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A symposium to discuss topics around talking about dying was recently held at St Catherine's College in Oxford.
Local anaesthetic transperineal biopsy versus transrectal prostate biopsy in prostate cancer detection (TRANSLATE): a multicentre, randomised, controlled trial.
BACKGROUND: 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 1·5 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] 1·32 [95% CI 1·03-1·70]; p=0·031). 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 1·23 [95% CI 0·93 to 1·65]), 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 0·36 [95% CI -0·38 to 1·10]), nor sexual function (median International Index of Erectile Function score: LATP 5 [2-25] vs TRUS 8 [3-24], OR -0·60 [-1·79 to 0·58]) 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 1·84 [95% CI 1·40 to 2·43]). 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.
Genetic variants predisposing to increased risk of kidney stone disease.
BACKGROUND: Kidney stone disease (KSD) affects ~10% of adults, is heritable, and associated with mineral metabolic abnormalities. METHODS: Genetic variants and pathways increasing KSD risk via calcium and phosphate homeostasis were ascertained using genome-wide association analyses, region-specific Mendelian randomization (MR), and genetic colocalization. Utility of pathway modulation was estimated via drug-target MR, and effects of variants on calcium-sensing receptor (CaSR)-signaling characterized. RESULTS: Seventy-nine independent KSD-associated genetic signals at 71 loci were identified. MR identified three loci affecting KSD risk via increased serum calcium or decreased serum phosphate concentrations (odds ratios for genomic regions=4.30, 11.42, and 13.83 per 1 standard deviation alteration; p<5.6x10-10). Colocalization analyses defined putative, non-coding KSD-causing variants estimated to account for 11-19% of KSD cases in proximity to diacylglycerol kinase delta (DGKD), a CaSR-signalling partner; solute carrier family 34 member 1 (SLC34A1), a renal sodium-phosphate transporter; and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), which degrades 1,25-dihydroxyvitamin D. Drug- target MR indicated that reducing serum calcium by 0.08mmol/L via CASR, DGKD, or CYP24A1, or increasing serum phosphate by 0.16mmol/L via SLC34A1 may reduce KSD relative risk by up to 90%. Furthermore, reduced DGKδ expression and KSD-associated DGKD missense variants impaired CaSR-signal transduction in vitro, which was ameliorated by cinacalcet, a positive CaSR-allosteric modulator. CONCLUSION: DGKD-, SLC34A1-, and CYP24A1-associated variants linked to reduced CaSR-signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation, respectively, are common causes of KSD. Genotyping patients with KSD may facilitate personalised KSD-risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.
A deployment safety case for AI-assisted prostate cancer diagnosis.
Deep learning (DL) has the potential to deliver significant clinical benefits. In recent years, an increasing number of DL-based systems have been approved by the relevant regulators, e.g. FDA. Although obtaining regulatory approvals is a prerequisite to deploy such systems for real world use, it may not be sufficient. Regulatory approvals give confidence in the development process for such systems, but new hazardous events can arise depending on how the systems have been deployed in the intended clinical pathways or how they have been used with other systems in complex healthcare settings. These kinds of events can be difficult to predict during the development process. Indeed, most health systems and hospitals require self-verification before deploying a diagnostic medical device, which could be viewed as an additional safety measure. This shows that it is important to carry on assuring the safety of such systems in deployment. In this work, we address this urgent need based on the experience of a prospective study in UK hospitals as part of the ARTICULATE PRO project. In particular, the system considered in this work is developed by Paige for prostate cancer diagnosis, which has obtained FDA approval in the US and UKCA marks in the UK. The methodology presented in this work starts by mapping out the clinical workflow within which the system has been deployed, then carries out hazard and risk analysis based on the clinical workflow, and finally presents a deployment safety case, which provides a basis for deployment and continual monitoring of the safety of this system in use. In this work we systematically address the emergence of new hazardous events from the deployment and to present a way to continually assure the safety of a regulatorily approved system in use.
A lot of mental illness starts in adolescence. Therefore should we shift some of the spending from adult to adolescent mental health services?
In May 2015 the UK elected a new government. In election campaigns, health is one of the most important areas of debate and over the preceding 12 months, the state of child and adolescent mental health services (CAMHS) had held a particularly high profile in the media and in political debate. Many had suggested that the rate of mental illness starting in adolescence is increasing and that service provision is not of sufficient quality or scale to meet this need. A brief review of the sources for these statistics reveals that whilst this may be true, there is a dearth of accurate and up to date data on the scale of the need for CAMHS or the extent to which it is being met. Nonetheless, members of all parties claimed to support improvements in mental health service provision for children and adolescents through increases in funding. A key question for policy makers has therefore become, from where any additional funding might be derived. One suggestion has been that funding be transferred from spending on adult mental health services. The exact practical nature of such a policy is yet to be explored in detail by government or stakeholders. The primary purpose of the present discussion is therefore to consider the possible ethical implications of such a policy in principle. The discussion forms part of a wider and evolving political and professional discourse on society's and government's attitude towards mental illness, towards the balance of individual and societal needs and towards the balance between preventative and supportive interventions to improve health.
Thalamic deep brain stimulation for central poststroke pain syndrome: an international multicenter study.
OBJECTIVE: The effectiveness and optimal stimulation site of deep brain stimulation (DBS) for central poststroke pain (CPSP) remain elusive. The objective of this retrospective international multicenter study was to assess clinical as well as neuroimaging-based predictors of long-term outcomes after DBS for CPSP. METHODS: The authors analyzed patient-based clinical and neuroimaging data of previously published and unpublished cohorts from 6 international DBS centers. DBS leads were reconstructed and normalized. A stimulation map was constructed on the basis of individual stimulation settings and associated outcomes. Furthermore, the authors projected the individual segmented stroke lesions and volumes of tissue activated (VTAs) of the stimulating electrode onto a normalized human connectome to obtain the connectivity profiles of the individual lesions and VTAs. RESULTS: The authors analyzed the data of 54 patients, of whom 15 were excluded from the final analysis due to a lack of imaging data. Among the remaining 39 patients from 6 different cohorts, the authors found 14 (35.9%) responders who were defined by pain relief of at least 50% at 12-month follow-up. Stimulation mapping identified areas in the posterior limb of the internal capsule, the sensorimotor thalamus, and the medial and intralaminar thalamus as effective for pain reduction. Baseline characteristics did not differ between responders and nonresponders. The stimulation sites of the responders showed significantly reduced structural connectivity to the sensory areas of the cerebral cortex compared to nonresponders. CONCLUSIONS: This comprehensive, multicenter analysis corroborates the efficacy of DBS in treating CPSP for a relevant number of patients. The posterior limb of the internal capsule and the sensorimotor thalamus emerged as potential stimulation sweet spots. The difference in structural connectivity between responders and nonresponders may constitute a biomarker of effective stimulation that can help guide surgical planning in future well-designed prospective trials.
Local anaesthetic transperineal (LATP) prostate biopsy using a probe-mounted transperineal access system: a multicentre prospective outcome analysis.
OBJECTIVES: To assess the feasibility of local anaesthetic transperineal (LATP) technique using a single-freehand transperineal (TP) access device, and report initial prostate cancer (PCa) detection, infection rates, and tolerability. PATIENTS AND METHODS: Observational study of a multicentre prospective cohort, including all consecutive cases. LATP was performed in three settings: (i) first biopsy in suspected PCa, (ii) confirmatory biopsies for active surveillance, and (iii) repeat biopsy in suspected PCa. All patients received pre-procedure antibiotics according to local hospital guidelines. Local anaesthesia was achieved by perineal skin infiltration and periprostatic nerve block without sedation. Ginsburg protocol principles were followed for systematic biopsies including cognitive magnetic resonance imaging-targeted biopsies when needed using the PrecisionPoint™ TP access device. Procedure-related complications and oncological outcomes were prospectively and consecutively collected. A validated questionnaire was used in a subset of centres to collect data on patient-reported outcome measures (PROMs). RESULTS: Some 1218 patients underwent LATP biopsies at 10 centres: 55%, 24%, and 21% for each of the three settings, respectively. Any grade PCa was diagnosed in 816 patients (67%), of which 634 (52% of total) had clinically significant disease. Two cases of sepsis were documented (0.16%) and urinary retention was observed in 19 patients (1.6%). PROMs were distributed to 419 patients, with a 56% response rate (n = 234). In these men, pain during the biopsy was described as either 'not at all' or 'a little' painful by 64% of patients. Haematuria was the most common reported symptom (77%). When exploring attitude to re-biopsy, 48% said it would be 'not a problem' and in contrast 8.1% would consider it a 'major problem'. Most of the patients (81%) described the biopsy as a 'minor or moderate procedure tolerable under local anaesthesia', while 5.6% perceived it as a 'major procedure that requires general anaesthesia'. CONCLUSION: Our data suggest that LATP biopsy using a TP access system mounted to the ultrasound probe achieves excellent PCa detection, with a very low sepsis rate, and is safe and well tolerated. We believe a randomised controlled trial comparing LATP with transrectal ultrasound-guided biopsy (TRUS) to investigate the relative trade-offs between each biopsy technique would be helpful.
The New Lithotripsy Index predicts success of shock wave lithotripsy.
AIM: The aim of this study is to evaluate the factors affecting treatment success in patients who underwent Shock wave lithotripsy (SWL) and to investigate the effect of the Storz Medical Lithotripsy Index (SMLI) on treatment effectiveness. METHODS: Prospective data were collected on patients undergoing SWL treatment for kidney stones between January 2013 and May 2021. Stone location, number and size were determined with non-contrast CT (NCCT) for all patients. All patients underwent SWL with a Storz Modulith SLK lithotripsy machine without anaesthesia. The total amount of energy applied to the stone was calculated using the SMLI. All patients were evaluated for stone-free status by X-ray at least 2 weeks after treatment. The success of the procedure was defined as the patient being completely stone free or the detection of residual fragments
Research biopsies in kidney transplantation: an evaluation of surgical techniques and optimal tissue mass allowing molecular and histological analyses.
BACKGROUND: Research biopsies have great potential to advance scientific knowledge by helping to establish predictors of favourable or unfavourable outcomes in kidney transplantation. We evaluated punch and core biopsies of different sizes to determine the optimal size for clinical use. METHODS: A total of 54 punch biopsies and 18 core needle biopsies were retrieved by three transplant surgeons. Each surgeon obtained three separate 2 mm, 3 mm and 4 mm punch biopsy samples and three 23 mm (length) core needle biopsies from two pig kidneys. RESULTS: 4 mm punch biopsies yielded the greatest amount of protein (2.11 ± 0.41 mg) with good reproducibility between surgeons and biopsy types (Coefficient of Variation ∼ 22.13%). All surgeons found 2 mm biopsies technically challenging to obtain and sample processing was difficult due to the sample size. Shotgun proteomics identified 3853 gene products with no significant difference in the quantitative proteome of 2 mm and 3 mm punch biopsies. However, the expression of 158 Kidney enriched genes, was higher in bigger and deeper 4 mm punch and core needle biopsies compared to 2 mm biopsy. Only 80% of 2 mm biopsies demonstrated the presence of glomeruli, whereas glomeruli were present in 100% of all other biopsy sizes. CONCLUSIONS: The 2 mm punch biopsy has been shown to be challenging to use and frequently provides inadequate tissue for histology and proteomics while 3 mm research biopsies were the smallest size that were technically obtainable with adequate tissue for molecular studies.