Survival paradox between stage IIB/C and stage IIIA colon cancer: is it time to revise the American Joint Committee on Cancer TNM system?

INTRODUCTION: A survival paradox between T4N0 (Stage IIB/IIC) and Stage IIIA colon cancer exists, even after adjusting for adequate lymph node (LN) retrieval and receipt of adjuvant chemotherapy (C). We conducted a large hospital-based study to re-evaluate this survival paradox based on the newest 8th edition staging system. METHODS: The National Cancer Data Base was queried to evaluate 35,606 patients diagnosed with Stage IIB, IIC, and IIIA colon cancer between 2010 and 2017. The Kaplan-Meier method and log-rank test were used to compare unadjusted overall survival (OS). Multivariable Cox proportional hazards model was used to determine the association of stage with hazard ratios adjusted for relevant demographic and clinical variables including ≥ 12 LNs retrieved and receipt of adjuvant chemotherapy. P value < 0.05 was considered statistically significant. RESULTS: The 5-year OS for optimally treated stage IIIA colon cancer (receipt of C) was 84.3%, which was significantly higher than stage IIB/C (≥ 12 LNs retrieved + C) (72.8%; P < 0.0001). Stage was an independent predictor of OS. Among optimally treated Stage IIIA patients, T1N1 had the best survival (90.6%) while stage T4bN0 (stage IIC) had the worst (70.9%) (P < 0.0001). Compared to stage IIB, stage IIC had a 17% increased risk of overall death while stage IIIA had a 21% reduction in death (P < 0.0001). CONCLUSION: Stage IIB/C and Stage IIIA survival paradox persists even after accounting for receipt of adjuvant chemotherapy and adequate lymph node retrieval. Future iteration of the TNM system should take this paradox into consideration.

Dominance hierarchy regulates social behavior during spatial movement.

Rodents establish dominance hierarchy as a social ranking system in which one subject acts as dominant over all the other subordinate individuals. Dominance hierarchy regulates food access and mating opportunities, but little is known about its significance in other social behaviors, for instance during collective navigation for foraging or migration. Here, we implemented a simplified goal-directed spatial task in mice, in which animals navigated individually or collectively with their littermates foraging for food. We compared between conditions and found that the social condition exerts significant influence on individual displacement patterns, even when efficient navigation rules leading to reward had been previously learned. Thus, movement patterns and consequent task performance were strongly dependent on contingent social interactions arising during collective displacement, yet their influence on individual behavior was determined by dominance hierarchy. Dominant animals did not behave as leaders during collective displacement; conversely, they were most sensitive to the social environment adjusting their performance accordingly. Social ranking in turn was associated with specific spontaneous neural activity patterns in the prefrontal cortex and hippocampus, with dominant mice showing higher firing rates, larger ripple oscillations, and stronger neuronal entrainment by ripples than subordinate animals. Moreover, dominant animals selectively increased their cortical spiking activity during collective movement, while subordinate mice did not modify their firing rates, consistent with dominant animals being more sensitive to the social context. These results suggest that dominance hierarchy influences behavioral performance during contingent social interactions, likely supported by the coordinated activity in the hippocampal-prefrontal circuit.

GRASSY TILLERS1 (GT1) and SIX-ROWED SPIKE1 (VRS1) homologs share conserved roles in growth repression.

Crop engineering and de novo domestication using gene editing are new frontiers in agriculture. However, outside of well-studied crops and model systems, prioritizing engineering targets remains challenging. Evolution can guide us, revealing genes with deeply conserved roles that have repeatedly been selected in the evolution of plant form. Homologs of the transcription factor genes GRASSY TILLERS1 (GT1) and SIX-ROWED SPIKE1 (VRS1) have repeatedly been targets of selection in domestication and evolution, where they repress growth in many developmental contexts. This suggests a conserved role for these genes in regulating growth repression. To test this, we determined the roles of GT1 and VRS1 homologs in maize (Zea mays) and the distantly related grass brachypodium (Brachypodium distachyon) using gene editing and mutant analysis. In maize, gt1; vrs1-like1 (vrl1) mutants have derepressed growth of floral organs. In addition, gt1; vrl1 mutants bore more ears and more branches, indicating broad roles in growth repression. In brachypodium, Bdgt1; Bdvrl1 mutants have more branches, spikelets, and flowers than wild-type plants, indicating conserved roles for GT1 and VRS1 homologs in growth suppression over ca. 59 My of grass evolution. Importantly, many of these traits influence crop productivity. Notably, maize GT1 can suppress growth in arabidopsis (Arabidopsis thaliana) floral organs, despite ca. 160 My of evolution separating the grasses and arabidopsis. Thus, GT1 and VRS1 maintain their potency as growth regulators across vast timescales and in distinct developmental contexts. This work highlights the power of evolution to inform gene editing in crop improvement.

Rural versus urban commuting patients with stage III colon cancer: is there a difference in treatment and outcome?

BACKGROUND: To evaluate if there are differences in outcomes for patients with stage III colon cancer in those from urban vs. rural commuting areas. METHODS: Data were evaluated on patients diagnosed with stage III colon cancer between 2012 and2018 from the Louisiana Tumor Registry. Patients were classified into rural and urban groups. Data on overall survival, time from diagnosis to surgery and time from surgery to chemotherapy, and sociodemographic factors (including race, age, and poverty level) were recorded. RESULTS: Of 2652 patients identified, 2159 were urban (81.4%) and 493 rural (18.6%). No age difference between rural and urban patients (p = 0.56). Stage IIIB accounted for 66.7%, followed by IIIC (21.6%) and IIIA (11%), with a significant difference between rural and urban patients based on stage (p = 0.02). There was no difference in the extent of surgery (p = 0.34) or tumor size (p = 0.72) between urban and rural settings. No difference in undergoing chemotherapy (p = 0.12). There was a statistically significant difference in receiving timely treatment for hospital volume (p < 0.0001) and poverty level (p < 0.0001), but no difference in time from diagnosis to surgery (p = 0.48), and time from surgery to chemotherapy (p = 0.27). Non-Hispanic Blacks were less likely to receive timely treatment when compared with non-Hispanic Whites for both surgery and adjuvant chemotherapy, (aHR 0.91, 95% CI 0.83-0.99) and (aHR 0.86, 95% CI 0.77-0.97), respectively. There was no difference in Kaplan-Meier overall survival curves comparing rural vs. urban patients (p = 0.77). CONCLUSIONS: There was no statistical difference in overall survival, time to surgery, and time to adjuvant chemotherapy between rural and urban patients with Stage III colon cancer.

Heart failure virtual consultation: caters for frailer, multimorbid and remote patients.

BACKGROUND: The heart failure (HF) virtual consultation (VC) is an eHealth tool for delivery of peer-to-peer specialist advice to general practitioners (GPs) to discuss HF diagnosis/management. We aim to investigate the impact of the VC service on onward referral rate and quality of assessment by GPs, as well as assess VC patient characteristics; Clinical Frailty Score (CSF), age and morbidity. METHODS: This prospective observational study collected VC data on: demographics, comorbidity, frailty, referral indication, the impact of VC on clinical care and the GP response to the question 'what would you have done without the VC service'. We compared patient characteristics to a control population of patients attending the HF unit (HFU) (n=118). REULTS: Between 2015 and 2021, 1681 VC cases were discussed. The majority of cases were discussed from remote areas (75%). Rediscussion cases increased from 0% to 34%. VC patients were older (76.2 (±11.3) vs 73.1 (±12.5) years, p<0.05), more frail (CSF=3.8 (±1.7) vs 3 (±1.6), p<0.01) and multimorbid (number of comorbidities=7.1 (±3.4) vs 3.8 (±1.9), p<0.001) compared with patients attending the HFU. Without the VC, 93% of cases would have been referred to face-to-face hospital services. Instead, VC resulted in only 9% of cases being referred to hospital services. The remainder of cases were managed by the VC service, in a shared GP-specialist approach. GP use of natriuretic peptide (NP) increased from 0% in 2015-2016 to 63% in 2021 and use of TTE increased from 0% in 2015-2016 to 69% by 2021. CONCLUSIONS: The VC service provides a platform for case discussion in particular for older, frailer patients and reduces onward hospital referrals. This may facilitate early diagnosis and management of suspected HF in the current era of long outpatient waiting times. The quality of community HF assessment improved as indicated by increased use of NP/TTE by GPs.

Use of the psychomotor vigilance test to aid in the selection of risk controls in an air medical transport operation.

Study Objectives: This study evaluated the utility and ecological validity of the 3-minute psychomotor vigilance test (PVT) completed by safety-critical personnel in an air medical transport operation as part of a fatigue risk management program. Methods: Crewmembers in an air medical transport operation self-administered an alertness assessment incorporating a 3-minute PVT at different time points during their duty schedule. The prevalence of alertness deficits was evaluated based on a failure threshold of 12 errors considering both lapses and false starts. To evaluate the ecological validity of the PVT, the relative frequency of failed assessments was evaluated relative to crewmember position, timing of the assessment within the duty schedule, time of day, and sleep quantity in the last 24 h. Results: 2.1% of assessments were associated with a failing PVT score. Crewmember position, timing of assessment within the duty shift, time of day, and sleep quantity in the last 24 h were found to affect the relative frequency of failed assessments. Obtaining less than 7-9 h of sleep was associated with systematic increases in the failure rate (F[1, 54 612] = 168.1, p < .001). Obtaining less than 4 h of sleep was associated with a frequency of a failed assessment 2.99 times higher than the frequency of a failed assessment when obtaining 7-9 h of sleep. Conclusions: Results provide evidence for the utility and ecological validity of the PVT as well as the suitability of the PVT failure threshold to support fatigue risk management in safety-critical operations.

Navigating the uncertainty of precision cancer screening: The role of shared decision-making.

Objective: Describe how applying a shared decision making (SDM) lens to the implementation of new technologies can improve patient-centeredness. Methods: This paper argues that the emergence of polygenic risk scores (PRS) for cancer screening presents an illustrative opportunity to include SDM when novel technologies enter clinical care. Results: PRS are novel tools that indicate an individual's genetic risk of a given disease relative to the population. PRS are anticipated to help identify individuals most and least likely to benefit from screening. However, PRS have several types of uncertainty, including validity across populations, disparate computational methods, and inclusion of different genomic data across laboratories. Conclusion: Implementing SDM alongside new technologies could prove useful for their ethical and patient-centered utilization. SDM's importance as an approach to decision-making will not diminish, as evidence, uncertainty, and patient values will remain intrinsic to the art and science of clinical care. Innovation: SDM can help providers and patients navigate the considerable uncertainty inherent in implementing new technologies, enabling decision-making based on existing evidence and patient values.

Effect of Sacubitril/Valsartan vs Valsartan on Left Atrial Volume in Patients With Pre-Heart Failure With Preserved Ejection Fraction: The PARABLE Randomized Clinical Trial.

Importance: Pre-heart failure with preserved ejection fraction (pre-HFpEF) is common and has no specific therapy aside from cardiovascular risk factor management. Objective: To investigate the hypothesis that sacubitril/valsartan vs valsartan would reduce left atrial volume index using volumetric cardiac magnetic resonance imaging in patients with pre-HFpEF. Design, Setting, and Participants: The Personalized Prospective Comparison of ARNI [angiotensin receptor/neprilysin inhibitor] With ARB [angiotensin-receptor blocker] in Patients With Natriuretic Peptide Elevation (PARABLE) trial was a prospective, double-blind, double-dummy, randomized clinical trial carried out over 18 months between April 2015 and June 2021. The study was conducted at a single outpatient cardiology center in Dublin, Ireland. Of 1460 patients in the STOP-HF program or outpatient cardiology clinics, 461 met initial criteria and were approached for inclusion. Of these, 323 were screened and 250 asymptomatic patients 40 years and older with hypertension or diabetes, elevated B-type natriuretic peptide (BNP) greater than 20 pg/mL or N-terminal pro-b-type natriuretic peptide greater than 100 pg/mL, left atrial volume index greater than 28 mL/m2, and preserved ejection fraction greater than 50% were included. Interventions: Patients were randomized to angiotensin receptor neprilysin inhibitor sacubitril/valsartan titrated to 200 mg twice daily or matching angiotensin receptor blocker valsartan titrated to 160 mg twice daily. Main Outcomes and Measures: Maximal left atrial volume index and left ventricular end diastolic volume index, ambulatory pulse pressure, N-terminal pro-BNP, and adverse cardiovascular events. Results: Among the 250 participants in this study, the median (IQR) age was 72.0 (68.0-77.0) years; 154 participants (61.6%) were men and 96 (38.4%) were women. Most (n = 245 [98.0%]) had hypertension and 60 (24.0%) had type 2 diabetes. Maximal left atrial volume index was increased in patients assigned to receive sacubitril/valsartan (6.9 mL/m2; 95% CI, 0.0 to 13.7) vs valsartan (0.7 mL/m2; 95% CI, -6.3 to 7.7; P < .001) despite reduced markers of filling pressure in both groups. Changes in pulse pressure and N-terminal pro-BNP were lower in the sacubitril/valsartan group (-4.2 mm Hg; 95% CI, -7.2 to -1.21 and -17.7%; 95% CI, -36.9 to 7.4, respectively; P < .001) than the valsartan group (-1.2 mm Hg; 95% CI, -4.1 to 1.7 and 9.4%; 95% CI, -15.6 to 4.9, respectively; P < .001). Major adverse cardiovascular events occurred in 6 patients (4.9%) assigned to sacubitril/valsartan and 17 (13.3%) assigned to receive valsartan (adjusted hazard ratio, 0.38; 95% CI, 0.17 to 0.89; adjusted P = .04). Conclusions and Relevance: In this trial of patients with pre-HFpEF, sacubitril/valsartan treatment was associated with a greater increase in left atrial volume index and improved markers of cardiovascular risk compared to valsartan. More work is needed to understand the observed increased cardiac volumes and long-term effects of sacubitril/valsartan in patients with pre-HFpEF. Trial Registration: ClinicalTrials.gov Identifier: NCT04687111.

Heartwatch: an Irish cardiovascular secondary prevention programme in primary care, a secondary analysis of patient outcomes.

OBJECTIVES: To investigate patient follow-up data from Heartwatch: Ireland's secondary prevention programme for cardiovascular disease delivered in general practice. DESIGN: Retrospective descriptive study based on secondary analysis of routinely collected data from Heartwatch. SETTING: Heartwatch targeted 20% of general practices in Ireland and recruited 475 general practitioners across 325 practices. PARTICIPANTS: The patient population included people with a history of acute myocardial infarction, percutaneous transluminal coronary angioplasty or a coronary artery bypass graft. Over 16 000 patients entered the programme however, to assess the long-term progress of patients, we identified a cohort of 5700 patients with at least 8 years in the programme. INTERVENTIONS: A standard protocol for continuing care of patients for the secondary prevention of cardiovascular disease was administered by general practices. The programme was designed using WHO and European Society of Cardiology guidelines on secondary prevention. OUTCOME MEASURES: A Continuing Care (CCare) score out of eight was the primary outcome measure used. It was calculated based on programme targets for well-known cardiovascular risk factors: exercise, systolic blood pressure, LDL cholesterol, optimally controlled glucose, smoking status, and pharmacological treatment. RESULTS: After 1 year, 37% of the 8-year cohort had achieved a CCare score >5 increasing to 44% after year 8. Patient sex was predictive of better scores; male patients had almost a half-point advantage (0.432, 99% CI: 0.335 to 0.509). Patients who enrolled earlier following their qualifying event and patients with more frequent visits were also more likely to achieve higher CCare scores. CONCLUSIONS: Overall, patients are not likely to meet all targets set by secondary prevention guidelines, however, supporting patient self-management may impact on this. Early enrolment after a cardiac event and frequent structured care visits should be priorities in the design and implementation of similar programmes. Ongoing evaluation of them is necessary to improve outcomes.

Assessment of Clinical Information Quality in Digital Health Technologies: International eDelphi Study.

BACKGROUND: Digital health technologies (DHTs), such as electronic health records and prescribing systems, are transforming health care delivery around the world. The quality of information in DHTs is key to the quality and safety of care. We developed a novel clinical information quality (CLIQ) framework to assess the quality of clinical information in DHTs. OBJECTIVE: This study explored clinicians' perspectives on the relevance, definition, and assessment of information quality dimensions in the CLIQ framework. METHODS: We used a systematic and iterative eDelphi approach to engage clinicians who had information governance roles or personal interest in information governance; the clinicians were recruited through purposive and snowball sampling techniques. Data were collected using semistructured online questionnaires until consensus was reached on the information quality dimensions in the CLIQ framework. Responses on the relevance of the dimensions were summarized to inform decisions on retention of the dimensions according to prespecified rules. Thematic analysis of the free-text responses was used to revise definitions and the assessment of dimensions. RESULTS: Thirty-five clinicians from 10 countries participated in the study, which was concluded after the second round. Consensus was reached on all dimensions and categories in the CLIQ framework: informativeness (accuracy, completeness, interpretability, plausibility, provenance, and relevance), availability (accessibility, portability, security, and timeliness), and usability (conformance, consistency, and maintainability). A new dimension, searchability, was introduced in the availability category to account for the ease of finding needed information in the DHTs. Certain dimensions were renamed, and some definitions were rephrased to improve clarity. CONCLUSIONS: The CLIQ framework reached a high expert consensus and clarity of language relating to the information quality dimensions. The framework can be used by health care managers and institutions as a pragmatic tool for identifying and forestalling information quality problems that could compromise patient safety and quality of care. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): RR2-10.1136/bmjopen-2021-057430.

Public perceptions of pharmacogenomic services in Ireland - Are people with chronic disease more likely to want service availability than those without? A questionnaire study.

Background: As pharmacogenomic services begin to emerge in primary care, the insight of the public is crucial for its integration into clinical practice. Objectives: To establish perceptions of pharmacogenomics (awareness, understanding, openness to availability, perceived benefits and concerns, willingness to pay, and service setting) and investigate if they differ between those with and without chronic disease(s). Methods: An anonymous, online questionnaire generated using Qualtrics® and circulated via social media and posters placed in eight participating community pharmacies was conducted with Irish adults. The questions were designed to consider existing literature on patient perceptions of pharmacogenomics. Descriptive statistics were used to summarize questionnaire responses. Chi-square test was used to compare categorical variables, while independent sample t-test and one-way ANOVA were used to compare the mean values of two (with and without chronic disease) and three groups (multimorbidity (two or more chronic conditions) and polypharmacy (prescribed four or more regular medicines) (MMPP), a single chronic disease, and those without existing medical conditions) respectively Logistic regression was used to evaluate age and gender adjusted associations of chronic disease(s) with responses. A p-value <0.05 was considered statistically significant. Results: A total of 421 responses were received, 30% (n = 120) of whom reported having a chronic disease. Overall, respondents reported low awareness (44%, n = 166) and poor knowledge (55%, n = 212) of pharmacogenomics. After explaining pharmacogenomics to respondents, patients with chronic disease(s) were 2.17 times more likely (p < 0.001) to want pharmacogenomic services availability than those without existing conditions, adjusted for age and gender (driven by preferences of those with MMPP than those with single chronic disease). Respondents demonstrated a high level of interest and noted both the potential benefits and downsides of pharmacogenomic testing. Willingness-to-pay was not associated with having a chronic disease and respondents were more positive about primary care (community pharmacy or general practice) rather than hospital-based pharmacogenomics implementation. Conclusion: The Irish public in general and those with chronic disease in particular are strongly supportive of pharmacogenomic testing, highlighting an unmet need for its incorporation in medicines optimization. These data underline the need for more research on the implementation of community-based pharmacogenomics services for MMPP patients and ubiquitous pharmacogenomics education programs.

A mixed methods study of the awareness and management of familial hypercholesterolaemia in Irish general practice.

Introduction: Familial Hypercholesterolemia (FH) is one of the most common genetic disorders, with an estimated global prevalence of 1:200-500, which leads to premature cardiovascular disease. Nevertheless, public and professional awareness of FH is often lacking, with an estimated 20,000 largely undiagnosed cases in Ireland. Purpose: The overall aim of the project was to test the feasibility of a model of care that would include electronic record screening, clinical assessment, and coding of possible FH patients across a network of general practices in Ireland. In addition, a secondary aim was to gauge the awareness and knowledge of FH across the network. Methods: This study took part in multiple phases, employing a mixed methods design. The study included a validated questionnaire, tailored online educational resources, a retrospective chart review of patients with a history of elevated LDL cholesterol (LDLc) and an active review with a selection of those patients. Results were analyzed using SPSS V27, where descriptive statistics and relevant correlation tests were employed. Results: Eighteen general practices agreed to take part in the study. In the initial survey, respondents rated their personal and practice familiarity with FH as slightly below average. Around one-third of respondents were not aware of FH guidelines. Of over 55,000 adult patient records searched, only 0.2% had a recorded FH diagnosis and 3.9% had ever had an LDLc above 4.9 mmol/l. Eight practices completed 198 chart reviews. Among these, 29.8% of patients had a family history recorded, and 22.2% had a family history of CVD recorded. Female patients had higher averages for highest and recent LDLc. Seventy patients underwent a clinical review-with 27% of these patients identified as "probable" or "definite FH." There was a statistically significant (p = 0.002) relationship between FH status and whether the patient had other CVD risk factors. Conclusion: General practitioners in Ireland had similar levels of awareness of FH compared to findings from elsewhere. The activities discussed encouraged clinicians to consider FH when talking to their patients, especially those with elevated LDLc at an early age. Broader awareness of the condition could increase conversations about FH and benefit patient outcomes.

Engineering nonphotosynthetic carbon fixation for production of bioplastics by methanogenic archaea.

The conversion of CO2 to value-added products allows both capture and recycling of greenhouse gas emissions. While plants and other photosynthetic organisms play a key role in closing the global carbon cycle, their dependence on light to drive carbon fixation can be limiting for industrial chemical synthesis. Methanogenic archaea provide an alternative platform as an autotrophic microbial species capable of non-photosynthetic CO2 fixation, providing a potential route to engineered microbial fermentation to synthesize chemicals from CO2 without the need for light irradiation. One major challenge in this goal is to connect upstream carbon-fixation pathways with downstream biosynthetic pathways, given the distinct differences in metabolism between archaea and typical heterotrophs. We engineered the model methanogen, Methanococcus maripaludis, to divert acetyl-coenzyme A toward biosynthesis of value-added chemicals, including the bioplastic polyhydroxybutyrate (PHB). A number of studies implicated limitations in the redox pool, with NAD(P)(H) pools in M. maripaludis measured to be <15% of that of Escherichia coli, likely since methanogenic archaea utilize F420 and ferredoxins instead. Multiple engineering strategies were used to precisely target and increase the cofactor pool, including heterologous expression of a synthetic nicotinamide salvage pathway as well as an NAD+-dependent formate dehydrogenase from Candida boidinii. Engineered strains of M. maripaludis with improved NADH pools produced up to 171 ± 4 mg/L PHB and 24.0 ± 1.9% of dry cell weight. The metabolic engineering strategies presented in this study broaden the utility of M. maripaludis for sustainable chemical synthesis using CO2 and may be transferable to related archaeal species.

Clinical information quality of digital health technologies: protocol for an international eDelphi study.

INTRODUCTION: Digital health technologies (DHTs) such as electronic health records, clinical decision support systems and electronic prescribing systems are widely used in healthcare. While adoption of DHTs can improve healthcare delivery, information quality (IQ) problems associated with DHTs can compromise quality and safety of care. The clinical information quality (CLIQ) framework for digital health is a novel approach to assessing the quality of clinical information from DHTs. This study aims to appraise the CLIQ framework by exploring clinicians' perspectives on the relevance, definition and assessment of IQ dimensions as defined in the framework. This study will adapt the CLIQ framework to the needs of clinical information users-the clinicians. The contextualised CLIQ framework will offer a pragmatic approach to assessing clinical information from DHTs and may help to forestall IQ problems that can compromise quality and safety of care. METHODS AND ANALYSIS: The electronic Delphi (eDelphi) approach will be used to engage a heterogeneous group of clinicians with patient-facing and/or information governance roles recruited through purposive and snowball sampling techniques. A semi-structured online questionnaire will be used to explore clinicians' perspectives on relevance, definition and assessment of IQ dimensions in the CLIQ framework. Survey responses on the relevance of dimensions will be summarised using descriptive statistics to inform decisions on retention of dimensions and termination of the study, based on pre-specified rules. Analysis of the free-text responses will be used to revise definition and assessment of dimensions. ETHICS AND DISSEMINATION: Ethics approval has been obtained from the Imperial College Research Governance and Integrity Team (Imperial College Research Ethics Committee (ICREC) Reference number: 20IC6396). The results of the study will be published in a peer-reviewed journal and presented at scientific conferences.

Pharmacogenetic interventions to improve outcomes in patients with multimorbidity or prescribed polypharmacy: a systematic review.

Conventional medicines optimisation interventions in people with multimorbidity and polypharmacy are complex and yet limited; a more holistic and integrated approach to healthcare delivery is required. Pharmacogenetics has potential as a component of medicines optimisation. Studies involving multi-medicine pharmacogenetics in adults with multimorbidity or polypharmacy, reporting on outcomes derived from relevant core outcome sets, were included in this systematic review. Narrative synthesis was undertaken to summarise the data; meta-analysis was inappropriate due to study heterogeneity. Fifteen studies of diverse design and variable quality were included. A small, randomised study involving pharmacist-led medicines optimisation, including pharmacogenetics, suggests this approach could have significant benefits for patients and health systems. However, due to study design heterogeneity and the quality of the included studies, it is difficult to draw generalisable conclusions. Further pragmatic, robust pharmacogenetics studies in diverse, real-world patient populations, are required to establish the benefit of multi-medicine pharmacogenetic screening on patient outcomes.

Recruitment of an ancient branching program to suppress carpel development in maize flowers.

Carpels in maize undergo programmed cell death in half of the flowers initiated in ears and in all flowers in tassels. The HD-ZIP I transcription factor gene GRASSY TILLERS1 (GT1) is one of only a few genes known to regulate this process. To identify additional regulators of carpel suppression, we performed a gt1 enhancer screen and found a genetic interaction between gt1 and ramosa3 (ra3). RA3 is a classic inflorescence meristem determinacy gene that encodes a trehalose-6-phosphate (T6P) phosphatase (TPP). Dissection of floral development revealed that ra3 single mutants have partially derepressed carpels, whereas gt1;ra3 double mutants have completely derepressed carpels. Surprisingly, gt1 suppresses ra3 inflorescence branching, revealing a role for gt1 in meristem determinacy. Supporting these genetic interactions, GT1 and RA3 proteins colocalize to carpel nuclei in developing flowers. Global expression profiling revealed common genes misregulated in single and double mutant flowers, as well as in derepressed gt1 axillary meristems. Indeed, we found that ra3 enhances gt1 vegetative branching, similar to the roles for the trehalose pathway and GT1 homologs in the eudicots. This functional conservation over ∼160 million years of evolution reveals ancient roles for GT1-like genes and the trehalose pathway in regulating axillary meristem suppression, later recruited to mediate carpel suppression. Our findings expose hidden pleiotropy of classic maize genes and show how an ancient developmental program was redeployed to sculpt floral form.

A survey of general practitioners' knowledge and clinical practice in relation to valvular heart disease.

INTRODUCTION: General practice has a key role in diagnosing patients with valvular heart disease (VHD) and referring them to appropriate services. METHODS: An anonymous survey was conducted to assess the knowledge and clinical practice behaviour of Irish general practitioners (GPs) in relation to VHD. In addition to demographic data, the survey captured information in the following domains: knowledge of VHD prevalence, knowledge of contemporary VHD treatments, barriers to diagnosis, and referral patterns. To augment responses, a monetary prize (donated to charity) was offered and the survey was also disseminated using social media and by the Irish College of General Practitioners. RESULTS: Valid survey responses were received from 197 GPs. The sample was well-balanced by gender, number of years in practice, and practice setting. A small proportion of GPs (16.8%) used a stethoscope to examine for VHD in all patients over 60 years, a figure that rose to 22.3% in patients over 75. Approximately half of participants (48%) felt confident in their ability to detect and diagnose VHD using a stethoscope, and 74% felt lack of access to echocardiography was a major barrier to making a VHD diagnosis. There was a high level of awareness among GPs of minimally invasive nonsurgical interventions now available for VHD treatment. DISCUSSION: Irish GPs displayed good understanding of contemporary VHD treatment options but reported low confidence and inconsistent practices in evaluating patients for VHD. Improved access to echocardiography might help address these deficiencies, but reorganisation of services will be required in a resource-limited public health service.

Heart Failure diagnosis based on deep learning techniques.

The aim of the study is to address the heart failure (HF) diagnosis with the application of deep learning approaches. Seven deep learning architectures are implemented, where stacked Restricted Boltzman Machines (RBMs) and stacked Autoencoders (AEs) are used to pre-train Deep Belief Networks (DBN) and Deep Neural Networks (DNN). The data is provided by the University College Dublin and the 2nd Department of Cardiology from the University Hospital of Ioannina. The features recorded are grouped into: general demographic information, physical examination, classical cardiovascular risk factors, personal history of cardiovascular disease, symptoms, medications, echocardiographic features, laboratory findings, lifestyle/habits and other diseases. The total number of subjects utilized is 422. The deep learning methods provide quite high results with the Autoencoder plus DNN approach to demonstrate accuracy 91.71%, sensitivity 90.74%, specificity 92.31% and f-score 89.36%.