Hull York Medical School

BACKGROUND:A phase 2 trial of setmelanotide, a melanocortin-4 receptor agonist, showed substantial weight loss in patients with acquired hypothalamic obesity, but additional data are needed. METHODS:We conducted a phase 3 trial in which participants were randomly assigned in a 2:1 ratio to receive setmelanotide (at a dose of 1.5 to 3.0 mg) or placebo administered subcutaneously once daily for 52 weeks after a dose-escalation period. Persons at least 4 years of age were potentially eligible for the trial if they had acquired hypothalamic obesity, which was defined by a body-mass index (BMI; the weight in kilograms divided by the square of the height in meters) that was at or above the 95th percentile for age and sex (for participants <18 years of age) or at least 30 (for participants ≥18 years of age) and a history of a hypothalamic tumor, lesion, or injury. The primary end point was the mean percent change in BMI from baseline to 52 weeks after the end of the dose-escalation period. Secondary end points included the mean change in the weekly average of the maximal daily hunger score (range, 0 to 10, with higher scores indicating more severe hunger), assessed in participants at least 12 years of age. RESULTS:From April 26, 2023, to March 18, 2025, a total of 120 participants were assigned to receive setmelanotide (81 participants) or placebo (39 participants). The mean (±SD) age was 19.9±13.8 years (range, 4 to 66). Among participants 18 years of age or older, the mean BMI was 41.2±9.7; the mean BMI z score among those younger than 18 years of age was 3.61±1.66. The least-squares mean (LSM) change in BMI at 52 weeks was -16.5% (95% confidence interval [CI], -19.3 to -13.8) with setmelanotide and 3.3% (95% CI, -0.6 to 7.2) with placebo (P<0.001), and the LSM change in the weekly average of maximal daily hunger scores was -2.73 (95% CI, -3.28 to -2.18) in the setmelanotide group and -1.45 (95% CI, -2.23 to -0.67) in the placebo group (P = 0.009). Adverse events were reported in 100% of the participants in the setmelanotide group and in 90% of those in the placebo group, and serious adverse events were reported in 28% and 8%, respectively. The most common adverse events with setmelanotide were skin hyperpigmentation, nausea, vomiting, and headache. CONCLUSIONS:Setmelanotide led to significantly greater reductions in BMI and hunger than placebo at 52 weeks among participants 4 to 66 years of age with acquired hypothalamic obesity. (Funded by Rhythm Pharmaceuticals; TRANSCEND ClincialTrials.gov number, NCT05774756.).

Diabetes related foot ulcers (DFU) are associated with significant physical, psychological and social dysfunction. Measuring the impact of treatments on patients' overall well-being is vital to ensure care is holistic. This study aimed to validate the Wound-Qol-14 quality of life assessment tool in people with a DFU. A single centre longitudinal prospective validation study in people with DFUs was conducted. Wound-Qol-14, Diabetic Foot Ulcer Scale-Short Form (DFS-SF) and EuroQol 5 dimensions 5 levels (EQ-5D-5L) were completed by people with DFUs at baseline and 6 months. Wound-Qol-14 was repeated within 7 days of the first questionnaire. Correlation coefficients with a cut off of ≥ 0.7 were used to assess convergent validity, divergent validity and responsiveness to changes in DFU severity. Reliability was assessed using Cronbach's α. The study aimed to recruit 100 people. One hundred and seven people were recruited. The mean age was 62 (SD 13) years and 85 (79.4%) were male. The mean DFU duration was 30 (SD 83) days and the mean DFU area was 6.2 (SD 10.7) cm2. Convergent validity was demonstrated in all domains of Wound-Qol-14 and DFS-SF (r - 0.695 to -0.799) except burden/bothered about ulcer care domains (r = -0.443). There was moderate correlation between Wound-Qol-14 domains and EQ-5D-5L dimensions (r = 0.477-0.501). Cronbach's α ranged from 0.683 to 0.919 for the domains of Wound-Qol-14. Wound-Qol-14 was not responsive to changes in DFU severity (r = -0.291; 95% CI -0.501 to -0.048) but was responsive to healing status (healed 1.14 [IQR 0.86] vs. unhealed 1.86 [IQR 1.47]; p = 0.017). Wound-Qol-14 is a valid and reliable tool to measure disease-specific quality of life in people with DFUs. Further work is needed to refine the responsiveness. EQ-5D-5L should be used to measure generic quality of life in people with DFUs.

Covalent Bruton tyrosine kinase inhibitor (cBTKi)-based regimens have redefined therapy for chronic lymphocytic leukemia (CLL). However, continuous treatment with BTKis can select for therapy resistance, typically associated with BTK C481 mutations and fosfolipasi C gamma 2 (PLCγ2) activation. In addition, continuous BTKi therapy poses challenges for treatment interruptions and dose modifications, with implications for clinical outcomes. Pirtobrutinib, a highly selective, reversible (noncovalent) BTKi, inhibits BTK independently of C481 and maintains sustained target engagement. In patients with cBTKi-pretreated relapsed/refractory (R/R) CLL, the BRUIN-CLL-321 trial demonstrated improved progression-free survival (PFS) and time to next treatment (TTNT) compared with idelalisib/rituximab or bendamustine/rituximab, accompanied by a favorable tolerability profile. Data from randomized phase III BRUIN-CLL-313 and BRUIN-CLL-314 trials demonstrate the superiority of pirtobrutinib over chemoimmunotherapy in untreated patients and non-inferiority to ibrutinib in untreated patients or in patients with R/R disease who had no prior exposure to cBTKis. These data are not sufficient to justify a change in clinical practice; however, they lay the groundwork for a potential future repositioning of pirtobrutinib from the treatment of R/R CLL to earlier lines of therapy. In this review, we address a range of current and prospective aspects of pirtobrutinib-based therapies: (1) the strengths and limitations of the trial datasets; (2) the biological rationale for frontline noncovalent BTK inhibition; (3) sequencing trade-offs; and (4) prospective scenarios, including combination strategies and time-limited regimens.

Objectives Higher specialty trainees are expected to achieve clinical and non-clinical skills during training in preparation for a consultant role. However, evidence from many specialties from different countries suggests that new consultants are less prepared in non-clinical skills. The transition from trainee to a consultant phase can be challenging. The study aims to identify if new UK Palliative Medicine consultants, within 5 years of their appointment, feel prepared in clinical and non-clinical skills after completing specialty training and understand the support available for them.Method An online survey, designed using previous literature, was distributed via the Association for Palliative Medicine email and social media. Five-point Likert scales and drop-down options to record preparedness were used. Ethics approval was obtained.Results Forty-four participants from different UK regions completed the survey; 80% were female. The majority felt very/extremely prepared in audit (84%), clinical skills (71%), interaction with colleagues (70%). Majority moderate preparation was human resources (50%), organisation structure (68%) and leadership (52%). Most were not at all or slightly prepared in financial management (70%) and in complaint management (43%). The majority (75%) reported that departmental colleagues gave the most support in stressful situations but almost 49% did not have formal support.Conclusion New palliative medicine consultants require support with some non-clinical roles such as management of complaints and finances. This is consistent with findings from other specialties. New consultants would benefit from formal support. Future research could focus on how trainees could be supported to gain more experience in non-clinical domains.