Mismatch repair-deficient (dMMR) prostate cancer is rare and has not been well studied. We aimed to evaluate the clinical characterization of dMMR metastatic castrationresistant prostate cancer (mCRPC) patients. The MMR genes include MLH1, MLH3, MSH2, MSH6, PMS1, PMS2, and EPCAM, and were analyzed by targeted sequencing of plasma cell-free DNA samples. A total of 109 mCRPC patients were identified, including 50 patients with MMR alterations (pathogenic alterations, n = 7; alterations of unknown significance, n = 43) and 59 patients with wild-type MMR. For the seven patients with pathogenic MMR alterations, the median age at diagnosis was 63.5 years, and 42.9% had a Gleason score ≥8. The median time from androgen deprivation therapy (ADT) initiation to CRPC was 24 months. Compared with the wild-type MMR subgroup, patients with MMR alterations, pathogenic MMR alterations, or MMR alterations of unknown significance showed higher rates of hotspot missense mutations or copy number amplifications in the AR gene (24/50 vs. 10/59, P = 7.8 × 10 −4 ; 7/7 vs. 10/59, P = 2.5 × 10 −5 ; 17/43 vs. 10/59, P = 0.013). The presence of any MMR alterations was associated with an inferior response to abiraterone [median progression-free survival (PFS): 5.0 vs. 10.9 months, P = 0.022]. Shorter PFS times were observed in both the pathogenic MMR alteration subgroup (median PFS: 5 months) and the MMR alterations of unknown significance subgroup (median PFS: 5.3 months), compared with the PFS of those with wild-type MMR genes (median PFS: 10.9 months, P = 0.052). There was no statistically significant difference in response to docetaxel chemotherapy between the MMR alterations of unknown significance and the wild-type MMR subgroups (median PFS: 8.2 vs. 8.1 months, P = 0.23). Our results demonstrate that dMMR mCRPC patients have an equivalent response to standard ADT and taxanebased chemotherapy treatments compared with wild-type MMR patients. Patients with both pathogenic and unknown significance alterations of MMR genes had poorer responses to abiraterone therapy.

ObjectThough significant correlations between rheumatoid arthritis (RA) and hypothyroidism have been found in earlier observational studies, their underlying causal relationship is still unknown. Mendelian randomization (MR) was used in the current study to assess the bidirectional causation between RA and hypothyroidism.MethodWe gathered summary data from genome-wide association studies (GWASs) of RA and hypothyroidism in people of European descent. Then, using data from the FinnGen consortium, we replicated our findings. Three approaches were employed to assess the causal link between RA and hypothyroidism: MR-Egger, weighted median (WM), and inverse variance weighted (IVW). The pleiotropy and heterogeneity were examined using a variety of techniques, including the MR-Egger intercept, the MR-PRESSO approach, the leave-one-out method, and the Cochran’s Q test.ResultsThe study looked at a bidirectional incidental relationship between RA and hypothyroidism. The risk of hypothyroidism increased with RA (IVW odds ratio (OR) = 1.28, 95% confidence interval (CI) = 1.18–1.39, P = 8.30E-10), as did the risk of secondary hypothyroidism (IVW OR = 1.12, 95% CI = 1.05–1.21, P = 9.64E-4). The results of reverse MR analysis revealed that hypothyroidism (IVW OR = 1.68, 95% CI = 1.51–1.88, P = 4.87E-21) and secondary hypothyroidism (IVW OR = 1.74, 95% CI = 1.50–2.01, P = 1.91E-13) were linked to an increased risk of RA. Additionally, we obtain the same results in the duplicated datasets as well, which makes our results even more reliable. This study revealed no evidence of horizontal pleiotropy.ConclusionThe present study established a bidirectional causal link between RA and hypothyroidism. However, it differs slightly from the findings of prior observational studies, suggesting that future research should concentrate on the interaction mechanisms between RA and hypothyroidism.

Background: Protracted withdrawal symptoms(PWS) play a crucial role in relapse. While medication maintenance or behavioral therapies such as cognitive behavioral therapy (CBT) can alleviate these symptoms, their implementation is still limited. Evidence suggests that Chinese tuina / massage therapy can improve mood and sleep quality in individuals experiencing PWS. However, high-quality, evidence-based studies supporting this claim are still lacking. Methods and analysis A prospective, parallel, three-armed, single-center, assessor-blinded, randomized controlled trial will be conducted with 69 patients at the Sichuan Ziyang Drug Rehabilitation Center (SZDRC). Patients undergoing PWS will be randomly assigned in a 1:1:1 ratio to three groups: CBT+tuina (Group A), CBT only (Group B), and waitlist (Group C). Group A will receive 2 sessions of CBT and 12 sessions of head and face massage for 4 weeks, while Group B will receive only 2 sessions of CBT over the same period. Group C will not receive any intervention during the treatment period and will receive the same compensatory treatment as Group A after the trial.The primary outcome will be measured using the Symptom Checklist 90 (SCL-90), and secondary outcomes will include the Self-Rating Anxiety Scale (SAS), Self-Rating Depression Scale (SDS), and Pittsburgh Sleep Quality Index (PSQI). Measurements will be obtained at baseline, 1 week after treatment completion, and at the end of follow-up. Data analysis will be conducted by independent statisticians using intention-to-treat analysis. Discussion: This study aims to investigate the efficacy and safety of CBT combined with head tuina/massage for protracted withdrawal symptoms. Questionnaires will be used to assess the degree of improvement in negative mood and sleep status. High-quality, evidence-based evidence will be obtained to reduce the pressure on the development of addiction treatment. Trial registration number: This study has been registered on Chinese Clinical Trials.gov with number ChiCTR2200058212 and has obtained ethics approvals from the Ethics Committee of the People's Hospital of Ziyang with number 2021-K-LS-2.