Genetic variation at the 19q13.3 KLK locus is linked with prostate cancer susceptibility in men. The non-synonymous KLK3 single nucleotide polymorphism (SNP), rs17632542 (c.536\u2009T\u2009>\u2009C; Ile163Thr-substitution in PSA) is associated with reduced prostate cancer risk, however, the functional relevance is unknown. Here, we identify that the SNP variant-induced change in PSA biochemical activity mediates prostate cancer pathogenesis. The 'Thr' PSA variant leads to small subcutaneous tumours, supporting reduced prostate cancer risk. However, 'Thr' PSA also displays higher metastatic potential with pronounced osteolytic activity in an experimental metastasis in-vivo model. Biochemical characterisation of this PSA variant demonstrates markedly reduced proteolytic activity that correlates with differences in in-vivo tumour burden. The SNP is associated with increased risk for aggressive disease and prostate cancer-specific mortality in three independent cohorts, highlighting its critical function in mediating metastasis. Carriers of this SNP allele have reduced serum total PSA and a higher free/total PSA ratio that could contribute to late biopsy decisions and delay in diagnosis. Our results provide a molecular explanation for the prominent 19q13.3 KLK locus, rs17632542 SNP, association with a spectrum of prostate cancer clinical outcomes.
\n \n\n \n \nEpithelial cancers are typically heterogeneous with primary prostate cancer being a typical example of histological and genomic variation. Prior studies of primary prostate cancer tumour genetics revealed extensive inter and intra-patient genomic tumour heterogeneity. Recent advances in machine learning have enabled the inference of ground-truth genomic single-nucleotide and copy number variant status from transcript data. While these inferred SNV and CNV states can be used to resolve clonal phylogenies, however, it is still unknown how faithfully transcript-based tumour phylogenies reconstruct ground truth DNA-based tumour phylogenies. We sought to study the accuracy of inferred-transcript to recapitulate DNA-based tumour phylogenies. We first performed in-silico comparisons of inferred and directly resolved SNV and CNV status, from single cancer cells, from three different cell lines. We found that inferred SNV phylogenies accurately recapitulate DNA phylogenies (entanglement = 0.097). We observed similar results in iCNV and CNV based phylogenies (entanglement = 0.11). Analysis of published prostate cancer DNA phylogenies and inferred CNV, SNV and transcript based phylogenies demonstrated phylogenetic concordance. Finally, a comparison of pseudo-bulked spatial transcriptomic data to adjacent sections with WGS data also demonstrated recapitulation of ground truth (entanglement = 0.35). These results suggest that transcript-based inferred phylogenies recapitulate conventional genomic phylogenies. Further work will need to be done to increase accuracy, genomic, and spatial resolution.
\n \n\n \n \nBACKGROUND: Prostate cancer diagnosis requires biopsy, traditionally performed under local anaesthetic with ultrasound guidance via a transrectal approach (TRUS). Local anaesthetic ultrasound-guided transperineal biopsy (LATP) is gaining popularity in this setting; however, there is uncertainty regarding prostate sampling, infection rates, tolerability, side-effects, and cost-effectiveness. TRANSLATE was a randomised clinical trial that aimed to compare detection of Gleason Grade Group (GGG) 2 or higher prostate cancer, side-effects, tolerability, and patient-reported outcomes, after LATP versus TRUS biopsy. METHODS: In this randomised clinical trial which was done at ten hospitals in the UK, patients aged 18 years or older were eligible if investigated for suspected prostate cancer based on elevated age-specific prostate-specific antigen or abnormal digital rectal examination, and if biopsy-naive having received pre-biopsy MRI on a 1\u00b75 or higher Tesla scanner. Individuals were excluded if they had any previous prostate biopsy, extensive local disease easily detectable by any biopsy (prostate-specific antigen >50 ng/mL or entire gland replaced by tumour on MRI), symptoms of concurrent or recent urinary tract infection, history of immunocompromise, need for enhanced antibiotic prophylaxis, absent rectum, or inability to position in lithotomy. Participants were randomly assigned in a 1:1 ratio to receive LATP or TRUS biopsy, using web-based software with a randomisation sequence using a minimisation algorithm to ensure balanced allocation across biopsy groups for minimisation factors (recruitment site, and location of the MRI lesion). The primary outcome was detection of GGG 2 or higher prostate cancer, analysed in the modified intention-to-treat population (all randomly assigned to treatment who had a biopsy result available). Key secondary endpoints assessing post-biopsy adverse events were infection, bleeding, urinary and sexual function, tolerability, and patient-reported outcomes. This trial is registered with ClinicalTrials.gov (NCT05179694) and at ISRCTN (ISRCTN98159689), and is complete. FINDINGS: Between Dec 3, 2021, and Sept 26, 2023, 2078 (76%) of 2727 assessed individuals were eligible, and 1126 (41%) of 2727 agreed to participate. 1044 (93%) of the 1126 participants were White British. Participants were allocated to TRUS (n=564) or LATP (n=562) biopsy, and were followed up at time of biopsy, and at 7 days, 35 days, and 4 months post-biopsy. We found GGG 2 or higher prostate cancer in 329 (60%) of 547 participants with biopsy results randomly assigned to LATP compared with 294 (54%) of 540 participants with biopsy results randomly assigned to TRUS biopsy (odds ratio [OR] 1\u00b732 [95% CI 1\u00b703-1\u00b770]; p=0\u00b7031). Infection requiring admission to hospital within 35 days post-biopsy occurred in 2 (<1%) of 562 participants in the LATP group compared with 9 (2%) of 564 in the TRUS group. No statistically significant difference was observed in the reporting of overall biopsy-related complications (LATP 454 [81%] of 562 vs TRUS 436 [77%] of 564, OR 1\u00b723 [95% CI 0\u00b793 to 1\u00b765]), urinary retention requiring catheterisation (LATP 35 [6%] of 562 vs TRUS 27 [5%] of 564), urinary symptoms (median International Prostate Symptom Score: LATP 8 [IQR 4-14] vs TRUS 8 [4-13], OR 0\u00b736 [95% CI -0\u00b738 to 1\u00b710]), nor sexual function (median International Index of Erectile Function score: LATP 5 [2-25] vs TRUS 8 [3-24], OR -0\u00b760 [-1\u00b779 to 0\u00b758]) at 4 months after biopsy. Trial participants more commonly reported LATP biopsy to be immediately painful and embarrassing compared with TRUS (LATP 216 [38%] of 562 vs TRUS 153 [27%] of 564; OR 1\u00b784 [95% CI 1\u00b740 to 2\u00b743]). Serious adverse events occurred in 14 (2%) of 562 participants in the LATP group and 25 (4%) of 564 in the TRUS group. INTERPRETATION: Among biopsy-naive individuals being investigated for possible prostate cancer, biopsy with LATP led to greater detection of GGG 2 or higher disease compared with TRUS. These findings will help to inform patients, clinicians, clinical guidelines, and policy makers regarding the important trade-offs between LATP and TRUS prostate biopsy. FUNDING: National Institute for Health and Care Research (NIHR) Health Technology Assessment.
\n \n\n \n \nBACKGROUND: Periacetabular osteotomy (PAO) is an established treatment for symptomatic developmental dysplasia of the hip (DDH) and femoroacetabular impingement (FAI; principally acetabular retroversion) in adults who are commonly of reproductive age. PURPOSE: To describe the effect of PAO on patient-reported sexual function (SF) using data from the UK Non-Arthroplasty Hip Registry (NAHR). STUDY DESIGN: Cohort study: Level of evidence, 3. METHODS: Adult patients who underwent isolated PAO between January 2012 and July 2022 were extracted from the NAHR. The EuroQol-5 Dimensions (EQ-5D) and International Hip Outcome Tool 12 (iHOT-12) questionnaires were collected preoperatively and at 6 and 12 months postoperatively. This included responses to 2 questions from the iHOT-12 questionnaire relevant to SF: (1) \"Are questions about SF relevant to you?\" and (2) \"How much trouble do you have with sexual activity because of your hip?\" (0 = severe; 100 = none). RESULTS: A total of 773 patients (median age, 29 years (IQR, 23-37), 92.5% female) who underwent PAO for DDH (n = 703; 90.9%) or FAI (n = 70; 9.1%) were identified after exclusions. Of iHOT-12 respondents, 88.2% indicated that SF was relevant to them. Baseline median iHOT-12 SF scores were 33 (IQR, 18-53) for female and 73 (IQR, 36-90) for male patients. Female iHOT-12 SF improved by a mean of +19.9 points (95% CI, 16.5-23.2) at 6 months (P < .0001), with continued improvement to +26.4 points (95% CI, 23.0-29.8) at 12 months (P < .0001) versus preoperative SF scores. At 12 months, median iHOT-12 SF scores were 70 (IQR, 40-90) and 89 (IQR, 70-99) for female and male patients, respectively. Preoperative SF scores were significantly lower (P = .001) in patients who underwent PAO for indication of FAI (female median score 22; IQR, 10-38) compared with DDH (female median score: 34; IQR, 18-54); however, both indications saw significant improvement in SF scores at 12 months. iHOT-12 SF scores improved for 77.1% and worsened for 19.1% of female respondents with DDH. A strong positive association was seen between health-related quality of life (EQ-5D) and SF scores, and there was significant improvement in SF across studied ages. CONCLUSION: PAO was associated with significant improvement in patient-reported SF for the majority of patients. Some patients may have trouble with sexual activity even 1 year after PAO for DDH, with almost 20% reporting poorer SF compared with preoperative baseline.
\n \n\n \n \nBackgroundThe opioid crisis has been a serious public health challenge in North America for decades, despite numerous efforts to mitigate its devastating consequences. As concerns grow about a similar situation developing in Europe, we evaluated the trends in opioid use and characterized prescribing indications across seven European countries.MethodsWe conducted a multinational cohort study using electronic health records from various healthcare settings: primary care [Clinical Practice Research Datalink (CPRD) GOLD (United Kingdom), Sistema d\u2019Informaci\u00f3 per al Desenvolupament de la Investigaci\u00f3 en Atenci\u00f3 Prim\u00e0ria (SIDIAP, Spain), and Integrated Primary Care Information Project (IPCI, the Netherlands)]; primary and outpatient specialist care [IQVIA Disease Analyzer (DA) Germany and IQVIA Longitudinal Patient Database (LPD) Belgium]; hospital care [Clinical Data Warehouse of Bordeaux University Hospital (CHUBX, France)]; and the Estonian Biobank (EBB). All data were mapped to the Observational Medical Outcomes Partnership (OMOP) Common Data Model (CDM). All people registered in a contributing database for \u2265365\u00a0days between 2012 and 2022 were included. Annual period prevalence and incidence rates of opioid prescriptions were estimated, and long-term trends were quantified as the percent change from 2012 to 2019. New opioid users were characterized, including potential prescribing indications.ResultsBetween 2012 and 2019, the incidence of opioid prescriptions in primary care decreased by \u221250\u00b77% (CPRD GOLD) and \u22122\u00b70% (SIDIAP), while it increased in EBB (+52\u00b78%) and CHUBX (+25\u00b73%) data. The incidence of codeine and tramadol use decreased in most databases. However, the prevalence of oxycodone, morphine, and fentanyl increased. Opioid use was highest among older age groups, and the majority of prescriptions were for oral formulations. Respiratory and pain-related conditions were the most common indications for new opioid users in outpatient settings.ConclusionDespite a decrease in new opioid prescriptions in many European countries, the prevalence of opioid use remained largely stable over the last decade. More data are needed to monitor evolving opioid prescription patterns in Europe, particularly in the post-pandemic era.
\n \n\n \n \nOBJECTIVE: To determine the importance of comorbidity measures when predicting mortality and revision surgery after elective primary shoulder replacement surgery. DESIGN: Population based cohort study. SETTING: Linked data from the National Joint Registry and NHS Hospital Episode Statistics were used to identify all elective primary shoulder replacements in England, 6 January 2012 to 30 March 2022. PARTICIPANTS: 37\u2009176 consenting patients, aged 18-100 years, who had elective primary shoulder replacement surgery. MAIN OUTCOME MEASURES: Risk of mortality at 90 and 365 days, and risk of long term revision surgery after the primary surgery. RESULTS: 37\u2009176 primary shoulder replacement procedures were included; 102 patients died within 90 days and 445 within 365 days of the primary surgery. 1219 patients had revision surgery over a maximum follow-up period of >10 years. The addition of comorbidity measures derived from Hospital Episode Statistics (Charlson comorbidity index with summary hospital mortality index weights, Elixhauser comorbidity index, and hospital frailty risk score) to simpler models resulted in little improvement in predictive performance. Optimism adjusted performance (C index) of the models that included age, sex, American Society of Anesthesiologists (ASA) grade, and main surgical indication was 0.76 (95% confidence interval (CI) 0.72 to 0.81) for 90 day mortality, 0.74 (0.71 to 0.76) for 365 day mortality, and 0.64 (0.63 to 0.66) for revision surgery. The best performing models that included a comorbidity measure had an optimism adjusted C index of 0.77 (95% CI 0.73 to 0.81) for 90 day mortality, 0.76 (0.74 to 0.78) for 365 day mortality, and 0.65 (0.63 to 0.66) for revision surgery. Heterogeneity in model performance across regions of England was low, and decision curve analysis showed minimal improvement in net benefit when including comorbidity measures. CONCLUSIONS: In this study, patient comorbidity scores added little improvement to simpler models that included age, sex, ASA grade, and main surgical indication for predicting mortality and revision surgery after elective primary shoulder replacement surgery. This improvement needs to be balanced against the additional challenges of routine data linkage to obtain these scores.
\n \n\n \n \n\nIntroduction\nHand trauma is common, and can be functionally limiting and psychologically distressing. Hand dysfunction that is persistent after trauma can be troublesome to manage. Patient-reported outcome measures (PROMs) are useful in assessing hand function, and an improvement has been associated with an increase in health-related quality of life. Hand therapy is important for managing patients with residual poor hand function after trauma, but minimal evidence exists to support commonly used treatments. This review aimed to evaluate the evidence for interventions, outcome measures, and the implications for future research in hand therapy.\n\n\nMethods\nA systematic review with narrative synthesis was conducted. Randomised controlled trials of residual hand dysfunction after trauma were included. The primary outcome measures were PROMs validated in hand trauma. Secondary outcomes included symptoms of hand dysfunction or validated tests that evaluate hand function.\n\n\nResults\n19 studies were included. Occupation-based interventions showed moderate strength of effect in improving hand function in terms of PROMs. Mirror therapy, robot-aided rehabilitation, orthotic management of the stiff hand, and oedema-reducing therapies were also evaluated. The findings were limited by a high risk of bias and lack of robust methodology in the included studies. PROMs were inconsistently utilised, along with a variety of other outcome measures.\n\n\nDiscussion\nNo firm recommendations for practice can be made based on the evidence included in this review. Well designed, multicentre trials are needed to generate more robust evidence. Standardisation of outcome measures and reporting, and the use of PROMs aligned with patient priorities will be crucial for advancing research in hand therapy.\n
\n \n\n \n \nThe Chatbot Assessment Reporting Tool (CHART) is a reporting guideline developed to provide reporting recommendations for studies evaluating the performance of generative artificial intelligence (AI)-driven chatbots when summarizing clinical evidence and providing health advice, referred to as Chatbot Health Advice (CHA) studies. CHART was developed in several phases after performing a comprehensive systematic review to identify variation in the conduct, reporting and methodology in CHA studies. Findings from the review were used to develop a draft checklist that was revised through an international, multidisciplinary modified asynchronous Delphi consensus process of 531 stakeholders, three synchronous panel consensus meetings of 48 stakeholders, and subsequent pilot testing of the checklist. CHART includes 12 items and 39 subitems to promote transparent and comprehensive reporting of CHA studies. These include Title (subitem 1a), Abstract/Summary (subitem 1b), Background (subitems 2ab), Model Identifiers (subitem 3ab), Model Details (subitems 4abc), Prompt Engineering (subitems 5ab), Query Strategy (subitems 6abcd), Performance Evaluation (subitems 7ab), Sample Size (subitem 8), Data Analysis (subitem 9a), Results (subitems 10abc), Discussion (subitems 11abc), Disclosures (subitem 12a), Funding (subitem 12b), Ethics (subitem 12c), Protocol (subitem 12d), and Data Availability (subitem 12e). The CHART checklist and corresponding methodological diagram were designed to support key stakeholders including clinicians, researchers, editors, peer reviewers, and readers in reporting, understanding, and interpreting the findings of CHA studies.
\n \n\n \n \nThe Chatbot Assessment Reporting Tool (CHART) reporting guideline promotes transparent and comprehensive reporting of studies evaluating the performance of generative artificial intelligence (AI)driven chatbots for the purposes of summarising clinical evidence and providing health advice, referred to here as chatbot health advice (CHA) studies. CHART is the product of an international, multi-phase, consensus based initiative involving various stakeholders and comprises a 12-item checklist with 39 subitems. The checklist includes items on open science, title and abstract, introduction, model identification, model details, prompt engineering, query strategy, performance definition and evaluation, statistical analysis, results, discussion, with an accompanying flow diagram. Each item includes distinct subitems. This explanation and elaboration article discusses each subitem and provides a detailed rationale for its inclusion in the CHART checklist.
\n \n\n \n \nPain is the primary complaint in individuals with osteoarthritis (OA) and changes as the disease progresses. Anatomical changes in several joint structures potentially contribute to pain, including the increased innervation of the periosteum, synovium and subchondral bone, and the pathological innervation of articular cartilage, which is aneural under physiological conditions. Research has focused on molecules that sensitize afferent neurons, such as neuropeptides, neurotrophins, pro-inflammatory cytokines and ion channels. The neurotrophin nerve growth factor (NGF) is the best validated target in OA pain, with proven analgesic effects in preclinical and clinical studies, although the development of NGF-targeted therapeutics has been hampered by serious side effects. One relatively neglected area of research is the contribution to OA pain of the molecular pathways that mediate remodelling of nerves in disease. Remodelling requires coordination between the nerve and the associated vasculature, along with signals that are received from the surrounding parenchyma. Key cell guidance molecules, including angiogenic factors, ephrins, semaphorins and\u00a0SLIT proteins are involved in nerve growth during development, and their expression is increased in osteoarthritic joints.
\n \n\n \n \nAIMS: Knee joint distraction (KJD) has been proposed as a joint-preserving alternative to arthroplasty. The objective of this study was to evaluate the clinical and cost-effectiveness of KJD compared to arthroplasty for knee osteoarthritis. METHODS: This phase III multicentre, pragmatic, randomized controlled non-inferiority trial recruited adults aged \u2264 65 years with symptomatic osteoarthritis refractory to non-surgical treatment and suitable for knee arthroplasty. Patients were randomized to static, linear, KJD of 5 mm, produced with an external fixator construct for six-week duration, or total knee arthroplasty. The primary outcome measure was the Knee injury and Osteoarthritis Outcomes Score (KOOS) pain subscale 12 months post-surgery. The trial was terminated early due to failure to recruit following cessation of elective orthopaedic surgery during the COVID-19 pandemic. RESULTS: A total of 24 participants were randomized with baseline characteristics balanced between groups. Improved median KOOS pain scores at 12 months postoperatively were observed in both treatment groups. The median KOOS pain score in the KJD group improved from 38.9 (IQR 30.6 to 41.7) at baseline to 55.6 (IQR 41.7 to 94.4) at 12 months, while corresponding scores in the arthroplasty group improved from 30.6 (IQR 11.1 to 36.1) to 75.0 (IQR 66.7 to 88.9). Similar improvements following KJD were seen across other KOOS subdomains and pain VAS, range of motion, or timed up-and-go test. The small sample size does not provide sufficient information to make meaningful comparisons between treatment groups. Pin site infection was seen in two patients, and a fracture through a pin site after frame removal following trauma in one patient. CONCLUSION: KJD appears to be associated with improved pain and function compared to baseline. The clinical and cost-effectiveness of KJD compared to arthroplasty remains uncertain.
\n \n\n \n \nApproximately 40% of patients with rheumatoid arthritis do not respond to individual biologic therapies, while biomarkers predictive of treatment response are lacking. Here we analyse RNA-sequencing (RNA-Seq) of pre-treatment synovial tissue from the biopsy-based, precision-medicine STRAP trial (n\u2009=\u2009208), to identify gene response signatures to the randomised therapies: etanercept (TNF-inhibitor), tocilizumab (interleukin-6 receptor inhibitor) and rituximab (anti-CD20 B-cell depleting antibody). Machine learning models applied to RNA-Seq predict clinical response to etanercept, tocilizumab and rituximab at the 16-week primary endpoint with area under receiver operating characteristic curve (AUC) values of 0.763, 0.748 and 0.754 respectively (n\u2009=\u200967-72) as determined by repeated nested cross-validation. Prediction models for tocilizumab and rituximab are validated in an independent cohort (R4RA): AUC 0.713 and 0.786 respectively (n\u2009=\u200965-68). Predictive signatures are converted for use with a custom synovium-specific 524-gene nCounter panel and retested on synovial biopsy RNA from STRAP patients, demonstrating accurate prediction of treatment response (AUC 0.82-0.87). The converted models are combined into a unified clinical decision algorithm that has the potential to transform future clinical practice by assisting the selection of biologic therapies.
\n \n\n \n \nWe investigate and compare the evolution of two aspects of culture, languages and weaving technologies, amongst the Kra-Dai (Tai-Kadai) peoples of southwest China and southeast Asia, using Bayesian Markov-Chain Monte Carlo methods to uncover phylogenies. The results show that languages and looms evolved in related but different ways, and bring some new insights into the diaspora of the Kra-Dai speakers across southeast Asia. We found that the languages and looms used by Hlai speakers of Hainan are outgroups in both linguistic and loom phylogenies, and that the looms used by speakers of closely related languages tend to belong to similar types. However, we also found discrepancies at a deep level between linguistic subgroups and loom types, in particular among widely dispersed South-Western Tai speakers, and we discuss possible reasons for this.
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