Background and ObjectivePain management in patients with prostate cancer receiving enzalutamide is challenging owing to its high potential for drug-drug interactions. Morphine is generally preferred because of its favorable metabolic profile, but the effect of enzalutamide on the pharmacokinetics of morphine is unclear. The objective of this study was to assess whether a drug-drug interaction exists between enzalutamide and morphine in patients with prostate cancer.MethodsIn a multicenter two-arm parallel study, 24 men with prostate cancer received morphine with enzalutamide (n = 12) and without enzalutamide (n = 12). Plasma concentrations of morphine and its active metabolite morphine-6-glucuronide were measured. Pharmacokinetic parameters were calculated using a non-compartmental analysis. Geometric mean ratios (GMR) of the area under the plasma concentration-time curves were calculated. No clinically relevant interaction was defined if 90% of the confidence interval (CI) of the GMR of morphine was within the range of 0.5-2.0.ResultsMorphine exposure was similar between both groups, with the 90% CI falling within the range of 0.5-2.0 (GMR 1.01; 90% CI 0.77-1.31). The exposure of morphine-6-glucuronide was increased with enzalutamide (GMR 1.77; 90% CI 1.43-2.17).ConclusionsThe exposure of morphine was unaffected by enzalutamide, while morphine-6-glucuronide exposure was increased. Because of the inconclusive potency of morphine-6-glucuronide and its uncertain ability to cross the blood-brain barrier, the increase is likely of modest clinical significance. Therefore, morphine and enzalutamide can be safely combined when starting at a low dose and titrated based on efficacy and tolerability.Clinical Trial RegistrationNCT05339672.
This study evaluates incisional hernia incidence 13 years after accrual ended. QuestionDoes small-bites fascial closure reduce the long-term incidence and severity of incisional hernias compared with large-bites closure after elective midline laparotomy?FindingsIn this multicenter randomized trial with median follow-up of 8 years (maximum 15 years), cumulative incidence of incisional hernia at 13 years was 34% in the small-bites group vs 49% in the large-bites group. Hernias in the small-bites group were smaller and quality of life was lower in patients with an incisional hernia.MeaningSmall-bites fascial closure significantly reduced long-term incidence and size of incisional hernia and should be considered standard practice. ImportanceIncisional hernia after midline laparotomy causes long-term morbidity and reduced quality of life; closure technique may affect long-term risk. Superiority of the small-bites fascial closure technique in reducing incisional hernia rate at 1 year after midline laparotomy was previously demonstrated in the STITCH trial.ObjectiveTo evaluate incisional hernia incidence 13 years after accrual ended.Design, Setting, and ParticipantsThis multicenter, double-blind randomized clinical trial took place between October 2009 and March 2012 at 10 participating centers in the Netherlands, including surgical and gynecological departments. The study included 559 patients undergoing elective midline laparotomy. These data were analyzed from January 2025 through June 2025.InterventionsContinuous small-bites fascial closure (5 mm & times; 5 mm, polydioxanone 2-0 on 31-mm needle) vs large bites (10 mm & times; 10 mm, looped polydioxanone on 48-mm needle) in the control group.Main Outcomes and MeasuresPrimary outcome was cumulative incidence of incisional hernia (clinical and radiologic) analyzed with time-to-event methods accounting for competing risks. Secondary outcomes included hernia width, repair rates, and patient-reported quality of life.ResultsA total of 275 patients were randomized to small-bites fascial closure and 284 to the control group. Median time to censoring was 8 (IQR, 2-13) years. At final follow-up, 170 patients were alive without evidence of incisional hernia. Of these, 122 (72%) underwent additional abdominal ultrasound. Abdominal imaging performed as part of patient care was available for 238 patients. At 13 years, cumulative incidence of incisional hernia was 34% in the small-bites group and 49% in the large-bites group (hazard ratio, 0.61; 95% CI, 0.43-0.86). Corresponding outcomes for hernia width more than 20 mm were 17% and 34%, respectively (hazard ratio, 0.36; 95%CI, 0.21-0.60). Hernias were significantly smaller after small-bites closure at final follow-up (mean, 25 mm vs 43 mm; P = .02). Hernia repair rates were similar. Patients with an incisional hernia reported significantly lower quality of life.Conclusions and RelevanceIn this study, the small-bites technique reduced the long-term risk and width of incisional hernias after elective midline laparotomy. Given its simplicity, cost neutrality, and broad applicability, it should be regarded standard practice. Further research should explore strategies to enhance adoption and assess broader patient-centered outcomes.Trial RegistrationClinicalTrials.gov Identifier: NCT01132209
Background: The lack of a gold standard in tarsal tunnel syndrome (TTS) diagnosis leads to diagnostic inconsistencies and variation in patient selection for treatment. Therefore, the aim of this review is to summarize the diagnostic criteria used in current studies on TTS based upon this best-evidence synthesis. Methods: Three databases were searched to identify all studies on TTS. Studies were included when they included (1) diagnosis or treatment of TTS as the primary focus, (2) a description of the diagnosis of TTS, (3) an original data set of TTS cases, and (4) a minimum of 10 adult patients diagnosed with TTS. A best-evidence synthesis was used to summarize the results. Results: In total, 4,213 patients were represented in 82 included studies. Among the varying diagnostic methods employed, aside from clinical symptoms, provocative testing was most often used (in 94% of studies, mandatory for diagnosis in 41% of studies) with the Tinel sign being the most prevalent (used in 89% of studies). Sensitivities of provocative tests, electrodiagnostic, and ultrasound measurements showed significant variability. Conclusion: We provided an overview of the diagnostic tools and workups reported in the literature on TTS. Our findings show that the lack of a standardized diagnostic approach results in considerable variability in clinical practice. Alongside typical clinical symptoms, the Tinel sign is the most frequently used diagnostic test. The varying sensitivities reported in literature underscore the need for evidence-based diagnostic guidelines on TTS diagnosis. Level of Evidence: Diagnostic Level III . See Instructions for Authors for a complete description of levels of evidence.
Survivors of critical illness frequently experience symptoms of post-intensive care syndrome (PICS), including post-traumatic stress disorder (PTSD), anxiety, and depression, with downstream impact on health-related quality of life (HRQoL). We evaluated whether an intensive care unit-specific virtual reality (ICU-VR) video improves mental health outcomes and whether timing (early vs. late) matters. We conducted an international, three-arm, multicentre randomized clinical trial across eleven hospitals. Adults (≥ 18 years) with ICU stay ≥ 72 h and mechanical ventilation ≥ 24 h were randomized 1:1:1 to (1) standard care, (2) early ICU-VR (within 7–15 days post-ICU), or (3) late ICU-VR (≈ 3 months, during aftercare). The primary endpoint was PTSD symptom severity at six months (T3) measured by the Impact of Event Scale-Revised (range 0–88). Secondary endpoints included anxiety/depression severity and prevalence, and HRQoL. We randomized 344 participants (median age 61 years; 62
Background and Aims Low-density lipoprotein cholesterol (LDL-C)-lowering therapies are proven effective in atherosclerotic cardiovascular disease (ASCVD), but real-world evidence for proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) monoclonal antibodies (mAb) remains limited. This study evaluated their impact in patients with ASCVD without prior ischaemic events. Methods Patients initiating PCSK9i mAb from January 2016 to December 2022 were identified in the Optum Research Database. A 1:2 propensity score-matched comparator cohort of PCSK9i non-initiators was developed. The primary endpoint was a composite of non-fatal myocardial infarction, non-fatal ischaemic stroke, or all-cause mortality. Key outcomes from the parametric G-formula were 5-year event rates, relative risk reduction (RRR) and absolute risk reduction (ARR), with intention-to-treat (ITT) analysis. Additional outcomes for PCSK9i mAb initiators included absolute and percent LDL-C reduction from baseline. Results Overall, 19 670 patients met selection criteria (6545 PCSK9i mAb initiators; 13 125 non-initiators). Baseline characteristics were well-balanced. Under ITT, estimated 5-year event rates were 17.5% [95% confidence interval (CI) 15.5%, 19.5%] with PCSK9i mAb vs 25.4% (95% CI 23.6%, 27.1%) without PCSK9i, yielding a RRR of 30.9% and ARR of 7.8%. Individual endpoints showed RRRs of 28.3% for myocardial infarction (P < .0001), 26.4% for ischaemic stroke (P = .02), and 28.5% for all-cause mortality (P < .0001). Among initiators, mean baseline and follow-up LDL-C were 117.8 and 54.7 mg/dL (on-treatment analysis), respectively, representing an absolute reduction of 63.1 mg/dL and percent reduction of 53.6%. Conclusions In ASCVD patients without prior events in clinical practice, PCSK9i mAb treatment was associated with lower ischaemic event and mortality rates.
