Search

We propose a rich foundational theory of typed data streams and stream transformers, motivated by two high-level goals. First, the type of a stream should be able to express complex sequential patterns of events over time. And second, it should describe the internal parallel structure of the stream, to support deterministic stream processing on parallel and distributed systems. To these ends, we introduce stream types, with operators capturing sequential composition, parallel composition, and iteration, plus a core calculus λST of transformers over typed streams that naturally supports a number of common streaming idioms, including punctuation, windowing, and parallel partitioning, as first-class constructions. λST exploits a Curry-Howard-like correspondence with an ordered variant of the Logic of Bunched Implication to program with streams compositionally and uses Brzozowski-style derivatives to enable an incremental, prefix-based operational semantics. To illustrate the programming style supported by the rich types of λST, we present a number of examples written in Delta, a prototype high-level language design based on λST.

Coronary artery calcification (CAC) is a measure of atherosclerosis and a well-established predictor of coronary artery disease (CAD) events. Here we describe a genome-wide association study (GWAS) of CAC in 22,400 participants from multiple ancestral groups. We confirmed associations with four known loci and identified two additional loci associated with CAC (ARSE and MMP16), with evidence of significant associations in replication analyses for both novel loci. Functional assays of ARSE and MMP16 in human vascular smooth muscle cells (VSMCs) demonstrate that ARSE is a promoter of VSMC calcification and VSMC phenotype switching from a contractile to a calcifying or osteogenic phenotype. Furthermore, we show that the association of variants near ARSE with reduced CAC is likely explained by reduced ARSE expression with the G allele of enhancer variant rs5982944. Our study highlights ARSE as an important contributor to atherosclerotic vascular calcification, and a potential drug target for vascular calcific disease.

Abstract Background The uptake of research findings into clinical practice is critical to providing health care that improves health outcomes for patients. This study explored how Patient-Centered Outcomes Research Institute (PCORI) awardees perceive the relationship between engagement of patients and other partners in research and three uses, or applications, of patient-centered comparative clinical effectiveness research (CER) study findings, which may lead to uptake in clinical practice: (1) Integration into clinical practice guidelines, recognized point-of-care decision tools, or documents that may inform policy; (2) Implementation beyond the study, including at sites outside of the study setting or patient populations; and (3) Active dissemination of findings to specific audiences by parties external to the study team. Methods This exploratory qualitative study examined awardee and partner perceptions of what led to each use of study findings and how engaged partners contributed. We purposively selected PCORI-funded research projects with documentation of each use and conducted virtual interviews with 42 individuals (15 PIs or project leads, 2 research team members, and 25 partners) from 17 projects. We conducted thematic analysis of individual projects or project sets, across projects within each use case, and across the three uses. Results Participants described three primary activities in which engaged partners made contributions before, during and after CER studies that facilitated the use of study findings: (1) generating relevant study findings, (2) distributing study findings strategically, and (3) making connections to people or organizations outside the study team. In addition, engagement continued to facilitate the use of study findings during subsequent PCORI-funded implementation and dissemination-specific projects, with partners adapting interventions and creating and tailoring dissemination messages and products. Finally, participants described attributes of teams’ engagement approaches that may have supported partner contributions, including early and ongoing engagement, leveraging partners’ connections and understanding of community needs, and using multiple engagement approaches. Conclusion This study identified examples of how engagement can help facilitate the use of CER study findings, especially when engagement contributions occur in meaningful ways. Findings from this study suggest a framework for future research on the relationship between engagement in research and uptake of study findings into clinical practice.

Abstract Whole genome sequences (WGS) enable discovery of rare variants which may contribute to missing heritability of coronary artery disease (CAD). To measure their contribution, we apply the GREML-LDMS-I approach to WGS of 4949 cases and 17,494 controls of European ancestry from the NHLBI TOPMed program. We estimate CAD heritability at 34.3% assuming a prevalence of 8.2%. Ultra-rare (minor allele frequency ≤ 0.1%) variants with low linkage disequilibrium (LD) score contribute ~50% of the heritability. We also investigate CAD heritability enrichment using a diverse set of functional annotations: i) constraint; ii) predicted protein-altering impact; iii) cis-regulatory elements from a cell-specific chromatin atlas of the human coronary; and iv) annotation principal components representing a wide range of functional processes. We observe marked enrichment of CAD heritability for most functional annotations. These results reveal the predominant role of ultra-rare variants in low LD on the heritability of CAD. Moreover, they highlight several functional processes including cell type-specific regulatory mechanisms as key drivers of CAD genetic risk.

Abstract Alpha-synuclein (αSyn) forms pathologic aggregates in Parkinson’s disease (PD) and is implicated in mechanisms underlying neurodegeneration. While pathologic αSyn has been extensively studied, there is currently no method to evaluate αSyn within the brains of living patients. Patients with PD are often treated with deep brain stimulation (DBS) surgery in which surgical instruments are in direct contact with neuronal tissue; herein, we describe a method by which tissue is collected from DBS surgical instruments in PD and essential tremor (ET) patients and demonstrate that αSyn is detected. 24 patients undergoing DBS surgery for PD (17 patients) or ET (7 patients) were enrolled; from patient samples, 81.2 ± 44.8 µg of protein (n = 15), on average, was collected from surgical instruments. Light microscopy revealed axons, capillaries, and blood cells as the primary components of purified tissue (n = 3). ELISA assay further confirmed the presence of neuronal and glial tissue in DBS samples (n = 4). Further analysis was conducted using western blot, demonstrating that multiple αSyn antibodies are reactive in PD (n = 5) and ET (n = 3) samples; truncated αSyn (1–125 αSyn) was significantly increased in PD (n = 5) compared to ET (n = 3), in which αSyn misfolding is not expected (0.64 ± 0.25 vs. 0.25 ± 0.12, P = 0.046), thus showing that multiple forms of αSyn can be detected from living PD patients with this method.

Abstract Background As rates of obesity and overweight continue to increase in the UK, calorie labels have been introduced on menus as a policy option to provide information to consumers on the energy content of foods and to enable informed choices. This study tested whether the addition of calorie labels to items in a simulated food delivery platform may reduce the energy content of items selected. Methods UK adults (n = 8,780) who used food delivery platforms were asked to use the simulated platform as they would in real life to order a meal for themselves. Participants were randomly allocated to a control condition (no calorie labels) or to one of seven intervention groups: (1) large size calorie labels adjacent to the price (LP), (2) large size label adjacent to the product name (LN), (3) small label adjacent to price (SP), (4) small label adjacent to product name (SN), (5) LP with a calorie label switch-off filter (LP + Off), (6) LP with a switch-on filter (LP + On), or, (7) LP with a summary label of the total basket energy content (LP + Sum). Regression analysis assessed the impact of calorie labels on energy content of foods selected compared to the control condition. Results The mean energy selected in the control condition was 1408 kcal (95%CI: 93, 2719). There was a statistically significant reduction in mean energy selected in five of the seven intervention trial arms (LN labels (-60 kcal, 95%CI: -111, -6), SN (-73, 95%CI: -125, -19), LP + Off (-110, 95%CI: -161, -57), LP + On (-109, 95%CI: -159, -57), LP + Sum (-85 kcal, 95%CI: -137, -30). There was no evidence the other two conditions (LP (-33, 95%CI: -88, 24) and SP (-52, 95%CI: -105, 2)) differed from control. There was no evidence of an effect of any intervention when the analysis was restricted to participants who were overweight or obese. Conclusion Adding calorie labels to food items in a simulated online food delivery platform reduced the energy content of foods selected in five out of seven labelling scenarios. This study provides useful information to inform the implementation of these labels in a food delivery platform context.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Abstract Background The rapid start of antiretroviral therapy (RSA) model initiates antiretroviral therapy (ART) as soon as possible after a new or preliminary diagnosis of HIV, in advance of HIV-1 RNA and other baseline laboratory testing. This observational study aims to determine if RSA with a single tablet regimen of bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) is an effective regimen for achieving viral suppression and accepted by patients at the time of diagnosis. Methods Adults newly or preliminarily diagnosed with HIV were enrolled from October 2018 through September 2021. Real world advantage, measured in days between clinical milestones and time to virologic suppression, associated with B/F/TAF RSA was compared to historical controls. Results All Study RSA participants (n = 45) accepted treatment at their first visit and 43(95.6%) achieved virologic suppression by week 48. Study RSA participants had a significantly shorter time (median 32 days) from diagnosis to ART initiation and virologic suppression, in comparison to historical controls (median 181 days) (n = 42). Qualitative feedback from study RSA participants showed high acceptance positive response to RSA. Conclusions RSA is feasible and well accepted by patients in a real-world community-based clinic setting. Promoting RSA in community-based clinics is an important tool in ending the HIV epidemic.

The objective was to explore if the regression of phenotypic performance for six milk production traits on the respective estimate of genetic merit for that trait differed by herd milking frequency; variance components for each trait in the two milking frequency environments were also estimated as well as the genetic correlation between the same trait in both environments. The data used included 12,581 lactations from 5,456 cows in 32 spring-calving once-a-day (OAD) milking herds. Each OAD herd was matched with three contemporary twice-a-day (TAD)-milking herds; 35,823 lactations from 15,188 cows in 96 TAD herds were used. Mean yield was 20% (fat yield) to 31% (milk yield) lower in OAD herds. Milk protein concentration was 11% higher in OAD herds, while milk fat concentration was 16% higher in OAD herds. The mean back-transformed somatic cell score (SCS) was 100,390 cells/mL in OAD herds and 72,493 cells/mL in TAD herds. The association between each milk production trait and its respective estimate of genetic merit differed by herd milking frequency; the estimated regression coefficients were larger in TAD for just milk yield and SCS. The genetic correlation between the same trait in OAD versus TAD was all ≥0.73 with the exception of SCS (genetic correlation of 0.48) which suggests some re-ranking of sires between environments. In conclusion, differences in the scale of the genetic variance were evident for both milking frequencies and possible re-ranking was evident for SCS.

Selection methods are commonly used in talent acquisition to predict future job performance and to find the best candidates, but questionnaire-based assessments can be lengthy and lead to candidate fatigue and poor engagement, affecting completion rates and producing poor data. Gamification can mitigate some of these issues through greater engagement and shorter testing times. One avenue of gamification is image-based tests. Although such assessments are starting to gain traction in personnel selection, few studies describing their validity and psychometric properties exist. The current study explores the potential of a five-minute, forced-choice, image-based assessment of the Big Five personality traits to be used in selection. Study 1 describes the creation of the image pairs and the selection of the 150 best-performing items based on a sample of 300 respondents. Study 2 describes the creation of machine-learning-based scoring algorithms and tests of their convergent and discriminate validity and adverse impact based on a sample of 431 respondents. All models showed good levels of convergent validity with the IPIP-NEO-120 (openness r = 0.71, conscientiousness r = 0.70, extraversion r = 0.78, agreeableness r = 0.60, and emotional stability r = 0.70) and were largely free from potential adverse impact. The implications for recruitment policy and practice and the need for further validation are discussed.

Long-term follow-up for individuals with hypospadias remains a critical area of need, yet evidence-based guidelines for such follow-up are lacking, and the role of involvement of relevant experts is not yet established. Using our hypospadias-specific health-related quality of life conceptual framework and a subsequent qualitative study of prepubertal males and parents of males with hypospadias, we identified potential priorities for long-term follow-up of youth with hypospadias. Using thematic codes from our patient and parent interviews, we searched PubMed for relevant articles and identified the specialties represented by all the authors of these articles. Our search strategy revealed consistent expertise across HRQOL themes and subthemes, including pediatric and adult urology, health psychology, psychiatry, endocrinology, genetics, and social work. Communication experts, as well as patients and families, were also represented in our literature search. Using these findings, we compiled a comprehensive list of potential stakeholders to inform the development of holistic care guidelines for individuals with hypospadias. By engaging these stakeholders, we aim to develop consensus-based, long-term follow-up guidelines and tools to address the evolving physical and psychosocial needs of people with hypospadias over a lifetime. The use of qualitatively derived thematic codes to search for relevant literature is an accessible approach to identifying relevant stakeholders. These findings underscore the importance of involving diverse, multidisciplinary expertise to ensure comprehensive, patient-centered care in complex genitourinary conditions.

IntroductionBacterial infection and biofilm formation contribute to impaired healing in chronic diabetic wounds. Staphylococcus aureus and Pseudomonas aeruginosa are found in human diabetic wound biofilms. They may develop antibiotic resistance, increasing the urgency for alternative or complementary therapies. Diabetic wound healing may be improved with the use of biomedically engineered scaffolds, which can also serve as delivery systems for antibacterial compounds. Manuka honey is a potent antibacterial and wound care agent due to its high osmolarity, low pH, and constituents (such as methylglyoxal). Honey exhibits bacteriostatic and bactericidal effects, modulates the expression of biofilm forming genes, and restores antibiotic susceptibility in previously drug resistant pathogens.MethodsIn this study, we created a dermal regeneration template (DRT) composed of polycaprolactone-gelatin (PCL-gelatin) and Manuka honey to retain honey in the wound and also provide a scaffold for tissue regeneration.Results and discussionSoluble Manuka honey inhibited the planktonic and biofilm growth of both S. aureus (UWH3) and P. aeruginosa (PA14) co-cultures. Manuka honey embedded PCL-gelatin scaffolds did not exhibit bacteriostatic or bactericidal effects on cocultures of UHW3 and PA14; however, they promoted the expression of AgrA, a gene associated with dispersal of S. aureus biofilms.

Although the intervertebral discs are the most studied region of the spinal motion segment with respect to their degeneration and contributions to back pain, it is becoming increasingly evident that degeneration of adjacent structures including the facet joints, vertebral endplates and paraspinal muscles occurs concomitant with disc degeneration. However, crosstalk between these adjacent components of the motion segment remains understudied, particularly in preclinical large animal models. In this study, intervertebral disc degeneration was induced in goat cervical discs via intradiscal injection of 2U or 5U of chondroitinase ABC (ChABC). Disc degeneration and trans-endplate small molecule diffusion into the disc were assessed at 12 weeks using in vivo MRI T2 mapping and post-contrast enhanced T1 mapping. Animals were euthanized at 12 weeks post-ChABC injection for end-term structure-function analysis of the disc, vertebral endplate and facet tissues. Intradiscal injection of ChABC yielded a spectrum of disc degeneration independent of ChABC dosage. Increasing severity of disc degeneration correlated with increased vertebral endplate bone density. In levels that did not exhibit severe degeneration or endplate resorptions, we demonstrated a significant correlation between NP T2 values and disc diffusion properties. Early-stage osteoarthritis of the facet joints was observed concomitant with disc degeneration, characterized primarily by alterations in facet cartilage mechanical properties. This work established a large animal model of whole spinal motion segment degeneration, including correlations between trans-endplate diffusion and disc health, which can be utilized to increase the translational relevance of studies evaluating strategies for disc regeneration or repair.

This article applies the Community of Inquiry (CoI) framework to a particular disciplinary context: first-year writing (FYW). Students enrolled in online FYW courses across three institutions (n = 272) completed a version of the CoI survey that was slightly modified to fit the disciplinary context of writing studies. A factor analysis was conducted to determine how well the CoI in Writing Studies data aligned with typical CoI survey research; teaching presence and cognitive presence loaded onto single factors, but the social presence items divided into multiple factors. The authors put their findings in conversation with other scholarship about social presence, especially Carlon et al. (2012) and Kreijns et al. (2014), and advocate for differentiating between survey items that relate to "social presence," "social comfort," "attitude," and "social learning." They also recommend that future disciplinary uses of the CoI Survey include survey items that ask students to report on the extent to which they engaged in the types of social learning that the discipline values.

Modern artificial neural networks (ANNs) have long been designed on foundations of mathematics as opposed to their original foundations of biomimicry. However, the structure and function of these modern ANNs are often analogous to real-life biological networks. We propose that the ubiquitous information-theoretic principles underlying the development of ANNs are similar to the principles guiding the macro-evolution of biological networks and that insights gained from one field can be applied to the other. We generate hypotheses on the bow-tie network structure of the Janus kinase - signal transducers and activators of transcription (JAK-STAT) pathway, additionally informed by the evolutionary considerations, and carry out ANN simulation experiments to demonstrate that an increase in the networks input and output complexity does not necessarily require a more complex intermediate layer. This observation should guide novel biomarker discovery-namely, to prioritize sections of the biological networks in which information is most compressed as opposed to biomarkers representing the periphery of the network.

In recent months, the general public has become more cognizant of the potential of oral minoxidil to promote hair growth; this was promulgated, in part, by an article published in the New York Times entitled, "An Old Medicine Grows New Hair for Pennies a Day, Doctors Say." Minoxidil was added to the pharmacologic armamentarium as an antihypertensive nearly 60 years ago and was found to trigger hypertrichosis in many patients, but its use dropped sharply as cardiologists observed a number of adverse cardiovascular events including ischemic heart disease, left ventricular hypertrophy, pleural effusions, and pericardial effusions. Studies in the realm of dermatology have explored the utility and safety of low dose oral minoxidil (LDOM) for management of alopecia. This article highlights potential clinical conundrums posed by these rare but severe cardiovascular complications and the importance of collaboration between cardiologists and dermatologists when employing this agent in patients with cardiorenal or cardiovascular risk factors.

Abstract Background Cadaveric intervertebral discs are often studied for a variety of research questions, and outcomes are interpreted in the in vivo context. Unfortunately, the cadaveric disc does not inherently represent the LIVE condition, such that the disc structure (geometry), composition (T2 relaxation time), and mechanical function (opening pressure, OP) measured in the cadaver do not necessarily represent the in vivo disc. Methods We conducted serial evaluations in the Yucatan minipig of disc geometry, T2 relaxation time, and OP to quantify the changes that occur with progressive dissection and used axial loading to restore the in vivo condition. Results We found no difference in any parameter from LIVE to TORSO; thus, within 2 h of sacrifice, the TORSO disc can represent the LIVE condition. With serial dissection and sample preparation the disc height increased (SEGMENT height 18% higher than TORSO), OP decreased (POTTED was 67% lower than TORSO), and T2 time was unchanged. With axial loading, an imposed stress of 0.20–0.33 MPa returned the disc to in vivo, LIVE disc geometry and OP, although T2 time was decreased. There was a linear correlation between applied stress and OP, and this was conserved across multiple studies and species. Conclusion To restore the LIVE disc state in human studies or other animal models, we recommend measuring the OP/stress relationship and using this relationship to select the applied stress necessary to recover the in vivo condition.

Business psychologists study and assess relevant individual differences, such as intelligence and personality, in the context of work. Such studies have informed the development of artificial intelligence systems (AI) designed to measure individual differences. This has been capitalized on by companies who have developed AI-driven recruitment solutions that include aggregation of appropriate candidates ("Hiretual"), interviewing through a chatbot ("Paradox"), video interview assessment ("MyInterview"), and CV-analysis ("Textio"), as well as estimation of psychometric characteristics through image-("Traitify") and game-based assessments ("HireVue") and video interviews ("Cammio"). However, driven by concern that such high-impact technology must be used responsibly due to the potential for unfair hiring to result from the algorithms used by these tools, there is an active effort towards proving mechanisms of governance for such automation. In this article, we apply a systematic algorithm audit framework in the context of the ethically critical industry of algorithmic recruitment systems, exploring how audit assessments on AI-driven systems can be used to assure that such systems are being responsibly deployed in a fair and well-governed manner. We outline sources of risk for the use of algorithmic hiring tools, suggest the most appropriate opportunities for audits to take place, recommend ways to measure bias in algorithms, and discuss the transparency of algorithms.

University leaders can support academic advising as an interactive process in which the adviser helps students set and achieve academic goals, acquire relevant information and services, and make responsible decisions consistent with their interests, goals, abilities, and degree requirements. The study adopted qualitative narrative inquiry research design. The data were collected via a semi-structured questionnaire administered to six faculty member on one-on-one basis and their students were also sent interview questions electronically for completion from January 25, 2019 February 25, 2019. The results revealed that Doctoral programs generally attract such students who are highly motivated to attain advanced degrees and who are willing to participate fully in the advisement process. Graduate students re-enhanced when they received appropriate academic advising at all stages of a doctoral degree program. Students were need of effective advising process at all times from being recruited, to career planning after graduation.

Abstract Background There is considerable variation in the functionality of bioethical services in different institutions and countries for children in hospital, despite new challenges due to increasing technology supports for children with serious illness and medical complexity. We aimed to understand how bioethics services address bioethical concerns that are increasingly encountered in paediatric intensive care. Methods A qualitative descriptive design was used to describe clinician’s perspectives on the functionality of clinical bioethics services for paediatric intensive care units. Clinicians who were members of formal or informal clinical bioethics groups, or who were closely involved with the process of working through ethically challenging decisions, were interviewed. Interviews took place online. Resulting transcripts were analysed using thematic analysis. Results From 33 interviews, we identified four themes that described the functionality of bioethics services when a child requires technology to sustain life: striving for consensus; the importance of guidelines; a structure that facilitates a time-sensitive and relevant response; and strong leadership and teamwork. Conclusions Clinical bioethics services have the potential to expand their role due to the challenges brought by advancing medical technology and the increasing options it brings for treatment. Further work is needed to identify where and how bioethics services can evolve and adapt to fully address the needs of the decision-makers in PICU.

Laren D Tan,1 Anthony A Hilliard,2 Ricardo L Peverini,3 Robert D Martin,4 Tamara L Thomas,5 Trevor G Wright,6 Lyndon C Edwards,6 Angela M Lalas,6 Helen M Staples-Evans,6 Barbara J Sharp,7 Stella L Ahn-Kim,7 Kent A Hansen,6 Richard H Hart8 1Department of Medicine, Pulmonary, Critical Care, Hyperbaric and Sleep Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA; 2Department of Medicine, Cardiology, Loma Linda University School of Medicine, Loma Linda, CA, USA; 3Department of Pediatrics, Neonatology, Loma Linda University School of Medicine, Loma Linda, CA, USA; 4Department of Anesthesia, Loma Linda University School of Medicine, Loma Linda, CA, USA; 5Department of Emergency Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USA; 6Loma Linda University Health, Loma Linda, CA, USA; 7Loma Linda University School of Medicine, Loma Linda, CA, USA; 8Department of Preventive Medicine, Loma Linda University School of Medicine, Loma Linda, CA, USACorrespondence: Laren D Tan, Email Latan@llu.eduAbstract: Navigating the healthcare conundrum in the Blue Zone of Loma Linda, California, requires understanding the unique factors that make this region stand out in terms of health and longevity. But more important is understanding the healthcare system sustaining the Blue Zone in Loma Linda, California. In an era marked by soaring healthcare costs and diminishing reimbursement rates, hospitals and physicians face an unprecedented challenge: providing excellent patient care while maintaining financial sustainability. This leadership perspective publication paper delves into the multifaceted struggles encountered by healthcare and hospital leaders, exploring the root causes, implications, and potential solutions for this complex issue. As we examine the evolving healthcare landscape, we aim to shed light on the critical need for innovative approaches to sustain the future of healthcare excellence in one of the five original Blue Zones.Keywords: blue zone, Loma Linda, healthcare cost, leadership healthcare, longevity, California