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Organochlorine pesticide exposure and risk of prostate cancer development and progression: a systematic review
Background: There is an increasing body of evidence linking the exposure of an individual to pesticides such as organochlorine pesticides (OPCs) and an increased risk of developing diseases such as cancer. Exposure to OPCs has been suggested to increase the risk of developing hormone-dependant cancers such as prostate cancer (PCa). However, there is a relative paucity of information about the influence of exposure to these pesticides on the evolution of PCa, including risk of tumour development, progression to metastasis, and disease recurrence following therapy. Methods: We used several databases such as PubMed MEDLINE Database, Web of Science, and Scopus, in order to conduct a systematic review of the available epidemiological data implicating an association between exposure to OCPs and biochemical recurrence (BCR) of PCa. We searched all peer-reviewed articles published up to July 31 st 2020. Pre-defined eligibility criteria for the inclusion of studies were that they be original studies, reviews, previous meta-analyses, or case–control or cohort studies. Results: Agent Orange is the most widely-studied OCP in the context of any possible causal role in the recurrence of PCa following radical prostatectomy, or in the progression to advanced disease. Only two studies didn’t demonstrate a significant association between exposure to OCPs and subsequent BCR following radical prostatectomy. Another study identified a significant association between exposure to Oxychlordane and PCB44 and progression to advanced PCa. Conclusion: This review confirmed a relative lack of high-quality evidence regarding this topic. However, the available evidence to date suggests the presence of a potential causal relationship between exposure to OPCs and PCa development and progression.
Multiple novel prostate cancer predisposition loci confirmed by an international study: the PRACTICAL Consortium.
A recent genome-wide association study found that genetic variants on chromosomes 3, 6, 7, 10, 11, 19 and X were associated with prostate cancer risk. We evaluated the most significant single-nucleotide polymorphisms (SNP) in these loci using a worldwide consortium of 13 groups (PRACTICAL). Blood DNA from 7,370 prostate cancer cases and 5,742 male controls was analyzed by genotyping assays. Odds ratios (OR) associated with each genotype were estimated using unconditional logistic regression. Six of the seven SNPs showed clear evidence of association with prostate cancer (P = 0.0007-P = 10(-17)). For each of these six SNPs, the estimated per-allele OR was similar to those previously reported and ranged from 1.12 to 1.29. One SNP on 3p12 (rs2660753) showed a weaker association than previously reported [per-allele OR, 1.08 (95% confidence interval, 1.00-1.16; P = 0.06) versus 1.18 (95% confidence interval, 1.06-1.31)]. The combined risks associated with each pair of SNPs were consistent with a multiplicative risk model. Under this model, and in combination with previously reported SNPs on 8q and 17q, these loci explain 16% of the familial risk of the disease, and men in the top 10% of the risk distribution have a 2.1-fold increased risk relative to general population rates. This study provides strong confirmation of these susceptibility loci in multiple populations and shows that they make an important contribution to prostate cancer risk prediction.
Systemic Lupus Erythematosus With Cardiac Tamponade and Myocardial Edema in the Early Postpartum Period.
BACKGROUND: Pericardial effusions are frequently caused by inflammatory diseases. In cases of serosal inflammation, which often present with concomitant systemic symptoms, cardiac tamponade can occur, requiring emergency drainage. Nevertheless, it is rare for the index presentation of a previously undiagnosed inflammatory disease to be with cardiac tamponade. CASE SUMMARY: We describe a case of a young woman who presented in the postpartum period with cardiac tamponade. Further investigations confirmed that the underlying diagnosis was systemic lupus erythematosus (SLE). DISCUSSION: SLE can be associated with pericardial effusion but rarely causes cardiac tamponade. Herein, we describe a case of an index presentation of SLE in the postpartum period with a large pericardial effusion and tamponade. Cardiac imaging showed myocardial edema, reflective of associated myocarditis. TAKE-HOME MESSAGES: SLE can present in the immediate postpartum period, and acute management of tamponade in this context includes drainage of the effusion and immunosuppressive therapy.
A PSA SNP associates with cellular function and clinical outcome in men with prostate cancer.
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 T > C; 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.
Change in Early Patient-Reported Sexual Function After Periacetabular Osteotomy: A Study Utilizing the UK Non-Arthroplasty Hip Registry.
BACKGROUND: 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.
Trends in prescription opioid use in Europe: A DARWIN EU® multinational cohort study including seven European countries
BackgroundThe 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’Informació per al Desenvolupament de la Investigació en Atenció Primària (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 ≥365 days 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 −50·7% (CPRD GOLD) and −2·0% (SIDIAP), while it increased in EBB (+52·8%) and CHUBX (+25·3%) 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.
Rehabilitation of persistent poor hand function after trauma: A systematic review of randomised controlled trials
Introduction Hand 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. Methods A 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. Results 19 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. Discussion No 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.
Reporting guideline for chatbot health advice studies: The CHART statement.
The 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.
Reporting guidelines for chatbot health advice studies: explanation and elaboration for the Chatbot Assessment Reporting Tool (CHART)
The 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.
Deep molecular profiling of synovial biopsies in the STRAP trial identifies signatures predictive of treatment response to biologic therapies in rheumatoid arthritis.
Approximately 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 = 208), 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 = 67-72) 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 = 65-68). 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.
Contrasting modes of cultural evolution: Kra-Dai languages and weaving technologies
We 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.
Perivascular RELMα-positive synovial macrophages recruit monocytes at the onset of inflammatory arthritis.
Macrophages, monocytes and neutrophils are major types of myeloid cells involved in inflammatory diseases, such as rheumatoid arthritis (RA). Recent scRNA-seq studies identified a remarkable diversity of synovial macrophages but, with the exception of lining macrophages, their geographical location and specific roles remain largely unexplored. Here, we localized the RELMα-positive macrophages, predicted to produce high levels of monocyte-recruiting chemokines, to the synovial interstitium and more specifically, to the vicinity of interstitial blood vessels. Using complementary reporter mouse models, CCL2mCherry to label CCL2-producing cells, and CCR2CRE/mKate2 marking CCR2 expressing monocytes, we demonstrated that RELMα-positive perivascular macrophages secrete CCL2 assisting in the recruitment of monocytes predominantly to the synovial interstitium at the onset of antigen-induced arthritis. The inflamed synovial environment guides the differentiation of the recruited monocytes into tissue-resident macrophages, including but not limited to macrophages expressing VSIG4, a characteristic marker of lining macrophages. Thus, RELMα-positive macrophages orchestrate monocyte recruitment to the synovium during articular inflammation, contributing to a local replenishment of synovial lining macrophages.