: Approximately 25% of patients with inflammatory bowel disease (IBD) discontinue azathioprine (AZA) or mercaptopurine (MP) therapy within 3 months of treatment initiation because of adverse drug reactions. Of these side-effects, about half are because of hepatotoxicity. The aim of this study was to validate and (subsequently) optimize a previously reported predictive algorithm for thiopurine-associated hepatotoxicity by increasing the number of patients with IBD benefitting from conventional thiopurine therapy. METHODS: This multicenter observational study included consecutive thiopurine-naive patients with IBD who received AZA or MP treatment. The primary outcome was hepatotoxicity within 12 weeks. The patients with and without hepatotoxicity were compared. Four determinants, namely, age, sex, body mass index (BMI), and 6-methylmercaptopurine ribonucleotide concentrations 1 week after treatment initiation (T = 1) were used to validate and optimize 2 (1 dichotomous and 1 continuous) algorithms using multivariable logistic regression analysis. RESULTS: Of 229 patients, 21 (9%) developed hepatotoxicity and 93% of the patients received MP with a median dose of 0.7 mg/kg (95% confidence interval 0.3-1.4 mg/kg). A difference in BMI was found between with and without hepatotoxicity groups (median 27.6 versus 24.2, P = 0.022). Specificities of 68% (Algorithm 1) and 77% (Algorithm 2) and sensitivities of 56% (Algorithm 1) and 50% (Algorithm 2) were obtained. CONCLUSIONS: Both algorithms demonstrated limited predictive accuracy for thiopurine-induced hepatotoxicity in the validation cohort. Relevant factors contributing to this outcome were changes in thiopurine prescription behavior over time, with more MP prescriptions at relatively lower dosages of MP.

Immediate sequential bilateral surgery versus delayed sequential bilateral surgery for cataracts.

BACKGROUND: Age-related cataract affects both eyes in most cases. Most people undergo cataract surgery in both eyes on separate days, referred to as delayed sequential bilateral cataract surgery (DSBCS). An alternative procedure involves operating on both eyes on the same day, but as two separate procedures, known as immediate sequential bilateral cataract surgery (ISBCS). Potential advantages of ISBCS include fewer hospital visits for the patient, faster visual recovery, and lower healthcare costs. Nevertheless, concerns exist about possible bilateral, postoperative, sight-threatening adverse effects with ISBCS. Therefore, there is a clear need for evaluating evidence regarding the safety, effectiveness, and cost-effectiveness of ISBCS versus DSBCS. OBJECTIVES: To assess the safety of ISBCS compared to DSBCS in people with bilateral age-related cataracts and to summarise current evidence for the incremental resource use, utilities, costs, and cost-effectiveness associated with the use of ISBCS compared to DSBCS in people with bilateral age-related cataracts (primary objectives). The secondary objective was to assess visual and patient-reported outcomes of ISBCS compared to DSBCS in people with bilateral age-related cataracts. SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register; 2021, Issue 5); Ovid MEDLINE; Ovid Embase; the ISRCTN registry; ClinicalTrials.gov; the WHO ICTRP; and DARE and NHS EED on the CRD Database on 11 May 2021. There were no language restrictions. We limited the searches to a date range of 2007 onwards. SELECTION CRITERIA: We included randomised controlled trials (RCTs) to assess complications, refractive outcomes, best-corrected distance visual acuity (BCDVA) and patient-reported outcome measures (PROMs) with ISBCS compared to DSBCS. We included non-randomised (NRSs), prospective, and retrospective cohort studies comparing ISBCS and DSBCS for safety assessment, because of the rare incidence of important adverse events. To assess cost-effectiveness of ISBCS compared to DSBCS, we included both full and partial economic evaluations, and both trial-based and model-based economic evaluations. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures and assessed risk of bias for NRSs using the ROBINS-I tool. For cost-evaluations, we used the CHEC-list, the CHEERS-checklist, and the NICE-checklist to investigate risk of bias. We assessed the certainty of evidence with the GRADE tool. We reported results for economic evaluations narratively. MAIN RESULTS: We included 14 studies in the review; two RCTs, seven NRSs, and six economic evaluations (one study was both an NRS and economic evaluation). The studies reported on 276,260 participants (7384 for ISBCS and 268,876 for DSBCS) and were conducted in Canada, the Czech Republic, Finland, Iran, (South) Korea, Spain (Canary Islands), Sweden, the UK, and the USA. Overall, we considered the included RCTs to be at 'high to some concerns' risk of bias for complications, 'some concerns' risk of bias for refractive outcomes and visual acuity, and 'high' risk of bias for PROMs. The overall risk of bias for NRSs was graded 'serious' regarding complications and 'serious to critical' regarding refractive outcomes.  With regard to endophthalmitis, we found that relative effects were estimated imprecisely and with low certainty, so that relative estimates were not reliable. Nonetheless, we found a very low risk of endophthalmitis in both ISBCS (1/14,076 participants) and DSBCS (55/556,246 participants) groups. Based on descriptive evidence and partially weak statistical evidence we found no evidence of an increased risk of endophthalmitis with ISBCS. Regarding refractive outcomes, we found moderate-certainty (RCTs) and low-certainty (NRSs) evidence there was no difference in the percentage of eyes that did not achieve refraction within 1.0 dioptre of target one to three months after surgery (RCTs: risk ratio (RR) 0.84, 95% confidence interval (CI) 0.57 to 1.26; NRSs: RR 1.02, 95% CI 0.60 to 1.75). Similarly, postoperative complications did not differ between groups (RCTs: RR 1.33, 95% CI 0.52 to 3.40; NRSs: 1.04, 95% CI 0.47 to 2.29), although the certainty of this evidence was very low for both RCTs and NRSs. Furthermore, we found low-certainty (RCTs) to very low-certainty (NRSs) evidence that total costs per participant were lower for ISBCS compared to DSBCS, although results of individual studies could not be pooled. Only one study reported on cost-effectiveness. This study found that ISBCS is cost-effective compared to DSBCS, but did not measure quality-adjusted life years using preferred methods and calculated costs erroneously. Finally, regarding secondary outcomes, we found limited evidence on BCDVA (data of two RCTs could not be pooled, although both studies individually found no difference between groups (very low-certainty evidence)). Regarding PROMs, we found moderate-certainty evidence (RCTs only) that there was no difference between groups one to three months after surgery (standardised mean difference -0.08, 95% CI -0.19 to 0.03). AUTHORS' CONCLUSIONS: Current evidence supports there are probably no clinically important differences in outcomes between ISBCS and DSBCS, but with lower costs for ISBCS. However, the amount of evidence is limited, and the certainty of the evidence was graded moderate to very low. In addition, there is a need for well-designed cost-effectiveness studies.

Control in the Hospital by Extensive Clinical rules for Unplanned hospitalizations in older Patients (CHECkUP); study design of a multicentre randomized study.

BACKGROUND: Due to ageing of the population the incidence of multimorbidity and polypharmacy is rising. Polypharmacy is a risk factor for medication-related (re)admission and therefore places a significant burden on the healthcare system. The reported incidence of medication-related (re)admissions varies widely due to the lack of a clear definition. Some medications are known to increase the risk for medication-related admission and are therefore published in the triggerlist of the Dutch guideline for Polypharmacy in older patients. Different interventions to support medication optimization have been studied to reduce medication-related (re)admissions. However, the optimal template of medication optimization is still unknown, which contributes to the large heterogeneity of their effect on hospital readmissions. Therefore, we implemented a clinical decision support system (CDSS) to optimize medication lists and investigate whether continuous use of a CDSS reduces the number of hospital readmissions in older patients, who previously have had an unplanned probably medication-related hospitalization. METHODS: The CHECkUP study is a multicentre randomized study in older (≥60 years) patients with an unplanned hospitalization, polypharmacy (≥5 medications) and using at least two medications from the triggerlist, from Zuyderland Medical Centre and Maastricht University Medical Centre+ in the Netherlands. Patients will be randomized. The intervention consists of continuous (weekly) use of a CDSS, which generates a Medication Optimization Profile, which will be sent to the patient's general practitioner and pharmacist. The control group will receive standard care. The primary outcome is hospital readmission within 1 year after study inclusion. Secondary outcomes are one-year mortality, number of emergency department visits, nursing home admissions, time to hospital readmissions and we will evaluate the quality of life and socio-economic status. DISCUSSION: This study is expected to add evidence on the knowledge of medication optimization and whether use of a continuous CDSS ameliorates the risk of adverse outcomes in older patients, already at an increased risk of medication-related (re)admission. To our knowledge, this is the first large study, providing one-year follow-up data and reporting not only on quality of care indicators, but also on quality-of-life. TRIAL REGISTRATION: The trial was registered in the Netherlands Trial Register on October 14, 2018, identifier: NL7449 (NTR7691). https://www.trialregister.nl/trial/7449 .

Shoulder muscle changes in patients with type 2 diabetes mellitus who have a painful shoulder: a quantitative muscle ultrasound study.

BACKGROUND: It is assumed that in patients with diabetic neuropathy, muscle denervation can result in shoulder disorders. Muscle denervation will lead to changes in muscle architecture, which can be assessed by quantitative muscle ultrasound (QMUS). The aim was to investigate whether increased muscle echogenicity, as a sign of neuropathy, is more often present in patients with shoulder pain who have type 2 diabetes mellitus (T2DM) than in those without. METHODS: Sixty-six patients with T2DM and 23 patients without diabetes mellitus (DM) having shoulder pain were included. Quantitative muscle ultrasound images were obtained bilaterally from the biceps brachii, deltoid, and supra- and infraspinatus muscles. The mean echogenicity (muscle ultrasound grey value) was transformed into z-scores and compared to reference values obtained from 50 healthy participants. Associations between muscle echogenicity and clinical variables were explored. RESULTS: In painful shoulders of both patients with T2DM and patients without DM, mean echogenicity z-scores of all muscles were significantly increased compared to healthy controls. No significant differences in echogenicity between patients with T2DM and those without DM were found. In patients with T2DM, a distal symmetric polyneuropathy was significantly associated with increased echogenicity of all muscles except the infraspinatus muscle. CONCLUSIONS: These findings indicate that patients with painful shoulders, irrespective of having T2DM, seem to have abnormal shoulder muscles. Future studies are needed to elucidate whether neuropathy or other conditions lead to these muscle changes.