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Background: Headaches, including migraines, are one of the most common causes of disability and account for nearly 20%-30% of referrals from primary care to neurology. In primary care, electronic health record-based alerts offer a mechanism to influence health care provider behaviors, manage neurology referrals, and optimize headache care. Objective: This project aimed to evaluate the impact of an electronic alert implemented in primary care on patients' overall headache management. Methods: We conducted a stratified cluster-randomized study across 38 primary care clinic sites between December 2021 to December 2022 at a large integrated health care delivery system in the United States. Clinics were stratified into 6 blocks based on region and patient-to-health care provider ratios and then 1:1 randomized within each block into either the control or intervention. Health care providers practicing at intervention clinics received an interruptive alert in the electronic health record. The primary end point was a change in headache burden, measured using the Headache Impact Test 6 scale, from baseline to 6 months. Secondary outcomes included changes in headache frequency and intensity, access to care, and resource use. We analyzed the difference-in-differences between the arms at follow-up at the individual patient level. Results: We enrolled 203 adult patients with a confirmed headache diagnosis. At baseline, the average Headache Impact Test 6 scores in each arm were not significantly different (intervention: mean 63, SD 6.9; control: mean 61.8, SD 6.6; P=.21). We observed a significant reduction in the headache burden only in the intervention arm at follow-up (3.5 points; P=.009). The reduction in the headache burden was not statistically different between groups (difference-in-differences estimate -1.89, 95% CI -5 to 1.31; P=.25). Similarly, secondary outcomes were not significantly different between groups. Only 11.32% (303/2677) of alerts were acted upon. Conclusions: The use of an interruptive electronic alert did not significantly improve headache outcomes. Low use of alerts by health care providers prompts future alterations of the alert and exploration of alternative approaches.

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BACKGROUND: Despite sodium-glucose cotransporter-2 inhibitors (SGLT2i) and angiotensin receptor/neprilysin inhibitors (ARNi) being cost-effective evidenced-based therapies for the management of Heart Failure with Reduced Ejection Fraction (HFrEF), research shows that less than 30% of patients with HFrEF are prescribed these agents. OBJECTIVE: This study aimed to understand clinician-perceived barriers and facilitators to prescribing ARNi and SGLT2i in patients with HFrEF. METHODS: We conducted virtual and in-person semi-structured interviews in a large integrated healthcare delivery system in the United States. Twenty cardiology clinicians managing patients with HFrEF were recruited using purposeful sampling to target providers across professions and practice sites. The interview guide was developed based on a literature review and insights from a practicing cardiologist. It inquired about perceived prescribing behaviors, focusing on factors affecting the use of ARNi and SGLT2i. We identified key themes using rapid qualitative analysis. RESULTS: Twenty clinicians were interviewed: 13 physicians, five advanced practitioners, and two clinic-based pharmacists. Eighteen interviews were analyzed; we excluded two as the clinicians interviewed did not meet the inclusion criteria. Three major themes were identified: 1) clinician-reported prescribing patterns don't always align with the American College of Cardiology/American Heart Association guidelines for the use of SGLT2i and ARNi due to clinical inertia, lack of familiarity, knowledge, and comfort with use, and concerns over polypharmacy or adverse events, 2) clinician-perceived and actual out-of-pocket cost reduced prescribing of ARNi or SGLT2i to patients, exacerbated by a lack of visibility into patients' prescription coverage, denials of coverage by insurance, and navigating prior authorization related workflows, and 3) incorporation of a clinic-based pharmacist increased the prescribing of these medications. CONCLUSIONS: Increasing cost transparency, implementing interventions to overcome clinical inertia and cost hurdles, and increasing clinic-based pharmacist support may improve evidenced-based prescribing in patients with HFrEF, especially for comparatively novel classes such as ARNi and SGLT2i.

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Mixed lineage kinase domain-like (MLKL) is a key signaling protein of necroptosis. Upon activation by phosphorylation, MLKL translocates to the plasma membrane and induces membrane permeabilization, which contributes to the necroptosis-associated inflammation. Membrane binding of MLKL is initially initiated by electrostatic interactions between the protein and membrane phospholipids. We previously showed that MLKL and its phosphorylated form (pMLKL) are S-acylated during necroptosis. Here, we characterize the acylation sites of MLKL and identify multiple cysteines that can undergo acylation with an interesting promiscuity at play. Our results show that MLKL and pMLKL undergo acylation at a single cysteine, with C184, C269, and C286 as possible acylation sites. Using all-atom molecular dynamic simulations, we identify differences that the acylation of MLKL causes at the protein and membrane levels. Through investigations of the S-palmitoyltransferases that might acylate pMLKL in necroptosis, we showed that zDHHC21 activity has the strongest effect on pMLKL acylation, inactivation of which profoundly reduced the pMLKL levels in cells and improved membrane integrity. These results suggest that blocking the acylation of pMLKL destabilizes the protein at the membrane interface and causes its degradation, ameliorating the necroptotic activity. At a broader level, our findings shed light on the effect of S-acylation on MLKL functioning in necroptosis and MLKL-membrane interactions mediated by its acylation.

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Aim: Pre-emptive testing of pharmacogenomic (PGx) variations has potential to improve medication safety and effectiveness; however, testing is not routine. Given the newfound payor coverage of multigene testing and the potential value of testing within aging patients, it is imperative to test local PGx testing capabilities, report results to patients and providers, and determine the value of testing. Materials & methods: We designed a randomized clinical pilot of a pre-emptive PGx testing process using the electronic health record compared with usual care among an aging primary care population. Results & conclusion: The impact of the program on prescribing patterns, healthcare utilization and costs of care will be evaluated. We hypothesize that implementation of a pre-emptive multigene PGx panel is feasible among elderly, polypharmacy, primary care patients, measured by the number of enrolled patients with PGx results entered in the medical record. Health system wide PGx implementation, including capacity needed to integrate these valuable results, is also described.

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Mixed lineage kinase domain-like (MLKL) is a key signaling protein of necroptosis. Upon activation by phosphorylation, MLKL translocates to the plasma membrane and induces membrane permeabilization which contributes to the necroptosis-associated inflammation. Membrane binding of MLKL is initially initiated by the electrostatic interactions between the protein and membrane phospholipids. We previously showed that MLKL and its phosphorylated form (pMLKL) are S-acylated during necroptosis. Here, we characterize acylation sites of MLKL and identify multiple cysteines that can undergo acylation with an interesting promiscuity at play. Our results show that MLKL and pMLKL undergo acylation at a single cysteine, C184, C269 and C286 are the possible acylation sites. Using all atom molecular dynamic simulations, we identify differences that the acylation of MLKL causes at the protein and membrane level. Through systematic investigations of the S-palmitoyltransferases that might acylate MLKL in necroptosis, we showed that zDHHC21 activity has the strongest effect on pMLKL acylation, inactivation of which profoundly reduced the pMLKL levels in cells and improved membrane integrity. These results suggest that blocking the acylation of pMLKL destabilizes the protein at the membrane interface and causes its degradation, ameliorating necroptotic activity. At a broader level, our findings shed light on the effect of S-acylation on MLKL functioning in necroptosis and MLKL-membrane interactions mediated by its acylation.

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Necroptosis is a type of programed cell death characterized by an inflammatory phenotype due to extensive membrane permeabilization and rupture. Initiation of necroptosis involves activation of tumor necrosis factor receptors by tumor necrosis factor alpha (TNFα) followed by coordinated activities of receptor-interacting protein kinases and mixed lineage kinase-like protein (MLKL). Subsequently, MLKL undergoes phosphorylation and translocates to the plasma membrane, leading to permeabilization. Such permeabilization results in the release of various cytokines and causes extensive inflammatory activity at the organismal level. This inflammatory activity is one of the major differences between apoptosis and necroptosis and links necroptosis to several human pathologies that exhibit inflammation, in addition to the ultimate cell death phenotype. Given the crosstalk between the activation of cell death pathway and inflammatory activity, approaches that provide insights on the regulation of transcripts, proteins and their processing at the global level have substantially improved our understanding of necroptosis and its involvement in different disease states. In this review, we highlight recent omic studies probing the transcriptome, proteome and lipidome which elucidate potential new mechanisms and signaling pathways during necroptosis and the necroptosis-associated inflammatory activity observed in various diseases. We specifically focus on studies investigating the transcriptome and intracellular and released proteome that contribute to inflammatory nature of necroptotic cells. We also highlight different lipids that have been implicated in necroptosis and lipidomic studies identifying lipid players in necroptosis. Finally, we review studies which suggest certain necroptosis-related genes as potential prognosis markers for different cancers and discuss their translational implications.

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Background: Maryland expanded its "Statewide Naloxone Standing Order" (NSO) in 2017 to eliminate training and prescription requirements for obtaining naloxone, improve naloxone access, help reverse opioid overdose, and reduce overdose fatality rates.Objectives: To assess the change in the trends of fatal opioid overdose rates following the expansion of the Naloxone Standing Order (eNSO) and its association with the social determinants of health (SDoH).Methods: Data on overdose deaths and SDoH from 2015-2019 was collected and analyzed using interrupted time series and multivariate Poisson regression models to study the change in trends and the associations.Results: There was a significant decrease in the rate of fatal overdoses after the intervention: prescription opioid estimate number of deaths declined by .25 per 100,000 (p = .02), heroin estimate number of deaths declined by 1.83 per 100,000 (p < .001), fentanyl estimate number of deaths declined by 2.54 per 100,000 (p < .001). After controlling for eNOS implementation in Maryland, state-level estimates with high proportions of female residents and those with bachelor's degree or higher were associated with reduction in overdose, while state-level estimates with high proportions of African Americans and higher employment rates were associated with an increase in overdose.Conclusions: Our analysis shows that the expanded naloxone standing order is associated with reducing opioid-related overdose death rates. Even though we observed a significant reduction in overdose death rate in fentanyl-related deaths, the rate of deaths post-eNSO was still increasing, suggesting the need for additional measures to impact the rates of fentanyl.

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Lipids, the structural part of membranes, play important roles in biological functions. However, our understanding of their implication in key cellular processes such as cell division and protein-lipid interaction is just emerging. This is the case for molecular interactions in mechanisms of cell death, where the role of lipids for protein localization and subsequent membrane permeabilization is key. For example, during the last stage of necroptosis, the mixed lineage kinase domain-like (MLKL) protein translocates and, eventually, permeabilizes the plasma membrane (PM). This process results in the leakage of cellular content, inducing an inflammatory response in the microenvironment that is conducive to oncogenesis and metastasis, among other pathologies that exhibit inflammatory activity. This work presents insights from long all-atom molecular dynamics (MD) simulations of complex membrane models for the PM of mammalian cells with an MLKL protein monomer. Our results show that the binding of the protein is initially driven by the electrostatic interactions of positively charged residues. The protein bound conformation modulates lipid recruitment to the binding site, which changes the local lipid environment recruiting PIP lipids and cholesterol, generating a unique fingerprint. These results increase our knowledge of protein-lipid interactions at the membrane interface in the context of molecular mechanisms of the necroptotic pathway, currently under investigation as a potential treatment target in cancer and inflamatory diseases.

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The common deletion of the third exon of the growth hormone receptor gene (GHRd3) in humans is associated with birth weight, growth after birth, and time of puberty. However, its evolutionary history and the molecular mechanisms through which it affects phenotypes remain unresolved. We present evidence that this deletion was nearly fixed in the ancestral population of anatomically modern humans and Neanderthals but underwent a recent adaptive reduction in frequency in East Asia. We documented that GHRd3 is associated with protection from severe malnutrition. Using a novel mouse model, we found that, under calorie restriction, Ghrd3 leads to the female-like gene expression in male livers and the disappearance of sexual dimorphism in weight. The sex- and diet-dependent effects of GHRd3 in our mouse model are consistent with a model in which the allele frequency of GHRd3 varies throughout human evolution as a response to fluctuations in resource availability.

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Liposomes containing small amounts of porphyrin-phospholipid (PoP) have been shown to encapsulate small molecular weight cargos and then release them upon exposure to red light. A putative mechanism involves transient pore formation in the bilayer induced by PoP-mediated photo-oxidation of unsaturated lipids. However, little is known about the properties of such pores. This study assesses whether large carbohydrate and protein molecules could be released from PoP liposomes upon red light exposure. A small fluorophore with ∼0.5 kDa in molecular weight, fluorescently labeled dextrans of ∼5 and ∼500 kDa, and a ∼240 kDa fluorescent protein were passively entrapped in PoP liposomes. When exposed to 665 nm irradiation, liposomes containing PoP, but not liposomes lacking it, released all these cargos in a size-dependent manner that occurred with oxidation of unsaturated lipids included in the bilayer. Thus, this study demonstrates the feasibility of light-triggered release of large biomacromolecules from liposomes.

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OBJECTIVE: To determine whether in vitro fertilization (IVF) with preimplantation genetic testing for aneuploidy (PGT-A) is cost effective to achieve a live birth compared with IVF alone in fresh donor oocyte cycles. DESIGN: Theoretical cost-effectiveness study. SETTING: Not applicable. PATIENTS: None. INTERVENTIONS: Comparison between the cost of IVF with PGT-A vs. IVF alone to achieve a live birth. The model analyzed a hypothetical single fresh oocyte donor IVF cycle with PGT-A vs. IVF alone and followed the progression of a single embryo through the different decision nodes. Cost estimates assigned to each clinical event were based on data obtained from the literature and institutional costs. MAIN OUTCOME MEASURES: Cost per live birth. RESULTS: In the base-case analysis, IVF with PGT-A was not cost effective in fresh donor oocyte cycles when compared with IVF alone to achieve a live birth. The cycles using PGT-A cost an additional $6,018.66. The incremental cost-effectiveness ratio was found to be $119,606.59 per additional live birth achieved with IVF with PGT-A. Monte Carlo simulations demonstrated that IVF with PGT-A was not cost effective in nearly all iterations. CONCLUSIONS: PGT-A in fresh donor oocyte IVF cycles is not cost effective compared with IVF alone over a wide range of probabilities and costs.

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Necroptosis is a form of cell death characterized by receptor-interacting protein kinase activity and plasma membrane permeabilization via mixed-lineage kinase-like protein (MLKL). This permeabilization is responsible for the inflammatory properties of necroptosis. We previously showed that very long chain fatty acids (VLCFAs) are functionally involved in necroptosis, potentially through protein fatty acylation. Here, we define the scope of protein acylation by saturated VLCFAs during necroptosis. We show that MLKL and phosphoMLKL, key for membrane permeabilization, are exclusively acylated during necroptosis. Reducing the levels of VLCFAs decreases their membrane recruitment, suggesting that acylation by VLCFAs contributes to their membrane localization. Acylation of phosphoMLKL occurs downstream of phosphorylation and oligomerization and appears to be, in part, mediated by ZDHHC5 (a palmitoyl transferase). We also show that disruption of endosomal trafficking increases cell viability during necroptosis, possibly by preventing recruitment, or removal, of phosphoMLKL from the plasma membrane.

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BACKGROUND: Addiction is one of the most rapidly growing epidemics that currently plagues nations around the world. In the United States, it has cost the government more than US $700 billion a year in terms of health care and other associated costs and is also associated with serious social, physical, and mental consequences. Increasing efforts have been made to tackle this issue at different levels, from primary prevention to rehabilitation across the globe. With the use of digital technology rapidly increasing, an effort to leverage the consumer health information technologies (CHITs) to combat the rising substance abuse epidemic has been underway. CHITs are identified as patient-focused technological platforms aimed to improve patient engagement in health care and aid them in navigating the complex health care system. OBJECTIVE: This review aimed to provide a holistic and overarching view of the breadth of research on primary prevention of substance abuse using CHIT conducted over nearly past five decades. It also aimed to map out the changing landscape of CHIT over this period. METHODS: We conducted a scoping review using the Arksey and O'Malley's modified methodological framework. We searched 4 electronic databases (PubMed, Cochrane, Scopus, and EMBASE). Papers were included if the studies addressed the use of CHIT for primary prevention of substance abuse and were published in English between 1809 and 2018. Studies that did not focus solely on primary prevention or assessed additional comorbid conditions were eliminated. RESULTS: Forty-two papers that met our inclusion criteria were included in the review. These studies were published between 1970 and 2018 and were not restricted by geography, age, race, or sex. The review mapped studies using the most commonly used CHIT platforms for substance abuse prevention from mass media in the 1970s to mobile and social media in 2018. Moreover, 191 studies that were exclusively focused on alcohol prevention were excluded and will be addressed in a separate paper. The studies included had diverse research designs although the majority were randomized controlled trials (RCT) or review papers. Many of the RCTs used interventions based on different behavioral theories such as family interactions, social cognitive theories, and harm-minimization framework. CONCLUSIONS: This review found CHIT platforms to be efficacious and cost-effective in the real-world settings. We also observed a gradual shift in the types and use of CHIT platforms over the past few decades and mapped out their progression. In addition, the review detected a shift in consumer preferences and behaviors from face-to-face interactions to technology-based platforms. However, the studies included in this review only focused on the aspect of primary prevention. Future reviews could assess the effectiveness of platforms for secondary prevention and for prevention of substance abuse among comorbid populations.

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