Suture repair of parastomal hernia should be abandoned because of increased recurrence rates. The use of mesh in parastomal hernia repair significantly reduces recurrence rates and is safe with a low overall rate of mesh infection. In laparoscopic repair, the Sugarbaker technique is superior over the keyhole technique showing fewer recurrences.

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E ndothelial cells synthesize paracrine hormones such as nitric oxide (NO), 1 which have important antiatherogenic properties.2 Early studies in humans that used intra-arterial infusion of endothelial stimulants and inhibitors established that endothelial function is impaired in individuals with cardiovascular diseases and risk factors [3][4][5][6] and that coronary 7,8 and peripheral 9-12 endothelial dysfunction can predict clinical events. In 1992, Celermajer et al 13 introduced an ultrasound technique involving temporary suprasystolic cuff inflation around the limbs and measurement of conduit artery dilation consequent to postischemic hyperemia and an arterial shear stress stimulus. Owing to its relative simplicity, its noninvasive nature, and prognostic research studies that have consistently suggested clinical utility, [14][15][16][17][18][19][20] this so-called flowmediated dilation (FMD) approach has become widely used by both scientists and clinicians.Despite the popularity of the FMD approach, important questions remained unanswered when it was introduced, and the uptake of the technique largely preceded detailed physiological description of underlying mechanisms. In the watershed article of Celermajer and Deanfield, it was reasonably assumed, on the basis of previous animal data, 21,22 that FMD was a flow-and NO-mediated response, despite no evidence being available about its NO dependency. Eventually, the assumption that FMD reflected NO-mediated vascular function was reinforced by physiological experiments that infused NO blockers upstream from an insonated conduit artery and reported that dilator responses to ischemia and shear stress were almost completely abolished. [23][24][25][26] Nonetheless, there have been some well-designed and controlled studies that have been unable to inhibit FMD using NO blockade. 27,28 This disparity in the literature may not only be related to differences in the methodology used to measure FMD, but also to the inclusion of different population groups.Therefore, the aim of this study was to systematically review and meta-analyze the literature relating to crossover studies that have compared FMD under local infusion of saline (FMD saline ) with FMD under local infusion of theto obtain an estimate of the contribution of NO to FMD in human conduit arteries. We used a staged approach and explored the contribution of NO in FMD studies that adopted the standardized approach (ie, using distal cuff placement and ≈5-minute cuff inflation in healthy individuals). Finally, the effect of automated, continuous method of analysis on NO dependency was explored. Abstract-Flow-mediated dilation (FMD) is a noninvasive index of endothelial function and vascular health in humans.Studies examining the role of nitric oxide (NO) are not conclusive. In this article, we quantified the contribution of NO in FMD of conduit arteries and explored the effect of the protocol (ie, distal cuff, ≈5-minute ischemia) and method of analysis (ie, automated and continuous edge detection) on the NO dependenc...

IMPORTANCE In rare diseases it is difficult to achieve high-quality evidence of treatment efficacy because of small cohorts and clinical heterogeneity. With emerging treatments for rare diseases, innovative trial designs are needed. OBJECTIVE To investigate the effectiveness of mexiletine in nondystrophic myotonia using an aggregated N-of-1 trials design and compare results between this innovative design and a previously conducted RCT. DESIGN, SETTING, AND PARTICIPANTS A series of aggregated, double-blind, randomized, placebo-controlled N-of-1-trials, performed in a single academic referral center. Thirty Dutch adult patients with genetically confirmed nondystrophic myotonia (38 patients screened) were enrolled between February 2014 and June 2015. Follow-up was completed in September 2016. INTERVENTIONS Mexiletine (600 mg daily) vs placebo during multiple treatment periods of 4 weeks. MAIN OUTCOMES AND MEASURES Reduction in daily-reported muscle stiffness on a scale of 1 to 9, with higher scores indicating more impairment. A Bayesian hierarchical model aggregated individual N-of-1 trial data to determine the posterior probability of reaching a clinically meaningful effect of a greater than 0.75-point difference. RESULTS Among 30 enrolled patients (mean age, 43.4 [SD, 15.24] years; 22% men; 19 CLCN1 and 11 SCN4A genotype), 27 completed the study and 3 dropped out (1 because of a serious adverse event). In 24 of the 27 completers, a clinically meaningful treatment effect was found. In the Bayesian hierarchical model, mexiletine resulted in a 100% posterior probability of reaching a clinically meaningful reduction in self-reported muscle stiffness for the nondystrophic myotonia group overall and the CLCN1 genotype subgroup and 93% posterior probability for the SCN4A genotype subgroup. In the total nondystrophic myotonia group, the median muscle stiffness score was 6.08 (interquartile range, 4.71-6.80) at baseline and was 2.50 (95% credible interval [CrI], 1.77-3.24) during the mexiletine period and 5.56 (95% CrI, 4.73-6.39) during the placebo period; difference in symptom score reduction, 3.06 (95% CrI, 1.96-4.15; n = 27) favoring mexiletine. The most common adverse event was gastrointestinal discomfort (21 mexiletine [70%], 1 placebo [3%]). One serious adverse event occurred (1 mexiletine [3%]; allergic skin reaction). Using frequentist reanalysis, mexiletine compared with placebo resulted in a mean reduction in daily-reported muscle stiffness of 3.12 (95% CI, 2.46-3.78), consistent with the previous RCT treatment effect of 2.69 (95% CI, 2.12-3.26). CONCLUSIONS AND RELEVANCE In a series of N-of-1 trials of mexiletine vs placebo in patients with nondystrophic myotonia, there was a reduction in mean daily-reported muscle stiffness that was consistent with the treatment effect in a previous randomized clinical trial. These findings support the efficacy of mexiletine for treatment of nondystrophic myotonia as well as the feasibility of N-of-1 trials for assessing interventions in some chronic rare diseases.

IMPORTANCE Biologics revolutionized the treatment of psoriasis. Biologics are given in a fixed dose, but lower doses might be possible. OBJECTIVE To investigate whether dose reduction (DR) of biologics in patients with stable psoriasis is noninferior to usual care (UC). DESIGN, SETTING, AND PARTICIPANTS This pragmatic, open-label, prospective, controlled, noninferiority randomized clinical trial was conducted from March 1, 2016, to July 22, 2018, at 6 dermatology departments in the Netherlands. A total of 120 patients with plaque psoriasis and stable low disease activity who were receiving treatment with adalimumab, etanercept, or ustekinumab were studied. INTERVENTIONS Patients were randomized 1:1 to DR (n = 60) or UC (n = 60). In the DR group, injection intervals were prolonged stepwise, leading to 67% and 50% of the original dose. MAIN OUTCOMES AND MEASURES The primary outcome was between-group difference in disease activity corrected for baseline at 12 months compared with the predefined noninferiority margin of 0.5. Secondary outcomes were Psoriasis Area and Severity Index (PASI) score and health-related quality of life (including Dermatology Life Quality Index [DLQI] and Medical Outcomes Study 36-Item Short Form Health Survey scores), proportion of patients with short and persistent flares (defined as PASI and/or DLQI scores >5 for Ն3 months), and proportion of patients with successful dose tapering. RESULTS Of 120 patients (mean [SD] age, 54.0 [13.2] years; 82 [68%] male), 2 patients were lost to follow-up, 2 patients had a protocol violation, and 5 patients had a protocol deviation, leaving 111 patients for the per-protocol analysis (53 in the DR group and 58 in the UC group). The median PASI scores at month 12 were 3.4 (interquartile range [IQR], 2.2-4.5) in the DR group and 2.1 (IQR, 0.6-3.6) in the UC group (mean difference, 1.2; 95% CI, 0.7-1.8). This indicates that noninferiority was not demonstrated for DR compared to UC. The median DLQI score at month 12 was 1.0 (IQR, 0.0-2.0) in the DR group and 0.0 (IQR, 0.0-2.0) in the UC group (mean difference, 0.8; 95% CI, 0.3-1.3), indicating noninferiority for DR compared with UC. No significant difference was found regarding persistent flares between groups (n = 5 in both groups). Twenty-eight patients (53%; 95% CI, 39%-67%) in the DR group tapered their dose successfully at 12 months. No severe adverse events related to the intervention occurred. CONCLUSIONS AND RELEVANCE In this trial, noninferiority was not demonstrated for DR of adalimumab, etanercept, and ustekinumab based on the PASI in patients with psoriasis compared with UC with the chosen noninferiority margin. However, the strategy was noninferior based on the DLQI. Dose tapering did not lead to persistent flares or safety issues.

ObjectiveTo compare the effectiveness of pain exposure physical therapy (PEPT) with conventional treatment in patients with complex regional pain syndrome type 1 (CRPS-1) in a randomised controlled trial with a blinded assessor.SettingThe study was conducted at a level 1 trauma centre in the Netherlands.Participants56 adult patients with CRPS-1 participated. Three patients were lost to follow-up.InterventionsPatients received either PEPT in a maximum of five treatment sessions, or conventional treatment following the Dutch multidisciplinary guideline.MeasurementsOutcomes were assessed at baseline and at 3, 6 and 9 months after randomisation. The primary outcome measure was the Impairment level Sum Score—Restricted Version (ISS-RV), consisting of visual analogue scale for pain (VAS-pain), McGill Pain Questionnaire, active range of motion (AROM) and skin temperature. Secondary outcome measures included Pain Disability Index (PDI); muscle strength; Short Form 36 (SF-36); disability of arm, shoulder and hand; Lower Limb Tasks Questionnaire (LLTQ); 10 m walk test; timed up-and-go test (TUG) and EuroQol-5D.ResultsThe intention-to-treat analysis showed a clinically relevant decrease in ISS-RV (6.7 points for PEPT and 6.2 points for conventional treatment), but the between-group difference was not significant (0.96, 95% CI −1.56 to 3.48). Participants allocated to PEPT experienced a greater improvement in AROM (between-group difference 0.51, 95% CI 0.07 to 0.94; p=0.02). The per protocol analysis showed larger and significant between-group effects on ISS-RV, VAS-pain, AROM, PDI, SF-36, LLTQ and TUG.ConclusionsWe cannot conclude that PEPT is superior to conventional treatment for patients with CRPS-1. Further high-quality research on the effects of PEPT is warranted given the potential effects as indicated by the per protocol analysis.Trial registration numbersNCT00817128 and NTR 2090.

BackgroundTo investigate the efficacy of adding supplemental fusion or arthroplasty after cervical anterior discectomy for symptomatic mono-level cervical degenerative disease (radiculopathy), which has not been substantiated in controlled trials until now.MethodsA randomized controlled trial is reported with 9 years follow up comparing anterior cervical anterior discectomy without fusion, with fusion by cage standalone, or with disc prosthesis. Patients suffering from symptomatic cervical disk degeneration at one level referred to spinal sections of department of neurosurgery or orthopedic surgery of a large general hospital with educational facilities were eligible. Neck Disability Index (NDI), McGill Pain Questionnaire Dutch language version (MPQ-DLV), physical-component summary (PCS), and mental-component summary (MCS) of the 36-item Short-Form Health Survey (SF-36), and re operation rate were evaluated.Findings142 patients between 18 and 55 years were allocated. The median follow-up was 8.9±1.9 years (5.6 to 12.2 years). The response rate at last follow-up was 98.5%. NDI at the last follow-up did not differ between the three treatment groups, nor did the secondary outcomes as MPQ-DLV and PCS or MCS from SF-36. The major improvement occurred within the first 6 weeks after surgery. Afterward, it remained stable. Eleven patients underwent surgery for recurrent symptoms and signs due to nerve root compression at the index or adjacent level.ConclusionsThis randomized trial could not detect a difference between three surgical modalities for treating a single-level degenerative disk disease. Anterior cervical discectomy without implant seems to be similar to anterior cervical discectomy with fusion by cage stand-alone or with disk prosthesis. Due to the small study sample size, this statement should be considered as inconclusive so far.Trial registrationISRCTN41681847

Pregnant women and healthcare professionals differ significantly in their preferences regarding prenatal test characteristics. Healthcare professionals should take these differences into consideration when counseling pregnant women on prenatal testing.