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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.

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.

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

The sex aetates mundi constituted the defining framework for understanding biblical and salvation history in the Early Christian and Late Antique worlds. The origins of the idea that history can be divided into six epochs, each lasting roughly a thousand years, are commonly attributed to Augustine of Hippo. Although Augustine’s engagement with this notion significantly influenced its later popularity due to the prolific circulation of his works, he was by no means the sole progenitor of this concept. This bipartite study undertakes the first conspectus in English-speaking scholarship to date of the origins and evolution of the sex aetates mundi. Part I of this study traces the early origins of historiographical periodisation in writings from classical and biblical antiquity, taking account in particular of the role of numerology and notions of historical eras that are present in biblical texts. Expressions of the world ages in the writings of the Church Fathers are then traced in detail. Due consideration is afforded to attendant issues that influenced the six ages, including calendrical debates concerning the age of the world and the evolution of eschatological, apocalyptic, and millenarian thought. Overall, this article surveys the myriad intellectual and exegetical currents that converged in Early Christianity and Late Antiquity to create this sixfold historiographical and theological framework. The first instalment of this study lays the groundwork for understanding Augustine’s engagement with this motif in his writings, which is treated in Part II.

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 prespecified 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. Published version This study is part of the doctoral research of the lead author (KPF) sponsored by the Federal Government of Nigeria. The study is independent research supported in part by the National Institute for Health Research (NIHR) Applied Research Collaboration Northwest London (NIHR200180).

ObjectivesTo investigate patient follow-up data from Heartwatch: Ireland’s secondary prevention programme for cardiovascular disease delivered in general practice.DesignRetrospective descriptive study based on secondary analysis of routinely collected data from Heartwatch.SettingHeartwatch targeted 20% of general practices in Ireland and recruited 475 general practitioners across 325 practices.ParticipantsThe 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.InterventionsA 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 measuresA 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.ResultsAfter 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.ConclusionsOverall, 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.

Significance Floral morphology is immensely diverse. One developmental process acting to shape this diversity is growth suppression. For example, grass flowers exhibit extreme diversity in floral sexuality, arising through differential suppression of stamens or carpels. The genes regulating this growth suppression and how they have evolved remain largely unknown. We discovered that two classic developmental genes with ancient roles in controlling vegetative branching were recruited to suppress carpel development in maize. Our results highlight the power of forward genetics to reveal unpredictable genetic interactions and hidden pleiotropy of developmental genes. More broadly, our findings illustrate how ancient gene functions are recruited to new developmental contexts in the evolution of plant form., 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.

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%.

Open Access funding provided by the IReL Consortium. In the early medieval period, history was commonly organised into six epochs lasting roughly one thousand years each, according to certain calculations of the world’s age. The idea of the six ages emerged from and was consolidated by allegorical interpretations of the Hexameron in which the material endurance of the world was thought to mirror the initial length of its Creation. This historical schematisation enjoyed widespread currency in Anglo-Saxon England, even after Bede had proved that the world was not, in fact, approaching 6,000 years. This article analyses how the topos of the six ages is used and adapted within a hitherto understudied group of related encyclopaedic notes in three Anglo-Saxon manuscripts. How these texts relate to and differ from the wider corpus of encyclopaedic texts on this subject is also charted. The following study investigates the ways in which encyclopaedic texts on the six ages were adapted, expanded and transmitted, and the religious and political motivations driving such changes. This article offers the first in-depth analysis of this particular group of texts, foregrounding the sophistication of micro-texts that explain the six ages. Overall, this study emphasises the pedagogical, theological and historiographical applications of this concept in early medieval English thought. Publisher PDF

In previous work of the first and third authors, we proposed a conjecture that the Kauffman bracket skein module of any knot in $S^3$ carries a natural action of the rank 1 double affine Hecke algebra $SH_{q,t_1, t_2}$ depending on 3 parameters $q, t_1, t_2$. As a consequence, for a knot $K$ satisfying this conjecture, we defined a three-variable polynomial invariant $J^K_n(q,t_1,t_2)$ generalizing the classical colored Jones polynomials $J^K_n(q)$. In this paper, we give explicit formulas and provide a quantum group interpretation for the generalized Jones polynomials $J^K_n(q,t_1,t_2)$. Our formulas generalize the so-called cyclotomic expansion of the classical Jones polynomials constructed by K.\ Habiro: as in the classical case, they imply the integrality of $J^K_n(q,t_1,t_2)$ and, in fact, make sense for an arbitrary knot $K$ independent of whether or not it satisfies our earlier conjecture. When one of the Hecke deformation parameters is set to be 1, we show that the coefficients of the (generalized) cyclotomic expansion of $J^K_n(q,t_1)$ are determined by Macdonald orthogonal polynomials of type $A_1$., Comment: 23 pages, minor corrections in v2

General practice has a key role in diagnosing patients with valvular heart disease (VHD) and referring them to appropriate services.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.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.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.

BACKGROUND Digital health technologies (DHTs) generate a large volume of information used in health care for administrative, educational, research, and clinical purposes. The clinical use of digital information for diagnostic, therapeutic, and prognostic purposes has multiple patient safety problems, some of which result from poor information quality (IQ). OBJECTIVE This systematic review aims to synthesize an IQ framework that could be used to evaluate the extent to which digital health information is fit for clinical purposes. METHODS The review was conducted according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) guidelines. We searched Embase, MEDLINE, PubMed, CINAHL, Maternity and Infant Care, PsycINFO, Global Health, ProQuest Dissertations and Theses Global, Scopus, and HMIC (the Health Management Information Consortium) from inception until October 2019. Multidimensional IQ frameworks for assessing DHTs used in the clinical context by health care professionals were included. A thematic synthesis approach was used to synthesize the Clinical Information Quality (CLIQ) framework for digital health. RESULTS We identified 10 existing IQ frameworks from which we developed the CLIQ framework for digital health with 13 unique dimensions: accessibility, completeness, portability, security, timeliness, accuracy, interpretability, plausibility, provenance, relevance, conformance, consistency, and maintainability, which were categorized into 3 meaningful categories: availability, informativeness, and usability. CONCLUSIONS This systematic review highlights the importance of the IQ of DHTs and its relevance to patient safety. The CLIQ framework for digital health will be useful in evaluating and conceptualizing IQ issues associated with digital health, thus forestalling potential patient safety problems. CLINICALTRIAL PROSPERO International Prospective Register of Systematic Reviews CRD42018097142; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=97142 INTERNATIONAL REGISTERED REPORT RR2-10.1136/bmjopen-2018-024722

Adaptive optics (AO) is a technology that optical designers are looking to more and more. AO can look like a magical solution: A completely blurred image can be restored to diffraction limited quality. In the beginning, this technology was developed for astronomical telescopes. It was soon transferred to vision science, and it is quickly becoming an essential technique in optical microscopy to compensate for specimen-induced optical aberrations to acquire high resolution images.

The nematode Caenorhabditis elegans has retained a rudimentary Hedgehog (Hh) signalling pathway; Hh and Smoothened (Smo) homologs are absent, but two highly related Patched gene homologs, ptc-1 and ptc-3, and 24 ptc-related (ptr) genes are present. We previously showed that ptc-1 is essential for germ line cytokinesis. Here, we report that ptc-3 is also an essential gene; the absence of ptc-3 results in a late embryonic lethality due to an apparent defect in osmoregulation. Rescue of a ptc-3 mutant with a ptc-3::gfp translational reporter reveals that ptc-3 is dynamically expressed in multiple tissues across development. Consistent with this pattern of expression, ptc-3(RNAi) reveals an additional postembryonic requirement for ptc-3 activity. Tissue-specific promoter studies indicate that hypodermal expression of ptc-3 is required for normal development. Missense changes in key residues of the sterol sensing domain (SSD) and the permease transporter domain GxxxD/E motif reveal that the transporter domain is essential for PTC-3 activity, whereas an intact SSD is dispensable. Taken together, our studies indicate that PTC proteins have retained essential roles in C. elegans that are independent of Smoothened (Smo). These observations reveal novel, and perhaps ancestral, roles for PTC proteins., Research Highlights ► C. elegans lacks conventional Hedgehog signalling, yet ptc-3 is an essential gene. ► Deletion of ptc-3 causes a lethal defect in osmoregulation. ► ptc-3 epidermal expression is necessary and sufficient for viability. ► An intact sterol sensing domain is dispensable for ptc-3 activity. ► Missense mutations highlight the importance of the ptc-3 transporter domain.

In recent years, increasing emphasis has been placed on quantitative characterization of drug metabolites for better insight into the correlation between metabolite exposure and toxicological observations or pharmacological efficacy. One common strategy for metabolite quantitation is to adopt the stable isotope labeled (STIL) parent drug as the internal standard in an isotope dilution liquid chromatography–tandem mass spectrometry (LC–MS/MS) assay. In the current work, we demonstrate this strategy could have a potential pitfall resulting in quantitation bias if the internal standard is subject to ion suppression from the co-eluting parent drug in the incurred samples. Propranolol and its metabolite 4-hydroxypropranolol were used as model compounds to demonstrate this phenomenon and to systematically evaluate different approaches to mitigate the issue, including atmospheric pressure chemical ionization (APCI) mode of ionization, increased internal standard concentration, quantitation without internal standard, the use of a structural analog as internal standard, and dilution of the samples. Case studies of metabolite quantitation in nonclinical and clinical studies in drug development were also included to demonstrate the importance of using an appropriate bioanalytical strategy for metabolite quantitation in the real world. We present that bias of metabolite concentrations could pose a potential for poor estimation of safety risk. A strategy for quantitation of metabolites in support of drug safety assessment is proposed.

Background Complications of ERCP are an important concern. We sought to determine predictors of post-ERCP complications at our institution. Methods GI TRAC is a comprehensive data set of patients who underwent ERCP at our institution from 1994 through 2006. Logistic regression models were used to evaluate 4 categories of complications: (1) overall complications, (2) pancreatitis, (3) bleeding, and (4) severe or fatal complications. Independent predictors of complications were determined with multivariable logistic regression. Results A total of 11,497 ERCP procedures were analyzed. There were 462 complications (4.0%), 42 of which were severe (0.36%) and 7 were fatal (0.06%). Specific complications of pancreatitis (2.6%) and bleeding (0.3%) were identified. Overall complications were statistically more likely among individuals with suspected sphincter of Oddi dysfunction (SOD) (odds ratio [OR] 1.91) and after a biliary sphincterotomy (OR 1.32). Subjects with a history of acute or chronic pancreatitis (OR 0.78) or who received a temporary small-caliber pancreatic stent (OR 0.69) had fewer complications. Post-ERCP pancreatitis was more likely to occur after a pancreatogram via the major papilla (OR 1.70) or minor papilla (OR 1.54) and among subjects with suspected SOD with stent placement (OR 1.45) or without stent placement (OR 1.84). Individuals undergoing biliary-stent exchange had less-frequent pancreatitis (OR 0.38). Biliary sphincterotomy was associated with bleeding (OR 4.71). Severe or fatal complications were associated with severe (OR 2.38) and incapacitating (OR 7.65) systemic disease, obesity (OR 5.18), known or suspected bile-duct stones (OR 4.08), pancreatic manometry (OR 3.57), and complex (grade 3) procedures (OR 2.86). Conclusions This study characterizes a large series of ERCP procedures from a single institution and outlines the incidence and predictors of complications.