Hyperthermic intraperitoneal chemotherapy in colorectal cancer.

BACKGROUND: This study evaluated the efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer with peritoneal metastases (pmCRC) in a large international data set of patients. PATIENTS AND METHODS: Patients with pmCRC from 39 centres who underwent cytoreductive surgery with HIPEC between 1991 and 2018 were selected and compared for the HIPEC protocols received-oxaliplatin-HIPEC versus mitomycin-HIPEC. Following analysis of crude data, propensity-score matching (PSM) and Cox-proportional hazard modelling were performed. Outcomes of interest were overall survival (OS), recurrence-free survival (RFS) and the HIPEC dose-response effects (high versus low dose, dose intensification and double drug protocols) on OS, RFS and 90-day morbidity. Furthermore, the impact of the treatment time period was assessed. RESULTS: Of 2760 patients, 2093 patients were included. Median OS was 43 months (95% c.i. 41 to 46 months) with a median RFS of 12 months (95% c.i. 12 to 13 months). The oxaliplatin-HIPEC group had an OS of 47 months (95% c.i. 42 to 53 months) versus 39 months (95% c.i. 36 to 43 months) in the mitomycin-HIPEC group (P = 0.002), aHR 0.77, 95% c.i. 0.67 to 0.90, P < 0.001. The OS benefit persisted after PSM of the oxaliplatin-HIPEC group and mitomycin-HIPEC group (48 months (95% c.i. 42 to 59 months) versus 40 months (95% c.i. 37 to 44 months)), P < 0.001, aHR 0.78 (95% c.i. 0.65 to 0.94), P = 0.009. Similarly, matched RFS was significantly higher for oxaliplatin-HIPEC versus others (13 months (95% c.i. 12 to 15 months) versus 11 months (95% c.i. 10 to 12 months, P = 0.02)). High-dose mitomycin-HIPEC protocols had similar OS compared to oxaliplatin-HIPEC. HIPEC dose intensification within each protocol resulted in improved survival. Oxaliplatin + irinotecan-HIPEC resulted in the most improved OS (61 months (95% c.i. 51 to 101 months)). Ninety-day mortality in both crude and PSM analysis was worse for mitomycin-HIPEC. There was no change in treatment effect depending on the analysed time period. CONCLUSIONS: Oxaliplatin-based HIPEC provided better outcomes compared to mitomycin-based HIPEC. High-dose mitomycin-HIPEC was similar to oxaliplatin-HIPEC. The 90-day mortality difference favours the oxaliplatin-HIPEC group. A trend for dose-response between low- and high-dose HIPEC was reported.

Prognostic impact of prostate-specific membrane antigen positron emission tomography (PSMA PET) staging for clinically node-positive prostate cancer.

INTRODUCTION: In the current American Joint Committee on Cancer staging system, patients with pelvic nodal metastases are considered stage IV prostate cancer. This study aims to investigate whether men with prostate-specific membrane antigen positron emission tomography (PSMA PET)-detected pelvic node-positive prostate cancer at diagnosis have a better outcome compared to men with node-positive disease identified on conventional imaging. METHODS: This is a retrospective cohort study comparing the outcomes of men with node-positive prostate cancer and disease confined to the pelvis, staged with conventional versus PSMA PET imaging. Men had to be treated definitively with a combination of androgen deprivation therapy and radiation treatment to the prostate and pelvic lymph nodes. Kaplan-Meier and Cox regression analysis was used to compare biochemical failure-free survival (BFFS) and overall survival (OS). RESULTS: Seventy-six men with nodal metastases confined to the pelvis were identified. Fifty-one were detected with PSMA PET while 25 were staged with conventional imaging. PSMA PET staged patients had a lower proportion of Gleason 8-10 disease (78% vs. 96%) as well as a lower median prostate-specific antigen (11 ng/mL vs. 26 ng/mL). BFFS at 4 years was 72% with PSMA PET-detected node-positive disease vs. 38% with conventionally detected node-positive disease. Four-year OS was 93% with PSMA PET staged patients vs. 76% with conventionally staged patients. On multivariate analysis, the PSMA PET staged group was associated with improved BFFS (Adjusted HR = 3.00, 95% CI 1.43, 6.29, P = 0.004) and OS (Adjusted HR = 5.81, 95% CI 1.43, 23.7, P = 0.007). CONCLUSION: Men with PSMA PET-detected node-positive prostate cancer confined to the pelvis have significantly better biochemical control and survival compared to those with node-positive pelvic disease identified through conventional staging.

Potentiating Activity of GmhA Inhibitors on Gram-Negative Bacteria.

Inhibition of the biosynthesis of bacterial heptoses opens novel perspectives for antimicrobial therapies. The enzyme GmhA responsible for the first committed biosynthetic step catalyzes the conversion of sedoheptulose 7-phosphate into d-glycero-d-manno-heptose 7-phosphate and harbors a Zn2+ ion in the active site. A series of phosphoryl- and phosphonyl-substituted derivatives featuring a hydroxamate moiety were designed and prepared from suitably protected ribose or hexose derivatives. High-resolution crystal structures of GmhA complexed to two N-formyl hydroxamate inhibitors confirmed the binding interactions to a central Zn2+ ion coordination site. Some of these compounds were found to be nanomolar inhibitors of GmhA. While devoid of HepG2 cytotoxicity and antibacterial activity of their own, they demonstrated in vitro lipopolysaccharide heptosylation inhibition in Enterobacteriaceae as well as the potentiation of erythromycin and rifampicin in a wild-type Escherichia coli strain. These inhibitors pave the way for a novel treatment of Gram-negative infections.

Towards leaving no one behind in North Macedonia: a mixed methods assessment of barriers to effective coverage with health services.

BACKGROUND: The Government of North Macedonia's Primary Health Care reform is committed to leaving no one behind on the path to Universal health Coverage (UHC). During mid-2022 to March 2023, the World Health Organization (WHO) collaborated with the Government and other national stakeholders for an assessment of barriers to effective coverage with health services experienced by adult citizens, with a specific focus on rural areas and subpopulations in situations of vulnerability. METHODS: This study constituted the piloting of a draft forthcoming WHO handbook on assessing barriers for health services, grounded in the Tanahashi framework for effective coverage with health services. In North Macedonia, the convergent parallel mixed methods study involved four sources. These were: a nationally representative Computer Assisted Telephone Interview Survey (1,139 respondents); 24 key informant interviews with representatives from government, professional associations, non-governmental and civil society organizations, and development partners; 12 focus groups in four regions with adults from vulnerable/high risk groups in rural areas and small urban settlements and an additional focus group with persons with disabilities; and a literature review. Instrument design was underpinned by the Tanahashi framework, which also orientated data triangulation and deductive analysis. The research team synergistically incorporated emerging themes in an inductive way. A key component of the assessment was participatory design of the study protocol with inputs from national stakeholders as well as participatory deliberation of the results and the ways forward. RESULTS: Despite considerable progress towards UHC in North Macedonia, the assessment elucidated remaining challenges. These included: insufficient numbers of health workers, in general and particularly in the more disadvantaged regions of the country; inadequate number of outpatient medicines covered by health insurance; distance and transportation obstacles, including indirect travel costs, particularly in rural areas; adverse gender norms and relations for both women and men inhibiting timely treatment seeking; perceived discrimination by providers on multiple grounds; bottlenecks including waiting times to get appointments for specialist referrals; and lack of patient adherence, due several factors including costs of medicines and health products. CONCLUSIONS: The outputs from this study of barriers to effective coverage with health services for adult citizens of North Macedonia are feeding into the ongoing Primary Health Care reform, and provide evidence for equity-related actions in the forthcoming National Development Strategy.

A second hotspot for pathogenic exon-skipping variants in CDC45.

Biallelic pathogenic variants in CDC45 are associated with Meier-Gorlin syndrome with craniosynostosis (MGORS type 7), which also includes short stature and absent/hypoplastic patellae. Identified variants act through a hypomorphic loss of function mechanism, to reduce CDC45 activity and impact DNA replication initiation. In addition to missense and premature termination variants, several pathogenic synonymous variants have been identified, most of which cause increased exon skipping of exon 4, which encodes an essential part of the RecJ-orthologue's DHH domain. Here we have identified a second cohort of families segregating CDC45 variants, where patients have craniosynostosis and a reduction in height, alongside common facial dysmorphisms, including thin eyebrows, consistent with MGORS7. Skipping of exon 15 is a consequence of two different variants, including a shared synonymous variant that is enriched in individuals of East Asian ancestry, while other variants in trans are predicted to alter key intramolecular interactions in α/ß domain II, or cause retention of an intron within the 3'UTR. Our cohort and functional data confirm exon skipping is a relatively common pathogenic mechanism in CDC45, and highlights the need for alternative splicing events, such as exon skipping, to be especially considered for variants initially predicted to be less likely to cause the phenotype, particularly synonymous variants.

Can templates-for-rejection suppress real-world affective objects in visual search?

Previous evidence has suggested that feature-based templates-for-rejection can be maintained in working memory to suppress matching features in the environment. Currently, this effect has only been demonstrated using abstract neutral shapes, meaning that it is unclear whether this generalizes to real-world images, including aversive stimuli. In the current investigation, participants searched amongst an array of real-world objects for a target, after being precued with either a distractor template, target template, or a no template baseline. In Experiment 1, where both distractor and target template cues were presented randomly on a trial-by-trial basis, there was moderate evidence of increased capture by aversive distractors after the distractor template cue. In Experiment 2a, however, when distractor templates were the only available cue and more time was given to encode the cue features, there was moderate evidence of effective distractor inhibition for real-world aversive and neutral stimuli. In Experiment 2b, when the task required a slower more effortful comparison of target features to stereotypical object representations, there was weaker evidence of inhibition, though there was still modest evidence suggesting effective inhibition of aversive distractors. A Bayesian meta-analysis revealed that across Experiment 2, aversive distractors showed strong cumulative evidence of effective inhibition, but inconsistent inhibition for neutral distractors. The results are interpreted from a rational search behaviour framework, which suggests that individuals utilize informative cues when they enable the most beneficial strategy and are accessible, and apply these to distractors when they cause sufficient disruption, either to search speed or emotional state.

First-line chemoimmunotherapy and immunotherapy in patients with non-small cell lung cancer and brain metastases: a registry study.

Introduction: Brain metastases commonly occur in patients with non-small cell lung cancer (NSCLC). Standard first-line treatment for NSCLC, without an EGFR, ALK or ROS1 mutation, is either chemoimmunotherapy or anti-PD-1 monotherapy. Traditionally, patients with symptomatic or untreated brain metastases were excluded from the pivotal clinical trials that established first-line treatment recommendations. The intracranial effectiveness of these treatment protocols has only recently been elucidated in small-scale prospective trials. Methods: Patients with NSCLC and brain metastases, treated with first-line chemoimmunotherapy or anti-PD-1 monotherapy were selected from the Australian Registry and biObank of thoracic cancers (AURORA) clinical database covering seven institutions. The primary outcome was a composite time-to-event (TTE) outcome, including extracranial and intracranial progression, death, or need for local intracranial therapy, which served as a surrogate for disease progression. The secondary outcome included overall survival (OS), intracranial objective response rate (iORR) and objective response rate (ORR). Results: 116 patients were included. 63% received combination chemoimmunotherapy and 37% received anti-PD-1 monotherapy. 69% of patients received upfront local therapy either with surgery, radiotherapy or both. The median TTE was 7.1 months (95% CI 5 - 9) with extracranial progression being the most common progression event. Neither type of systemic therapy or upfront local therapy were predictive of TTE in a multivariate analysis. The median OS was 17 months (95% CI 13-27). Treatment with chemoimmunotherapy was predictive of longer OS in multivariate analysis (HR 0.35; 95% CI 0.14 - 0.86; p=0.01). The iORR was 46.6%. The iORR was higher in patients treated with chemoimmunotherapy compared to immunotherapy (58% versus 31%, p=0.01). The use of chemoimmunotherapy being predictive of iORR in a multivariate analysis (OR 2.88; 95% CI 1.68 - 9.98; p=0.04). Conclusion: The results of this study of real-world data demonstrate the promising intracranial efficacy of chemoimmunotherapy in the first-line setting, potentially surpassing that of immunotherapy alone. No demonstrable difference in survival or TTE was seen between receipt of upfront local therapy. Prospective studies are required to assist clinical decision making regarding optimal sequencing of local and systemic therapies.

A Phase II trial of alternating osimertinib and gefitinib therapy in advanced EGFR-T790M positive non-small cell lung cancer: OSCILLATE.

In this phase II, single arm trial (ACTRN12617000720314), we investigate if alternating osimertinib and gefitinib would delay the development of resistance to osimertinib in advanced, non-small cell lung cancer (NSCLC) with the epidermal growth factor receptor (EGFR) T790M mutation (n = 47) by modulating selective pressure on resistant clones. The primary endpoint is progression free-survival (PFS) rate at 12 months, and secondary endpoints include: feasibility of alternating therapy, overall response rate (ORR), overall survival (OS), and safety. The 12-month PFS rate is 38% (95% CI 27.5-55), not meeting the pre-specified primary endpoint. Serial circulating tumor DNA (ctDNA) analysis reveals decrease and clearance of the original activating EGFR and EGFR-T790M mutations which are prognostic of clinical outcomes. In 73% of participants, loss of T790M ctDNA is observed at progression and no participants have evidence of the EGFR C797S resistance mutation following the alternating regimen. These findings highlight the challenges of treatment strategies designed to modulate clonal evolution and the clinical importance of resistance mechanisms beyond suppression of selected genetic mutations in driving therapeutic escape to highly potent targeted therapies.

Development of clinically meaningful quality indicators for contemporary lung cancer care, and piloting and evaluation in a retrospective cohort; experiences of the Embedding Research (and Evidence) in Cancer Healthcare (EnRICH) Program.

OBJECTIVES: Lung cancer continues to be the most common cause of cancer-related death and the leading cause of morbidity and burden of disease across Australia. There is an ongoing need to identify and reduce unwarranted clinical variation that may contribute to these poor outcomes for patients with lung cancer. An Australian national strategy acknowledges clinical quality outcome data as a critical component of a continuously improving healthcare system but there is a need to ensure clinical quality indicators adequately measure evidence-based contemporary care, including novel and emerging treatments. This study aimed to develop a suite of lung cancer-specific, evidence-based, clinically acceptable quality indicators to measure quality of care and outcomes, and an associated comparative feedback dashboard to provide performance data to clinicians and hospital administrators. DESIGN: A multistage modified Delphi process was undertaken with a Clinical Advisory Group of multidisciplinary lung cancer specialists, with patient representation, to update and prioritise potential indicators of lung cancer care derived from a targeted review of published literature and reports from national and international lung cancer quality registries. Quality indicators were piloted and evaluated with multidisciplinary teams in a retrospective observational cohort study using clinical audit data from the Embedding Research (and Evidence) in Cancer Healthcare Program, a prospective clinical cohort of over 2000 patients with lung cancer diagnosed from May 2016 to October 2021. SETTING AND PARTICIPANTS: Six tertiary specialist cancer centres in metropolitan and regional New South Wales, Australia. RESULTS: From an initial 37 potential quality indicators, a final set of 10 indicators spanning diagnostic, treatment, quality of life and survival domains was agreed. CONCLUSIONS: These indicators build on and update previously available measures of lung cancer care and outcomes in use by national and international lung cancer clinical quality registries which, to our knowledge, have not been recently updated to reflect the changing lung cancer treatment paradigm.

ASPiRATION: Australian observational cohort study of comprehensive genomic profiling in metastatic lung cancer tissue.

ASPiRATION is a national prospective observational cohort study assessing the feasibility, clinical and economic value of up-front tissue-based comprehensive genomic profiling (CGP) to identify actionable genomic alterations in participants with newly diagnosed metastatic non-squamous non-small-cell lung cancer in Australia. This study will enrol 1000 participants with tumor available for CGP and standard of care molecular testing (EGFR/ALK/ROS1). Participants with actionable variants may receive novel targeted treatments through ASPiRATION-specific substudies, other trials/programs. Clinical outcome data will be collected for a minimum of 2 years. Study outcomes are descriptive, including the ability of CGP to identify additional actionable variants, leading to personalized treatment recommendations, and will describe the feasibility, efficiency, cost and utility of implementation of CGP nationally.

Lung cancer is the most common cause of cancer death in Australia and worldwide. This disease often happens due to alterations in specific genes that allow cancer cells to develop and spread. Scientists have designed targeted drugs that are better at attacking cancer cells that have specific 'actionable' gene alterations and have less effect on other cells in the body. The result is often more benefit from treatment and fewer side effects than other standard treatments (chemotherapy or immunotherapy). The targeted drugs are well established as the best initial treatments for some gene alterations, but more research is needed to know if this is true for some of the less common or recently identified gene alterations, and where the targeted drugs are very new. Comprehensive genomic profiling is a new way of testing lung cancer cells for all the gene alterations (the well-known ones as well as the rare ones) in a single test. It is expected that this test will find many more of these gene alterations, which will allow more people to have safer and more effective targeted treatments leading to potentially better outcomes, and will allow some people to join clinical trials testing newer targeted treatments. The ASPiRATION study will help work out whether comprehensive genomic profiling is better than the current way of testing for gene alterations in Australia, and if it is feasible to use in all people diagnosed with advanced lung cancer in Australia. Clinical Trial Registration: ACTRN12621000221853 (ANZCTR).

Sequencing by avidity enables high accuracy with low reagent consumption.

We present avidity sequencing, a sequencing chemistry that separately optimizes the processes of stepping along a DNA template and that of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer-nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar and yield negligible dissociation rates. Avidity sequencing achieves high accuracy, with 96.2% and 85.4% of base calls having an average of one error per 1,000 and 10,000 base pairs, respectively. We show that the average error rate of avidity sequencing remained stable following a long homopolymer.

Mental imagery and visual attentional templates: A dissociation.

There is a growing interest in the relationship between mental images and attentional templates as both are considered pictorial representations that involve similar neural mechanisms. Here, we investigated the role of mental imagery in the automatic implementation of attentional templates and their effect on involuntary attention. We developed a novel version of the contingent capture paradigm designed to encourage the generation of a new template on each trial and measure contingent spatial capture by a template-matching visual feature (color). Participants were required to search at four different locations for a specific object indicated at the start of each trial. Immediately prior to the search display, color cues were presented surrounding the potential target locations, one of which matched the target color (e.g., red for strawberry). Across three experiments, our task induced a robust contingent capture effect, reflected by faster responses when the target appeared in the location previously occupied by the target-matching cue. Contrary to our predictions, this effect remained consistent regardless of self-reported individual differences in visual mental imagery (Experiment 1, N = 216) or trial-by-trial variation of voluntary imagery vividness (Experiment 2, N = 121). Moreover, contingent capture was observed even among aphantasic participants, who report no imagery (Experiment 3, N = 91). The magnitude of the effect was not reduced in aphantasics compared to a control sample of non-aphantasics, although the two groups reported substantial differences in their search strategy and exhibited differences in overall speed and accuracy. Our results hence establish a dissociation between the generation and implementation of attentional templates for a visual feature (color) and subjectively experienced imagery.

Feasibility of Symptom monitoring WIth Feedback Trial (SWIFT) for adults on hemodialysis: a registry-based cluster randomized pilot trial.

BACKGROUND: Patients with kidney failure on hemodialysis (HD) experience considerable symptom burden and poor health-related quality of life (HRQoL). There is limited use of patient reported outcome measures (PROMs) in facility HD units to direct immediate care, with response rates in other studies between 36 to 70%. The aim of this pilot study was to evaluate feasibility of electronic PROMs (e-PROMs) in HD participants, with feedback 3-monthly to the participants' treating team, for severe or worsening symptoms as identified by the Integrated Palliative Outcome Scale (IPOS-Renal), with linkage to the Australian and New Zealand Dialysis and Transplant (ANZDATA) registry, compared with usual care. METHODS: This is a registry-based cluster-randomized controlled pilot trial involving all adults receiving HD in 4 satellite units in Australia over a 6-month period. HD units were cluster randomized 1:1 to the control (HRQoL data collection only) or intervention arm (symptom monitoring with feedback to treating team every 3 months). Feasibility was assessed by participant response rate (percentage of eligible HD participants, including new incident participants, who completed the questionnaire at each time point); retention rate (percentage of participants who completed the baseline questionnaire and all subsequent measures); and completion time. HRQoL and symptom burden scores are described. RESULTS: There were 226 unique participants who completed the e-PROMs (mean age 62 years, 69% males, 78% White-European, median dialysis vintage 1.62 years). At 6 months, response rate and retention rate for the intervention arm were 54% and 68%, respectively, and 89% and 97% in the control arm. Median time to complete IPOS-Renal was 6.6 min (5.3, 10.1) at 3 months, and when combined with the outcome measure (EQ-5D-5L), the median time was 9.4 min (6.9, 13.6) at 6 months. CONCLUSIONS: Electronic symptom monitoring among HD participants with feedback to clinicians is feasible. Variations in response and retention rates could be potentially explained by the lengthier questionnaire, and higher frequency of data collection time points for participants in the intervention arm. A definitive national RCT is underway. TRIAL REGISTRATION: ACTRN12618001976279 (07/12/2018).

Leptomeningeal neuraxis relapse in glioblastoma is an uncommon but not rare event associated with poor outcome.

BACKGROUND: Spinal neuraxis leptomeningeal metastasis (LM) relapse in glioblastoma is an uncommon event that is challenging to manage. This study aims to determine the incidence, associated factors, and outcome of LM relapse in patients with glioblastoma managed with radical intent. METHODS: Patients managed for glioblastoma using the EORTC-NCIC (Stupp) Protocol from 2007 to 2019 were entered into a prospective ethics-approved database. Follow-up included routine cranial MRI surveillance with further imaging as clinically indicated. LM relapse was determined by MRI findings and/or cerebrospinal fluid analysis. The chi-square test of independence was used to evaluate clinico-pathologic factors associated with increased risk of subsequent LM relapse. Median survival post-LM relapse was calculated using Kaplan-Meier technique. RESULTS: Four-hundred-and-seven patients were eligible, with median follow-up of 60 months for surviving patients. Eleven (2.7%) had LM at first relapse and in total 21 (5.1%) experienced LM in the entire follow-up period. Sites of LM relapse were 8 (38%) focal spinal, 2 (10%) focal brainstem medulla and 11 (52%) diffuse spinal. Median overall survival from initial diagnosis for the entire cohort was 17.6 months (95% CI 16.7-19.0). Median survival from LM relapse to death was 39 days (95% CI: 19-107). Factors associated with LM relapse were age less than 50 years (p < 0.01), initial disease located in the temporal lobe (p < 0.01) and tumours lacking MGMT promoter methylation (p < 0.01). CONCLUSIONS: LM relapse is an uncommon but not rare event in patients managed radically for glioblastoma. It is associated with poor outcome with the majority of patients deceased within two months of recognition.

Second chance: The paradox of felony convictions.

Every year, hundreds of thousands of individuals with felony convictions are released into the community with the expectation that those reentering society will be "successful" upon reentry. Society tells persons with criminal backgrounds they have a "second chance" upon release, yet we are reluctant to provide the resources necessary to make this happen. Stigma is frequently identified as a potential obstacle to reentry (DeFina & Hannon, 2009; Shivy et al., 2007); however, research examining stigma surrounding conviction and obstacles to employment for felony convictions is lacking. Interviews with 14 men with felonies were examined to identify how the stigma associated with felony convictions has affected their perceived choice of employment options, including the potential barriers they experience to employment. Participants reported postconviction obstacles, specifically employment/job-related obstacles. They discussed experiencing stigma related to their felony convictions and described strategies employed to mitigate that stigma. Participants' work history involved largely manual labor work, and they discussed having work aspirations despite their felony convictions. Implications for counseling, future research, and limitations are discussed. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Decision Regret and Bother With the Addition of Androgen Deprivation Therapy to Definitive Radiation Treatment for Localized Prostate Cancer.

PURPOSE: Androgen deprivation therapy (ADT) combined with radiation treatment (RT) is recommended by the National Comprehensive Cancer Network guidelines for unfavorable intermediate and high-risk localized prostate cancer. Although there is a variable survival benefit conferred by ADT, there are potential side effects to consider for patient decision-making. We aimed to assess the side effects and bother of adding ADT to RT, the degree of regret, and what overall survival (OS) benefit men would want to justify adding or extending the duration of ADT, after their experience with this treatment. METHODS AND MATERIALS: Men receiving ADT with definitive RT completed a questionnaire asking about the side effects and degree of bother from ADT using a 4-point scale. They were also asked about regret, and what survival benefit would warrant ADT. RESULTS: In the study, 846 patients received definitive RT, of whom 356 received ADT and were asked about their experience with ADT. Of these, 234 responded (66%). In 54%, ADT caused some bother, most commonly hot flushes (32%), fatigue (29%), and sexual problems (29%). Five percent regretted receiving ADT "quite a lot" or "very much." Approximately one-third of men deemed a 1% OS benefit from ADT worthwhile, whereas one-third (34%) would want a >10% OS benefit enough to justify choosing ADT again. In addition, 49% of patients who received short-term ADT would accept longer duration ADT for a 6% OS benefit. CONCLUSIONS: Significant regret for ADT was low (5%). There was a clear dichotomy between those who deemed any OS benefit from ADT worthwhile versus those who needed a significant survival benefit to justify the side effects. Given that some men may change their opinion on the relative value of ADT after experiencing its effects, this study emphasizes the importance of revisiting patients after 6 months to given patients an opportunity to renegotiate their treatment.

Breaking Bias: The Role of Artificial Intelligence in Improving Clinical Decision-Making.

This case report reflects on a delayed diagnosis for a 27-year-old woman who reported chest pain and shortness of breath to the emergency department. The treating clinician reflects upon how cognitive biases influenced their diagnostic process and how multiple missed opportunities resulted in missteps. Using artificial intelligence (AI) tools for clinical decision-making, we suggest how AI could augment the clinician, and in this case, delayed diagnosis avoided. Incorporating AI tools into clinical decision-making brings potential benefits, including improved diagnostic accuracy and addressing human factors contributing to medical errors. For example, they may support a real-time interpretation of medical imaging and assist clinicians in generating a differential diagnosis in ensuring that critical diagnoses are considered. However, it is vital to be aware of the potential pitfalls associated with the use of AI, such as automation bias, input data quality issues, limited clinician training in interpreting AI methods, and the legal and ethical considerations associated with their use. The report draws attention to the utility of AI clinical decision-support tools in overcoming human cognitive biases. It also emphasizes the importance of clinicians developing skills needed to steward the adoption of AI tools in healthcare and serve as patient advocates, ensuring safe and effective use of health data.

Electrocardiogram-based biometrics for user identification - Using your heartbeat as a digital key.

External biometrics such as thumbprint and facial recognition have become standard tools for securing our digital devices and protecting our data. These systems, however, are potentially prone to copying and cybercrime access. Researchers have therefore explored internal biometrics, such as the electrical patterns within an electrocardiogram (ECG). The heart's electrical signals carry sufficient distinctiveness to allow the ECG to be used as an internal biometric for user authentication and identification. Using the ECG in this way has many potential advantages and limitations. This article reviews the history of ECG biometrics and explores some of the technical and security considerations. It also explores current and future uses of the ECG as an internal biometric.

Lapses in the Person Radar: ADHD Symptoms Predict Difficulty in Interpersonal Distancing.

OBJECTIVE: Across contexts, from social cognition to the COVID-19 pandemic response, individual variation in the regulation of interpersonal distance has typically been viewed as a voluntary choice. Here we examine the frequency of unintentional lapses in interpersonal distancing, and their relationship with childhood ADHD symptoms. METHOD: We administered a novel measure of difficulty with interpersonal distancing across three undergraduate samples (total N = 1,225), in addition to measures of recalled childhood ADHD symptoms, mind wandering, and hyperfocus. RESULTS: Almost all (>97%) participants reported unintentional lapses in maintaining interpersonal distance, with 16% experiencing such lapses frequently. Thirty percent of the variance in these reports was accounted for by attentional traits: Inattentive and hyperactive/impulsive ADHD symptoms jointly predicted difficulties with interpersonal distancing, with the former relationship fully mediated by hyperfocus and spontaneous mind wandering. CONCLUSION: Both inattentive and hyperactive/impulsive ADHD symptoms confer vulnerability to frequent unintentional lapses in interpersonal distancing.

A Prox1 enhancer represses haematopoiesis in the lymphatic vasculature.

Transcriptional enhancer elements are responsible for orchestrating the temporal and spatial control over gene expression that is crucial for programming cell identity during development1-3. Here we describe a novel enhancer element that is important for regulating the expression of Prox1 in lymphatic endothelial cells. This evolutionarily conserved enhancer is bound by key lymphatic transcriptional regulators including GATA2, FOXC2, NFATC1 and PROX1. Genome editing of the enhancer to remove five nucleotides encompassing the GATA2-binding site resulted in perinatal death of homozygous mutant mice due to profound lymphatic vascular defects. Lymphatic endothelial cells in enhancer mutant mice exhibited reduced expression of genes characteristic of lymphatic endothelial cell identity and increased expression of genes characteristic of haemogenic endothelium, and acquired the capacity to generate haematopoietic cells. These data not only reveal a transcriptional enhancer element important for regulating Prox1 expression and lymphatic endothelial cell identity but also demonstrate that the lymphatic endothelium has haemogenic capacity, ordinarily repressed by Prox1.