The National Lung Matrix Trial of personalized therapy in lung cancer.

The majority of targeted therapies for non-small-cell lung cancer (NSCLC) are directed against oncogenic drivers that are more prevalent in patients with light exposure to tobacco smoke1-3. As this group represents around 20% of all patients with lung cancer, the discovery of stratified medicine options for tobacco-associated NSCLC is a high priority. Umbrella trials seek to streamline the investigation of genotype-based treatments by screening tumours for multiple genomic alterations and triaging patients to one of several genotype-matched therapeutic agents. Here we report the current outcomes of 19 drug-biomarker cohorts from the ongoing National Lung Matrix Trial, the largest umbrella trial in NSCLC. We use next-generation sequencing to match patients to appropriate targeted therapies on the basis of their tumour genotype. The Bayesian trial design enables outcome data from open cohorts that are still recruiting to be reported alongside data from closed cohorts. Of the 5,467 patients that were screened, 2,007 were molecularly eligible for entry into the trial, and 302 entered the trial to receive genotype-matched therapy-including 14 that re-registered to the trial for a sequential trial drug. Despite pre-clinical data supporting the drug-biomarker combinations, current evidence shows that a limited number of combinations demonstrate clinically relevant benefits, which remain concentrated in patients with lung cancers that are associated with minimal exposure to tobacco smoke.

Publisher Correction: The National Lung Matrix Trial of personalized therapy in lung cancer.

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

Anhydrous Proton Conduction Through a Chemically Robust Electrolyte Enabling a High-Temperature Non-Precious Metal Catalyzed Fuel Cell.

Fuel cells offer great promise for portable electricity generation, but their use is currently limited by their low durability, excessive operating temperatures, and expensive precious metal electrodes. It is therefore essential to develop fuel cell systems that can perform effectively using more robust electrolyte materials, at reasonable temperatures, with lower-cost electrodes. Recently, proton exchange membrane fuel cells have attracted attention due to their generally favorable chemical stability and quick start-up times. However, in most membrane materials, water is required for proton conduction, severely limiting operational temperatures. Here, for the first time it is demonstrated that when acidified, PAF-1 can conduct protons at high temperatures, via a unique framework diffusion mechanism. It shows that this acidified PAF-1 material can be pressed into pellets with high proton conduction properties even at high temperatures and pellet thickness, highlighting the processibility, and ease of use of this material. Furthermore, a fuel cell is shown with high power density output is possible using a non-precious metal copper electrode. Acid-doped PAF-1 therefore represents a significant step forward in the potential for a broad-purpose fuel cell due to it being cheap, robust, efficient, and easily processible.

Clinical and economic impact of the introduction of pre-biopsy MRI-based assessment on a large prostate cancer centre diagnostic population and activity: 10 years on.

INTRODUCTION: Prostate mpMRI was introduced in 2011 as a secondary test and subsequently integrated into a prostate cancer (PCa) diagnostics unit representing a population of approximately 550,000 people. The following represents an audit of its step-wise introduction between 2 index years, 2009 and 2018, focusing on the activity, patient outcomes and economic benefits. PATIENTS AND METHODS: The 2 distinct years were selected for relying on a transrectal ultrasound biopsy pathway in 2009 to an mpMRI-based pathway in 2018. All referrals were retrospectively screened and compared for age, PSA levels, DRE findings, biopsy history, biopsy and mpMRI allocation data. Cost analysis was determined using local unit procedure costs. RESULTS: Patients referred included 648 in 2009 and 714 in 2018. mpMRI seldomly informed decision to biopsy in 2009 (9.8%), while in 2018 it was performed in the pre-biopsy setting in 87.9% cases and enabled biopsy avoidance in 137 patients. In 2018, there was a 31.8% decrease in the number of biopsies in patients without previous PCa diagnosis, coupled with an increase in diagnostic rates of csPCa, from 28.6 to 49.0% (p < 0.0001) and a reduction in negative biopsy rates from 52.3 to 33.8%. mpMRI had a positive impact on the system with reduced patient morbidity and post-procedural complications. The estimated overall cost savings amount to approximately £75,000/year for PCa diagnosis and £11,000/year due to reduced complications. CONCLUSION: Our evaluation shows the mpMRI-based pathway has improved early detection of csPCa and reduction of repeat biopsies, resulting in significant financial benefits for the local healthcare system.

Association of Gastric Acid Suppression and Sorafenib Efficacy in Advanced Hepatocellular Carcinoma.

BACKGROUND: Recent studies have revealed that coadministration of gastric acid suppressants reduces the efficacy of the tyrosine kinase inhibitors erlotinib and sunitinib in patients with non-small cell lung cancer and renal cell carcinoma, respectively. The authors have therefore assessed if the concurrent use of gastric acid suppressants and sorafenib impairs outcomes in patients with advanced hepatocellular carcinoma (HCC). METHODS: A retrospective analysis was conducted on all patients treated with sorafenib for advanced HCC at a single tertiary referral unit in the United Kingdom, between January 2008 and January 2014. A multivariate Cox proportional hazard model was used to assess the effect of the concomitant use of gastric acid suppression and sorafenib on progression-free survival (PFS) and overall survival (OS). RESULTS: Data were collected from 197 patients, of which 182 could be assessed for this study; 77 (42%) were on concurrent gastric acid suppression therapy. After adjusting for imbalances between the groups, a Cox regression analysis gave an adjusted hazard ratio for the concurrent acid suppression group compared with the no acid suppression group of 5.4 (95% confidence interval, 3.6-7.9) for PFS and 1.85 (95% confidence interval, 1.3-2.6) for OS. CONCLUSIONS: This single-center experience shows that patients with advanced HCC taking sorafenib and concomitant gastric acid suppression therapy have significantly inferior PFS and OS. This is the first time that this negative interaction has been reported and further prospective validation is warranted.

Pre-hospital thrombolysis for ST-segment elevation myocardial infarction in regional Australia: long-term follow up.

BACKGROUND: Delivering reperfusion therapy to patients with ST-segment elevation myocardial infarction (STEMI) in regional areas without access to tertiary cardiology care remains challenging. The systems of care in Hunter New England Health, New South Wales, Australia (area covered = 130 000 km2 ) to provide reperfusion to patients with STEMI involve a 12-lead electrocardiogram in the ambulance, discussion between cardiologist and paramedic, followed by pre-hospital thrombolysis (PHT) delivered in ambulance to appropriate patients >60 min from the cardiac catheterisation laboratories. Patients who can access the cardiac catheterisation laboratories within 60 min are treated with primary percutaneous coronary intervention (PCI). AIMS: We have previously reported excellent 12-month outcomes for patients receiving PHT and the aim of the current analysis is to look at the long term outcomes. METHODS: We assessed long-term all-cause mortality and major adverse cardiovascular events of STEMI patients undergoing PHT in our health district from August 2008 to August 2013 and compared with the primary PCI group. RESULTS: One hundred and fifty (mean age: 62 ± 13 years, males: 76%, n = 114) patients were administered PHT and 334 patients (mean age: 65 ± 13 years, males: 75%, n = 251) underwent primary PCI during the study period. During a median follow up of 6.2 years (interquartile range: 4.8-7.4 years) all-cause mortality was 16% and 19% in the PHT and primary PCI groups respectively (P = 0.4). CONCLUSION: Our real-world experience shows that PHT followed by early transfer to a primary PCI-capable centre is an effective reperfusion strategy, with comparable results to primary PCI, and mortality benefits are sustained to more than 6 years.

Watching the watchmen: an evaluation of educational supervision in a busy district general hospital.

INTRODUCTION: Educational supervisors (ESs) play a critical role in the training of Foundation doctors. Many hospital trusts do not currently offer formal mechanisms to ensure the quality of supervision is at a high standard. Our Trust wanted to empower trainees to offer objective feedback on the quality of the supervisors. METHODS: We introduced a feedback form sent to all Foundation doctors at our Trust. The questionnaire was designed to identify whether ESs were meeting their responsibilities as defined by the Health Education England South West's Severn Deanery. We collected data throughout the academic year 2017-2018 (Year 1) as a pilot, before rolling out the definitive questionnaire with minor modifications from 2018 to 2019 (Year 2). RESULTS: All respondents met with their supervisor within the first month of the placement and 90.7% of the trainees found it easy to meet with their supervisor. The Trust received generally very good feedback for all of its supervisors. Low numbers (4/120 trainees) reported supervisors not engaging with the exception reporting process. CONCLUSION: Our Trust provides ESs of a high standard. The authors believe collecting feedback for ESs will achieve three things: 1) Drive up standards through increasing accountability of ESs receiving objective feedback. This will be of critical importance in the context of the severe acute respiratory syndrome coronavirus 2 pandemic and the changes to our work it has necessitated. 2) Empower trainees to make informed decisions about where they wish to train and under which supervisors. 3) Facilitate revalidation and appraisal for supervisors by collecting data from trainees on the quality of their supervision.

Trends in the Incidence of First Acute Myocardial Infarction in Metropolitan and Regional Areas of the Hunter Region.

INTRODUCTION: There is conflicting information regarding the contemporary incidence of first acute myocardial infarction (AMI) in Australia. We sought to document the regional variations in first AMI incidence in a large health district. METHODS: We identified all patients presenting with first AMI in the Hunter region of New South Wales from 2004 to 2013. We calculated age and gender adjusted incidence of AMI and evaluated differences between patients from regional and metropolitan areas. We assessed 30-day and 12-month outcomes, including mortality, through linkage with the NSW Registry of Births Deaths and Marriages. RESULTS: The incidence of first AMI in regional areas was persistently higher throughout the study compared to metropolitan areas (IRR 1.244; 95% CI 1.14-1.35; p≤0.001). There were no significant differences between regional and metropolitan areas in 30-day and 12-month outcomes following presentation with first AMI. CONCLUSIONS: The study demonstrates persistently higher rates in regional compared to metropolitan areas, supporting the need for implementation of targeted intervention and prevention strategies.

Mortality and Readmission Following Hospitalisation for Heart Failure in Australia: A Systematic Review and Meta-Analysis.

BACKGROUND: Heart failure (HF) is a common, costly condition with an increasing burden on Australian health care system resources. Knowledge of the burden of HF on patients and on the health system is important for resource allocation. This study is the first systematic review to estimate the mortality and readmission rates after hospitalisation for HF in the Australian population. METHODS: We searched for studies of HF hospitalisation in Australia published between January 1990 and May 2016, using a systematic search of PubMed, Medline, Scopus, Web of Science, EMBASE and Cochrane Library databases. Studies reporting 30-day and/or 1-year outcomes for mortality or readmission following hospitalisation were eligible and included in this study. RESULTS: Out of 2889 articles matching the initial search criteria, a total of 13 studies representing 67,255 patients were included in the final analysis. The pooled mean age of heart failure patients was 76.3 years and 51% were male (n=34,271). The pooled estimated 30-day and 1-year all-cause mortality were 8% and 25% respectively. The pooled estimated 30-day and 1-year all-cause readmission rates were 20% and 56% respectively. There is a high prevalence of comorbidities in heart failure patients. There were limited data on readmission and mortality in rural patients and Indigenous people. CONCLUSIONS: Heart failure hospitalisations in Australia are followed by substantial readmission and mortality rates.

Disparities in the incidence of acute myocardial infarction: long-term trends from the Hunter region.

BACKGROUND: Trends in the incidence of acute myocardial infarction (AMI) provide important information for healthcare providers and can allow for accurate planning of future health needs and targeted interventions in areas with an excess burden of cardiovascular disease. AIM: To investigate the regional variations in AMI incidence in the Hunter region. METHODS: Incident cases of AMI identified between 1996 and 2013 from the Hunter New England Health Cardiac and Stroke Outcomes Unit were prospectively collected for this study. We calculated crude and age-adjusted incidence of AMI over an 18-year period and explored differences in remoteness, age, sex and indigenous status. RESULTS: During 1996-2013, a total of 15 480 cases of AMI were identified. There was a significantly higher incidence of AMI in patients from regional areas compared to patients from metropolitan areas. More importantly, while rates of AMI declined by 28% in metropolitan patients, they increased by 8% in regional patients. Males had higher rates of AMI throughout the study period than females, however there was trend over time towards a reduction in AMI incidence in males that was not seen in females. The age-adjusted incidence of AMI for indigenous patients increased by 48% from 2007 to 2013, compared to a 23% decrease in non-indigenous patients. CONCLUSION: Between 1996 and 2013 in the Hunter region, the adjusted incidence of AMI increased for regional patients compared to metropolitan patients with a trend towards a higher adjusted incidence of AMI in the indigenous population.

Heart Failure Hospitalisations in the Hunter New England Area Over 10 years. A Changing Trend.

BACKGROUND: Heart failure carries a major burden on our health system, mainly related to the high rate of hospital admission. An understanding of the recent trends in heart failure hospitalisation is essential to the future allocation of health resources. Our aim is to analyse the temporal trends in heart failure hospitalisation. METHODS: We extracted all separations in the Hunter New England Local Health District between 2005-2014 (n=40,119) with an ICD 10 code for heart failure (I-50) in the first four diagnoses on discharge. The numbers of hospitalisations were age-standardised to the 2001 Australian population and compared based on gender and remoteness. RESULTS: There was a decline in the age-standardised hospitalisation. However, there was a clear inflection point between 2009-2010, after which the decline levelled off. The absolute number of hospitalisations increased between 2010 and 2014. Heart failure hospitalisation was higher in males compared to females and rural compared to metropolitan inhabitants. CONCLUSION: The gains in heart failure treatment noted in recent years seem to have come to an end. Patients aged 75 years and older are contributing the majority of age-standardised hospitalisations.

Pre-hospital thrombolysis in ST-segment elevation myocardial infarction: a regional Australian experience.

OBJECTIVE: The system of care in the Hunter New England Local Health District for patients with ST-segment elevation myocardial infarction (STEMI) foresees pre-hospital thrombolysis (PHT) administered by paramedics to patients more than 60 minutes from the cardiac catheterisation laboratory (CCL), and primary percutaneous coronary intervention (PCI) at the CCL for others. We assessed the safety and effectiveness of the pre-hospital diagnosis strategy, which allocates patients to PHT or primary PCI according to travel time to the CCL. DESIGN, SETTING AND PARTICIPANTS: Prospective, non-randomised, consecutive, single-centre case series of STEMI patients diagnosed on the basis of a pre-hospital electrocardiogram (ECG), from August 2008 to August 2013. All patients were treated at the tertiary referral hospital (John Hunter Hospital, Newcastle). MAIN OUTCOME MEASURES: The primary efficacy endpoint was all-cause mortality at 12 months; the primary safety endpoint was bleeding. RESULTS: STEMI was diagnosed in 484 patients on the basis of pre-hospital ECG; 150 were administered PHT and 334 underwent primary PCI. The median time from first medical contact (FMC) to PHT was 35 minutes (IQR, 28-43 min) and to balloon inflation 130 minutes (IQR, 100-150 min). In the PHT group, 37 patients (27%) needed rescue PCI (median time, 4 h; IQR, 3-5 h). The 12-month all-cause mortality rate was 7.0% (PHT, 6.7%; PCI, 7.2%). The incidence of major bleeding (TIMI criteria) in the PHT group was 1.3%; no patients in the primary PCI group experienced major bleeding. CONCLUSION: PHT can be delivered safely by paramedical staff in regional and rural Australia with good clinical outcomes.

Integration of repulsive guidance cues generates avascular zones that shape mammalian blood vessels.

RATIONALE: Positive signals, such as vascular endothelial growth factor, direct endothelial cells (ECs) to specific locations during blood vessel formation. Less is known about repulsive signal contribution to shaping vessels. Recently, "neuronal guidance cues" have been shown to influence EC behavior, particularly in directing sprouting angiogenesis by repelling ECs. However, their role during de novo blood vessel formation remains unexplored. OBJECTIVE: To identify signals that guide and pattern the first mammalian blood vessels. METHODS AND RESULTS: Using genetic mouse models, we show that blood vessels are sculpted through the generation of stereotyped avascular zones by EC-repulsive cues. We demonstrate that Semaphorin3E (Sema3E) is a key factor that shapes the paired dorsal aortae in mouse, as sema3E(-/-) embryos develop an abnormally branched aortic plexus with a markedly narrowed avascular midline. In vitro cultures and avian grafting experiments show strong repulsion of ECs by Sema3E-expressing cells. We further identify the mouse notochord as a rich source of multiple redundant neuronal guidance cues. Mouse embryos that lack notochords fail to form cohesive aortic vessels because of loss of the avascular midline, yet maintain lateral avascular zones. We demonstrate that lateral avascular zones are directly generated by the lateral plate mesoderm, a critical source of Sema3E. CONCLUSIONS: These findings demonstrate that Sema3E-generated avascular zones are critical regulators of mammalian cardiovascular patterning and are the first to identify a repulsive role for the lateral plate mesoderm. Integration of multiple, and in some cases redundant, repulsive cues from various tissues is critical to patterning the first embryonic blood vessels.

EphB3 marks delaminating endocrine progenitor cells in the developing pancreas.

BACKGROUND: Understanding the process by which pancreatic beta-cells acquire their "fate" is critical to the development of in vitro directed differentiation protocols for cell replacement therapies for diabetics. To date, these efforts are hampered by a paucity of markers that distinguish pancreatic endocrine cells at different stages of differentiation. RESULTS: Here, we identify EphB3 as a novel pro-endocrine marker and use its expression to track delaminating islet lineages. First, we provide a detailed developmental expression profile for EphB3 and other EphB family members in the embryonic pancreas. We demonstrate that EphB3 transiently marks endocrine cells as they delaminate from the pancreatic epithelium, prior to their differentiation. Using a Tet-inducible EphB3(rtTA-lacZ) reporter line, we show that short-term pulse-labeled EphB3(+) cells co-express Pdx1, Nkx6.1, Ngn3, and Synaptophysin, but not insulin, glucagon, or other endocrine hormones. Prolonged labeling tracks EphB3(+) cells from their exit from the epithelium to their differentiation. CONCLUSIONS: These studies demonstrate that pro-endocrine cell differentiation during late gestation, from delamination to maturation, takes approximately 2 days. Together, these data introduce EphB3 as a new biomarker to identify beta-cells at a critical step during their step-wise differentiation and define the timeframe of endocrine differentiation.

Vector Prostate Biopsy: A Novel Magnetic Resonance Imaging/Ultrasound Image Fusion Transperineal Biopsy Technique Using Electromagnetic Needle Tracking Under Local Anaesthesia.

BACKGROUND: Prostate magnetic resonance imaging (MRI) is now standard for assessment of suspected prostate cancer (PCa). A variety of approaches to MRI-based targeting has revolutionised prostate biopsies. OBJECTIVE: To describe the procedure and show the accuracy and tolerability of a novel Vector MRI/ultrasound fusion transperineal (TP) biopsy technique that uses electromagnetic (EM) needle tracking under local anaesthesia (LA). DESIGN, SETTING, AND PARTICIPANTS: Vector prostate biopsy using BiopSee fusion software, EM tracking technology, and transrectal ultrasound was performed in 69 patients meeting the biopsy criteria in two UK centres between September 2020 and August 2022. SURGICAL PROCEDURE: Stepper-mounted rectal ultrasound images were fused with MRI scans. LA was applied into two defined perineal tracks and a needle sheath with an EM sensor was inserted. The biopsy needle was directed precisely through the sheath to MRI targets under EM tracking. Biopsies were taken without antibiotic prophylaxis. MEASUREMENTS: Cancer detection (any PCa; grade group ≥2), side effects, and patient experience measures were recorded. RESULTS AND LIMITATIONS: Cancer detection in patients with Likert 4-5 lesions was 98% for any PCa and 83% for grade group ≥2. According to the 50 questionnaires returned, 42 patients (84%) reported no or minimal pain, while 40 (80%) reported no or minimal discomfort. No episodes of postoperative urinary retention occurred, and only one patient required treatment for infection. Limitations include the low patient number and incomplete responses to questionnaires. CONCLUSIONS: This novel Vector technique provides a feasible and tolerable procedure for MRI/ultrasound fusion TP biopsy under LA, with high cancer detection rates. This is achieved while maintaining patient comfort and with minimal rates of complications. PATIENT SUMMARY: We report a novel technique that uses electromagnetic needle tracking to perform highly accurate and comfortable prostate biopsies through the perineum under local anaesthetic.

Natural History of Patients with Prostate MRI Likert 1-3 and Development of RosCaP: a Multivariate Risk Score for Clinically Significant Cancer.

INTRODUCTION: Clinically significant prostate cancer (csCaP) with Gleason ≥3 + 4 is found in 10% negative prebiopsy multiparametric (mp) MRI cases and varies widely for equivocal mpMRI cases. The objective of this study was to investigate long-term outcomes of patients with negative and equivocal mpMRIs and to develop a predictive score for csCaP risk stratification in this group. PATIENTS AND METHODS: Patients who underwent an upfront mpMRI between May 2015 and March 2018 with an MRI score Likert 1 to 3 were included in the study. Patients had either a CaP diagnosis at MRI-targeted biopsy or were not diagnosed and attended follow-up in the community. Outcomes were analysed through the Kaplan-Meier estimator and Cox Model. Regression coefficients of significant variables were used to develop a Risk of significant Cancer of the Prostate score (RosCaP). RESULTS: At first assessment 281/469 patients had mpMRI only and 188/469 mpMRI and biopsy, 26 csCaP were found at biopsy, including 10/26 in Likert 3 patients. 12/371 patients discharged without CaP after first assessment were diagnosed with csCaP during a median of 34.2 months' follow-up, 11/12 diagnosis occurred in patients omitting initial biopsy. csCaP diagnosis-free survival was 95.7% in the MRI group and 99.1% in the biopsy group. From these outcomes, a continuous RosCaP score was developed: RosCaP = 0.083 x Age - 0.202 x (1/PSA Density) + 0.786 (if Likert 3), and 4 risk classes were proposed. Limitations include retrospective design and absence of external validation. CONCLUSION: Age, PSA Density and MRI Likert score were significantly associated to the risk of csCaP and utilised to devise the novel RosCap predictive score focused to support risk assessment in patients with negative or equivocal mpMRI results.

Continence-Sparing Techniques in Radical Prostatectomy: A Systematic Review of Randomized Controlled Trials.

Background: Numerous continence-sparing radical prostatectomy techniques have been developed to enhance postoperative early continence (EC) recovery; however, evidence regarding the best approach remains controversial. The objectives are to provide a critical appraisal of various prostatectomy techniques, based on the evidence of quality-assessed randomized control trials (RCTs); to summarize the immediate continence and the EC reported; and to propose a new standardization for continence outcomes reporting. Methods: Data acquired from five medical registries were reported to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) standards. Evidence from published, English, full-text RCTs reporting postoperative urinary continence outcomes within 6 months from surgery was included. The heterogeneity of surgical techniques and continence definitions did not allow a meta-analysis. All RCTs were critically appraised, and quality assessed. Results: In total, 39 RCTs were included: 19 of 39 studies were low-quality RCTs, presenting small cohort, monocentric, or single-surgeon data. The best RCT-supported evidence is in favor of robot-assisted radical prostatectomy (RARP) compared with laparoscopic radical prostatectomy (LRP) and of the Retzius-sparing (RS) technique over the traditional prostatectomy. Other techniques such as bladder neck and puboprostatic ligament (PPL) preservation, posterior reconstruction with or without combination of anterior suspension technique, and nerve-sparing (NS) approach seem to enhance EC. Oppositely, the endopelvic fascia preservation, bladder neck mucosa eversion/plication/slings, and the selective ligature of dorsal venous complex (DVC) were not significantly associated with EC improvements. RCTs are lacking on pubovesical complex-sparing, seminal vesicle preservation, anterior reconstruction of the puboprostatic collar, musculofascial reconstruction, and DVC suspension to the periosteum of the pubic bone techniques. Conclusions: RARP and RS have high-quality evidence supporting their ability to enhance postoperative EC recovery. NS, bladder neck, and PPL preservation may contribute to better EC recovery, although the evidence level is low. Further multicenter RCTs are needed to establish the optimal combination of standard surgical techniques. A new continence outcome-reporting standardization was proposed.

Optimal biopsy approach for detection of clinically significant prostate cancer.

Prostate cancer (PCa) diagnostic and therapeutic work-up has evolved significantly in the last decade, with pre-biopsy multiparametric MRI now widely endorsed within international guidelines. There is potential to move away from the widespread use of systematic biopsy cores and towards an individualised risk-stratified approach. However, the evidence on the optimal biopsy approach remains heterogeneous, and the aim of this review is to highlight the most relevant features following a critical assessment of the literature. The commonest biopsy approaches are via the transperineal (TP) or transrectal (TR) routes. The former is considered more advantageous due to its negligible risk of post-procedural sepsis and reduced need for antimicrobial prophylaxis; the more recent development of local anaesthetic (LA) methods now makes this approach feasible in the clinic. Beyond this, several techniques are available, including cognitive registration, MRI-Ultrasound fusion imaging and direct MRI in-bore guided biopsy. Evidence shows that performing targeted biopsies reduces the number of cores required and can achieve acceptable rates of detection whilst helping to minimise complications and reducing pathologist workloads and costs to health-care facilities. Pre-biopsy MRI has revolutionised the diagnostic pathway for PCa, and optimising the biopsy process is now a focus. Combining MR imaging, TP biopsy and a more widespread use of LA in an outpatient setting seems a reasonable solution to balance health-care costs and benefits, however, local choices are likely to depend on the expertise and experience of clinicians and on the technology available.

Management of Acute Coronary Syndromes in Patients in Rural Australia: The MORACS Randomized Clinical Trial.

Importance: Treatment of ST-segment elevation myocardial infarction (STEMI) in rural settings involves thrombolysis followed by transfer to a percutaneous coronary intervention-capable hospital. The first step is accurate diagnosis via electrocardiography (ECG), but one-third of all STEMI incidents go unrecognized and hence untreated. Objective: To reduce missed diagnoses of STEMI. Design, Setting, and Participants: This cluster randomized clinical trial included 29 hospital emergency departments (EDs) in rural Australia with no emergency medicine specialists, which were randomized to usual care vs automatically triggered diagnostic support from the tertiary referral hospital (management of rural acute coronary syndromes [MORACS] intervention). Patients presenting with symptoms compatible with acute coronary syndromes (ACS) were eligible for inclusion. The study was conducted from December 2018 to April 2020. Data were analyzed in August 2021. Intervention: Triage of a patient with symptoms compatible with ACS triggered an automated notification to the tertiary hospital coronary care unit. The ECG and point-of-care troponin results were reviewed remotely and a phone call was made to the treating physician in the rural hospital to assist with diagnosis and initiation of treatment. Main Outcomes and Measures: The proportion of patients with missed STEMI diagnoses. Results: A total of 6249 patients were included in the study (mean [SD] age, 63.6 [12.2] years; 48% female). Of 7474 ED presentations with suspected ACS, STEMI accounted for 77 (2.0%) in usual care hospitals and 46 (1.3%) in MORACS hospitals. Missed diagnosis of STEMI occurred in 27 of 77 presentations (35%) in usual care hospitals and 0 of 46 (0%) in MORACS hospitals (P < .001). Of eligible patients, 48 of 75 (64%) in the usual care group and 36 of 36 (100%) in the MORACS group received primary reperfusion (P < .001). In the usual care group, 12-month mortality was 10.3% (n = 8) vs 6.5% (n = 3) in the MORACS group (relative risk, 0.64; 95% CI, 0.18-2.23). Patients with missed STEMI diagnoses had a mortality of 25.9% (n = 7) compared with 2.0% (n = 1) for those with accurately diagnosed STEMI (relative risk, 13.2; 95% CI, 1.71-102.00; P = .001). Overall, there were 6 patients who did not have STEMI as a final diagnosis; 5 had takotsubo cardiomyopathy and 1 had pericarditis. There was no difference between groups in the rate of alternative final diagnosis. Conclusion and Relevance: The findings indicate that MORACS diagnostic support service reduced the proportion of missed STEMI and improved the rates of primary reperfusion therapy. Accurate diagnosis of STEMI was associated with lower mortality. Trial Registration: anzctr.org.au Identifier: ACTRN12619000533190.