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In this study, the authors assessed return on investment (ROI) associated with a forensic assertive community treatment (FACT) program.A retrospective secondary data analysis of a randomized controlled trial comprising 70 legal-involved patients with severe mental illness was conducted in Rochester, New York. Patients were randomly assigned to receive either FACT or outpatient psychiatric treatment including intensive case management. Unit of service costs associated with psychiatric emergency department visits, psychiatric inpatient days, and days in jail were obtained from records of New York State Medicaid and the Department of Corrections. The total dollar value difference between the two trial arms calculated on a per-patient-per-year (PPPY) basis constituted the return from the FACT intervention. The FACT investment cost was defined by the total additional PPPY cost associated with FACT implementation relative to the control group. ROI was calculated by dividing the return by the investment cost.The estimated return from FACT was $27,588 PPPY (in 2019 dollars; 95% confidence interval [CI]=$3,262-$51,913), which was driven largely by reductions in psychiatric inpatient days, and the estimated investment cost was $18,440 PPPY (95% CI=$15,215-$21,665), implying an ROI of 1.50 (95% CI=0.35-2.97) for FACT.The Rochester FACT program was associated with approximately $1.50 return for every $1 spent on its implementation, even without considering potential returns from other sources, including reductions in acute medical care, crime-related damages, and public safety costs. ROI estimates were highly dependent on context-specific factors, particularly Medicaid reimbursement rates for assertive community treatment and hospital stays.

There is an increasing interest in inappropriate proton pump inhibitors prescription (InPPIp), as defined by the National Institute for Clinical Excellence (NICE) guidelines.To evaluate the rate, trend over time and factors associated with InPPIp upon discharge from internal medicine departments.We evaluated patients discharged from internal medicine departments with a PPI prescription in 2014 and 2017 at an academic referral center according to a developed algorithm.A total of 3,982 patients were included (50.8% women, 74% ≥ 65 years). The rate of InPPIp was 44.3% (95% CI 42.8-45.9) for the entire cohort; 68.1% for subjects aged65 years and 36.0% for those aged ≥ 65 years (p0.001); 43.2% in 2014 and 45.6% in 2017 (p = 0.130). In a decision-tree analysis, after the exclusion of 448 patients with gastrointestinal indications, 89.4% (1,580/1,766) of all InPPIp cases were of patients without dual antiplatelet treatment (DAPT) and 8.6% (151/1,766) were of patients younger than 65 years, who were taking aspirin.The rate of InPPIp is high, especially among patients not receiving DAPT and young patients taking aspirin. Time trend analysis showed no improvement over time. Our algorithm may serve as an automated quality measuring tool to reduce InPPIp.

Price cap regulation (PCR) as commonly implemented closely approximates atomistic Cournot competition in terms of the pass-through of industry and firm-specific cost-reducing innovation when the invariance property holds. A key finding is that the aggregate pass-through of cost-reducing innovation under PCR exceeds that under Cournot, holding the number of firms constant. The welfare gains under PCR are greater than Cournot when cost-reducing innovation is endogenous, the invariance property holds and demand is highly inelastic.

Herein, 14 severe quasi-linear convective systems (QLCS) covering a wide range of geographical locations and environmental conditions are simulated for both 1- and 3-km horizontal grid resolutions, to further clarify their comparative capabilities in representing convective system features associated with severe weather production. Emphasis is placed on validating the simulated reflectivity structures, cold pool strength, mesoscale vortex characteristics, and surface wind strength. As to the overall reflectivity characteristics, the basic leading-line trailing stratiform structure was often better defined at 1 versus 3 km, but both resolutions were capable of producing bow echo and line echo wave pattern type features. Cold pool characteristics for both the 1- and 3-km simulations were also well replicated for the differing environments, with the 1-km cold pools slightly colder and often a bit larger. Both resolutions captured the larger mesoscale vortices, such as line-end or bookend vortices, but smaller, leading-line mesoscale updraft vortices, that often promote QLCS tornadogenesis, were largely absent in the 3-km simulations. Finally, while maximum surface winds were only marginally well predicted for both resolutions, the simulations were able to reasonably differentiate the relative contributions of the cold pool versus mesoscale vortices. The present results suggest that while many QLCS characteristics can be reasonably represented at a grid scale of 3 km, some of the more detailed structures, such as overall reflectivity characteristics and the smaller leading-line mesoscale vortices would likely benefit from the finer 1-km grid spacing. Significance Statement High-resolution model forecasts using 3-km grid spacing have proven to offer significant forecast guidance enhancements for severe convective weather. However, it is unclear whether additional enhancements can be obtained by decreasing grid spacings further to 1 km. Herein, we compare forecasts of severe quasi-linear convective systems (QLCS) simulated using 1- versus 3-km grids to document the potential value added of such increases in grid resolutions. It is shown that some significant improvements can be obtained in the representation of many QLCS features, especially as regards reflectivity structure and in the development of small, leading-line mesoscale vortices that can contribute to both severe surface wind and tornado production.

Anthony Hecht’s “The Book of Yolek” may be read as a test case for understanding a strand of twentieth-century American Jewish poetry, one that takes up a series of questions about the very meaning of the term “Jewish poetics,” especially when it sets itself to the task of remembering what Hecht once described as the “very terrible aspects of existence.” Hecht’s resistance to sentimentalism in “The Book of Yolek,” which is also a resistance to the consolations of culture, engages his complicated inheritance of elegy and pastoral. Such anti-sentimentalism also resists confidence in the perpetuation of memory, even though “The Book of Yolek” is centrally concerned with the burdens and the imperatives of memory. The poem implicitly interrogates the tensions inherent in the post-Holocaust American Jew establishing a ground for joining the tradition of high lyric.

OBJECTIVE Cardiovascular risk reduction is an important focus in the management of people with diabetes. Although event rates have been declining over the long term, they have been observed to plateau or reverse in recent years. Furthermore, the impact of income-related disparities in cardiovascular events is unknown. The objective of this study is to evaluate age-, sex-, and income-related trends in cardiovascular hospitalization rates among people with diagnosed diabetes. RESEARCH DESIGN AND METHODS We calculated rates of hospitalization for acute myocardial infarction, stroke, heart failure, and lower-extremity amputation in annual cohorts of the entire population of Ontario, Canada, with diagnosed diabetes, from 1995 to 2019. Event rates were stratified by age, sex, and income level. RESULTS We studied nearly 1.7 million people with diabetes. The rate of acute myocardial infarction declined throughout the 25-year study period (P < 0.0001), such that the rate in 2019 was less than half the rate in 1995. Rates of stroke (P < 0.0001), heart failure (P < 0.0001), and amputation (P < 0.0001) also changed over time, but hospitalization rates stabilized through the 2010s. This apparent stabilization concealed a growing income-related disparity: wealthier patients showed continued declines in rates of these outcomes during the decade, whereas rates for lower-income patients increased (P for interaction < 0.0001 for all four outcomes). CONCLUSIONS During a quarter-century of follow-up, cardiovascular hospitalization rates among people with diabetes fell. However, the apparent stabilization in rates of stroke, heart failure, and amputation in recent years masks the fact that rates have risen for lower-income individuals.

Allegations of price-fixing by U.S. chicken suppliers in violation of Section 1 of the Sherman Act date back more than a half-century. The methods to facilitate this collusion have evolved over time from conference calls arranged by the National Broiler Marketing Association to more sophisticated methods of information sharing. Amid the highest rate of inflation in nearly forty years and persistent supply-chain bottlenecks as the country emerges from the pandemic, the chicken industry has been singled out by government officials for monopolistic pricing behavior. We examine the mechanism through which the “chicken cartel” was formed and sustained and its harmful effects on consumers. The analysis indicates that as early as 2008 a plan was hatched by U.S. chicken suppliers to collude in fixing the price of chicken. According to one complaint, this collusion, in concert with increased market concentration, raised chicken prices by approximately 50 percent. The associated consumer surplus losses are estimated at $8 to $10 billion annually with cumulative losses over the duration of the cartel ranging upward of $100 billion. Numerous indictments have been handed down and settlements reached, both civil and criminal.

Hidradenitis suppurativa (HS) is a chronic, debilitating, and painful inflammatory skin disease that significantly and negatively impacts patients' quality of life. The prevalence of HS in the USA is estimated to be 0.10%, with worldwide reports suggesting a prevalence closer to 1%. There is limited real-world evidence available on the care of patients with HS. We aimed to evaluate the trends in clinical care and treatment in the patient population with HS in the USA in a real-world setting.A cohort study was conducted using claims data from IBM MarketScan Databases, including the US Commercial Claims and Encounters with Medicare Supplemental and Coordination of Benefits (CCAE+MDCR) database and IBM US Medicaid database.The annual prevalence of HS increased from 0.06% (2008) to 0.14% (2017), and from 0.17% (2008) to 0.31% (2017) among CCAE+MDCR and Medicaid patients, respectively. Dermatologist visits increased from 31.9% (2008) to 47.8% (2019) in CCAE+MDCR patients, and decreased from 10.9% (2008) to 8.5% (2018) in Medicaid patients. Opioid use decreased from 45.4% (2008) to 25.5% (2019) among CCAE+MDCR patients, and from 71.3% (2008) to 48.1% (2018) among Medicaid patients. Only 8.4% of CCAE+MDCR patients and 5.8% of Medicaid patients were exposed to any biologic in 2018.Improved care and treatment of HS over the last decade, including the emergence of new treatments, have been accompanied by an increase in awareness and reported prevalence of the disease. However, there are still gaps in access to dermatologic care and low utilization of biologic therapies among patients with HS. INFOGRAPHIC.

Research on the antecedents of organizational identification (OI), individuals’ sense of oneness with the organization, has developed over time with four major categories: organizational characteristics, managerial policies and practices, interpersonal interactions, and personal attributes. OI research has flourished due to the exploration of antecedents under these four research categories, but it is not well integrated across them. The current lack of integration hinders understanding of the factors that can contribute to OI and how these might jointly shape OI development. To address this important unresolved issue, we seek to provide a comprehensive review of research on the antecedents of OI. In our review, we first summarize the existing research that reflects each of the four major research categories. We then suggest several avenues for future research, including exploration of the longitudinal dynamics between the antecedents and how the antecedents will operate in the context of key emerging work trends: remote work and digital transformation.

Introduction: After discharge from the emergency department (ED), pain management challenges parents, who have been shown to undertreat their children’s pain. Our goal was to evaluate the effectiveness of a five-minute instructional video for parents on pain treatment in the home setting to address common misconceptions about home pediatric pain management. Methods: We conducted a randomized, single-blinded clinical trial of parents of children ages 1-18 years who presented with a painful condition, were evaluated, and were discharged home from a large, tertiary care pediatric ED. Parents were randomized to a pain management intervention video or an injury prevention control video. The primary outcome was the proportion of parents that gave their child pain medication at home after discharge. These data were recorded in a home pain diary and analyzed using the chi square test to determine significant difference. Parents’ knowledge about components of at-home pain treatment were tested before, immediately following, and two days after intervention. We used McNemar’s test statistic to compare incorrect pretest/correct post-test answers between intervention and control groups. Results: A total of 100 parents were enrolled: 59 parents watched the pain education video, and 41 the control video. Overall, 75% of parents completed follow-up, providing information about home medication use. Significantly more parents provided pain medication to their children after watching the educational video: 96% vs 80% (difference 16%; 95% CI 7.8-31.3%). Significantly more parents had correct pain treatment knowledge immediately following the educational video about pain scores (P = 0.04); the positive effects of analgesics (P

IntroductionAtopic dermatitis (AD) is a chronic inflammatory skin disorder with limited treatment options for adolescents with moderate-to-severe disease. Lebrikizumab, a monoclonal antibody targeting interleukin (IL)-13, demonstrated clinical benefit in previous Phase 3 trials: ADvocate1 (NCT04146363), ADvocate2 (NCT04178967), and ADhere (NCT04250337). We report 52-week safety and efficacy outcomes from ADore (NCT04250350), a Phase 3, open-label study of lebrikizumab in adolescent patients with moderate-to-severe AD. The primary endpoint was to describe the proportion of patients who discontinued from study treatment because of adverse events (AEs) through the last treatment visit.MethodsAdolescent patients (N = 206) (≥ 12 to

The ability to distinguish endometrial serous carcinoma (SC) from high-grade endometrioid adenocarcinoma is of great importance given their differences in prognosis and management. In practice, this distinction typically relies upon the use of a focused immunohistochemical panel including p53, p16, and mismatch repair proteins. The expression of p16 is characteristically strong and diffuse in SCs, and weak and/or patchy in many high-grade endometrioid adenocarcinomas. Here, we report a subset of SCs that are entirely negative for p16 immunostaining, a pattern we refer to as "p16 null." This pattern was identified in 2 of 63 cases of SC diagnosed at our institution-1 with histologically classic features and 1 with ambiguous high-grade histologic features. These tumors otherwise showed a SC signature by immunohistochemical and demonstrated an SC pattern of genetic mutations. No mutation in the gene for p16, cyclin-dependent kinase inhibitor 2A (CDKN2A), was identified in either case. However, molecular correlates for the absent p16 expression were present, including homozygous deletion of CDKN2A in one case and hemizygous deletion of CDKN2A with promotor hypermethylation of the remaining allele in the other case. To our knowledge, this constitutes the first report conclusively demonstrating the existence of a small subset of SCs that are completely negative by p16 immunohistochemistry, and the molecular lesions responsible for this pattern. In the context of an otherwise clinically and histologically classic example of SC, we endorse this "null" p16 staining pattern as an alternative aberrant staining pattern that should not deter one from committing to this diagnosis.

Tuft cells are bottle-shaped, microvilli-projecting chemosensory cells located in the lining of a variety of epithelial tissues and, following their identification approximately 60 years ago, have been linked to immune system function in a variety of epithelia. Until recently, Tuft cells had not been convincingly demonstrated to be present in salivary glands with their detection by transmission electron microscopy only shown in a handful of earlier studies using rat salivary glands, and no follow-up work has been conducted to verify their presence in salivary glands of other species. Here, we demonstrate that Tuft cells are present in the submandibular glands of various species (i.e., mouse, pig and human) using transmission electron microscopy and confocal immunofluorescent analysis for the POU class 2 homeobox 3 (POU2F3), which is considered to be a master regulator of Tuft cell identity.

Effectiveness in academic and clinical communication depends upon agreement on what words and concepts denote and on the consequent ability to argue logically and accurately. In the pain medicine literature there are many examples of imprecision and confusion in this respect, including misnomers and fallacies in reasoning. This article firstly critically examines some of these misnomers. Identified themes include pain being conceptualised as a "thing," conflation between nociception and pain, and confusion between stimulus and response and between the perspectives of the experiencer and the observer of "pain." Secondly, fallacies in reasoning are identified that contribute to imprecision and confusion. These include reification of pain, attributing to the brain functions that belong to whole organisms, and the illusory truth effect. Thirdly, these themes are identified also in constructs that are shown to be based more on speculation than on fact. Taken together, these observations reveal a need to review and, where necessary, modify terminology and concepts used in Pain Medicine. PERSPECTIVE: This article examines a number of words and constructs commonly found in the pain literature from the perspective of accuracy in terms of their consistency of usage, concordance with fact, degree of speculation and logical argument. A common major theme is the error of considering pain as a "thing" that has agentive properties. A need to clarify much of the language used in Pain Medicine is identified.

There have been varying impacts of COVID-19 on racial, ethnic, and socioeconomic communities in the US. Recent literature suggests that Black Americans have the highest unadjusted and adjusted mortality rates from COVID-19, while White Americans have the lowest unadjusted and adjusted rates. However, the role of socioeconomic status and comorbidities in these disparities in health outcomes from COVID-19 are unclear. Thus, the purpose of this study is to evaluate how socioeconomic status and race impact COVID-19 outcomes in patients hospitalized with COVID-19 in a large health care system in the Mid-Atlantic region.We retrospectively analyzed the association of COVID-19 outcomes and race, ethnicity, and socioeconomic status using electronic medical records and the REDCap database from the time period of March 5, 2020 to June 3, 2020. The outcomes evaluated were intubation, ICU admission, and discharge destination. Multivariate logistic regression analysis was then performed to examine whether race and socioeconomic status were independent risk factors of mortality controlling for age, Charlson comorbidity index (CCI), and comorbidities.Race was not found to be an independent predictor for COVID-19 inpatient mortality. Race was found to be an independent risk factor for ICU admission with odds of ICU admission for Black patients to be 1.5 times higher (odds ratio (OR) 1.4 1.07 to 2.04) compared to Non-Black/Non-White (72.4% identifying as Hispanic) but no difference between Black and White races. Race was found not to be an independent risk factor for intubation nor was race an independent risk factor for increased length of ICU LOS, hospital LOS or intubation days. Socioeconomic status was not an independent risk factor for inpatient mortality although high income groups were significantly less likely to be admitted to the ICU compared to middle income patients.Our cohort of patients in a large mid-Atlantic health system showed that there was no statistically significant difference between race or socioeconomic status and COVID-19 related inpatient mortality. However, Black patients and individuals in the lower to middle socioeconomic group had a higher rate of COVID-19 hospitalizations when accounting for age, sex, and comorbidities. With ongoing vaccination efforts, equitable administration of resources should focus on disproportionately affected populations.

To evaluate whether thoracic radiologist review of computed tomography-detected incidental pulmonary nodules initially reported by non-thoracic imagers would change management recommendations.The Radiology Consultation Service identified 468 computed tomography scans (one per patient) performed through the adult emergency department from August 2018 through December 2020 that mentioned the presence of a pulmonary nodule. Forty percent (186/468) were read by thoracic radiologists and 60% (282/468) were read by non-thoracic radiologists. The Radiology Consultation Service contacted all patients in order to assess risk factors for lung malignancy. Sixty-seven patients were excluded because they were unreachable, declined participation, or were actively followed by a pulmonologist or oncologist. A thoracic radiologist assessed the nodule and follow up recommendations in all remaining cases.A total of 215 cases were re-reviewed by thoracic radiologists. The thoracic radiologist disagreed with the initial nodule recommendations in 38% (82/215) of cases and agreed in 62% (133/215) of cases. All discordant cases resulted in a change in management by the thoracic radiologist with approximately one-third (33%, 27/82) decreasing imaging utilization and two-thirds (67%, 55/82) increasing imaging utilization. Nodules were deemed benign and follow up eliminated in 11% (9/82) of discordant cases.Our study illustrates that nodule review by thoracic radiologists results in a change in management in a large percentage of patients. Continued research is needed to determine whether subspecialty imaging review results in increased or more timely lung cancer detection.

Since abortion was legalized throughout the United States in 1973, states have passed restrictive abortion policies, including permitting only obstetrician-gynecologist physicians (OBGYNs) to provide abortions. We are unaware of any research that directly compares patient safety-related outcomes by physician specialty. In this study, we compared major and any abortion-related morbidity and adverse events in abortion care provided by physicians of other specialties versus OBGYNs.Using the IBM Watson Health MarketScan claims database, we identified privately insured individuals who had an induced abortion between January 1, 2011, and December 31, 2014. The primary outcome was major abortion-related morbidity or adverse events, and the secondary outcome was any abortion-related morbidity or adverse events occurring within 6 weeks of the abortion.The study cohort included 34,764 patients who had 35,407 abortions-4,843 (13.7%) abortions provided by physicians of other specialties and 30,564 (86.3%) abortions provided by OBGYNs. Major and any abortion-related morbidity or adverse event occurred in 115 (0.3%) and 1,271 (3.6%) of 35,407 of abortions, respectively. In adjusted analyses, there was no statistically significant difference in major abortion-related morbidity or adverse events comparing physicians of other specialties versus OBGYNs (adjusted odds ratio, 1.02; 95% confidence interval, 0.59-1.75), and no statistically significant difference in any abortion-related morbidity or adverse events comparing physicians of other specialties versus OBGYNs (adjusted odds ratio, 0.91; 95% confidence interval, 0.77-1.09).There were no differences in abortion-related morbidity or adverse events by physician specialty. Our findings do not support state laws limiting abortion care to OBGYN physicians.

Objective Somatic symptom disorder (SSD) is one of the most common pediatric psychiatric disorders in adolescents, and several biological, psychological, and social factors have been considered to contribute to its development. The aim of the present study was to elucidate the link between psychological functioning (depression and anxiety), psychological characteristics (perfectionism and alexithymia), negative life events, and parental accommodation in children diagnosed with SSD. Methods Fifty patients (age range 7-18 years) were diagnosed with SSD in an outpatient clinic and completed multiple self-report questionnaires on SSD symptoms, negative life events, and psychological factors. Linear regression models were employed to indicate predictors of SSD symptoms. Cluster analysis was performed to identify gastrointestinal- and abdominal-related complaints and their associations. Results Association with SSD symptoms was strongest for state anxiety (Standardized β=0.85, 95% CI=0.44, 1.27, p=.0006), depression (β=0.72, 95% CI=0.38, 1.06, p=.0006), trait anxiety (β=0.60, 95% CI=0.22, 0.98, p=.0005), and family accommodation (β=0. 49, 95% CI=0.23, 0.75, p=.001). These factors were associated with gastrointestinal but not with neurological complaints. Family accommodation was associated with somatic complaints among children younger than 12 years (r=0.57, p=.007), while state anxiety (r=0.69, p=.007) and depression (r=0.65, p=.007) were significantly associated among older children. Conclusions Several psychological factors may result in a somatic response. The phenotypic expression of these factors may vary among different ages. Somatic complaints were related to parental accommodation among young children, while it was strongly associated with anxiety and depression among adolescents.

Climate change is increasingly recognized as a top global threat impacting human, environmental, and economic systems.When it comes to property & casualty insurance risk, AXA considers every aspect of the risk equation. As far as natural catastrophes risks are concerned, climate risk is a function of (i) the physical hazard (the severity and frequency of events); (ii) the exposure (the monetary value of insured asset(s)) and (iii) the vulnerability (the susceptibility or damageability of the insured asset(s) to a given hazard intensity). Each of these elements plays a unique role in driving climate risk both now and into the future. The changes AXA see in its year-on-year losses from climate-linked hazards are a function of all risks components and not just the hazard, which is a common misconception.AXA is developing internally Natural Hazard models (or Natural Catastrophe models) to estimate the climate risk damages and losses to individual risks or (re)insured portfolios.To perform forward looking analysis, AXA identified different complementary approaches that could be envisaged to assess the future of natural hazards risks according to both the peril and region combinations AXA has exposure to as the availability and quality of data for the three drivers of the risk. Those approaches have been notably used for several regulatory climate stress tests AXA was involved in.One of them is a global proportional approach simple to implement to consider at a large scale the evolution of hazard, exposure, vulnerability impacts on climate risk for long term time horizons and several warming scenarios. The model is built on current science knowledge related to climate change.A more sophisticated approach for local-scale assessment is currently being developed. It consists in integrating in the Natural Hazard models a modified view of hazard (stochastic events catalogue) / exposure / vulnerability capturing forward-looking scenarios. AXA is currently upgrading all its Natural Hazard models in that direction. AXA Europe Flood risk model is for instance assessing future of fluvial and pluvial risks from modified precipitation datasets representative of future warming scenarios. Future precipitation are made of baseline current precipitation from which a “delta” precipitation is added, based on CMIP6 temperature anomalies and Clausius-Clapeyron scaling. Hydrological and hydraulic models are then run using this new future precipitation datasets to generate stochastic flood events catalogue for future warming scenarios risks assessment.

AXA proposes a novel continental-scale generator of synthetic gridded rainfall daily timeseries (10km resolution) with applications to cross-country risk assessment under current and future climate scenarios. Europe serves as a case-study to demonstrate and assess its performance in terms of hazard modelling and extrapolation to unobserved extreme local and regional events. This generator belongs to the class of time and space reshuffling Stochastic Weather Generators (SWGs) and generates unobserved events by re-sequencing historical multisite timeseries (E-OBS). Consistency at continental scale is ensured by relying on weather regimes and atmospheric situations characterized from the ERA5 reanalysis over Europe. The use of atmospheric drivers and dry-wet alternating cycles allows for the determination of both precipitation-prone situations or on the contrary drier spells, while preserving the physics of the atmospheric water cycle. Spatial reshuffling is introduced by regional differentiation. Transitions between regimes can be either calibrated from the historical data or extrapolated to represent future states of the climate along with an appropriate uplifting of the humidity-related variables. This generator is operationally used at AXA as part of a European flood risk model and serves as the main input to an hydrological and hydraulic model.

Trafficking of cell-surface proteins from endosomes to the plasma membrane is a key mechanism to regulate synaptic function. In non-neuronal cells, proteins recycle to the plasma membrane either via the SNX27-Retromer-WASH pathway, or via the recently discovered SNX17-Retriever-CCC-WASH pathway. While SNX27 is responsible for the recycling of key neuronal receptors, the roles of SNX17 in neurons are less understood. Here, using cultured hippocampal neurons, we demonstrate that the SNX17 pathway regulates synaptic function and plasticity. Disruption of this pathway results in a loss of excitatory synapses and prevents structural plasticity during chemical long-term potentiation (cLTP). cLTP drives SNX17 recruitment to synapses, where its roles are in part mediated by regulating surface expression of β1-integrin. SNX17 recruitment relies on NMDAR activation, CamKII signaling, and requires binding to the Retriever and PI(3)P. Together, these findings provide molecular insights into the regulation of SNX17 at synapses, and define key roles for SNX17 in synaptic maintenance and in regulating enduring forms of synaptic plasticity.

P2Y receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on P2Y Receptors [3, 5, 189]) are activated by the endogenous ligands ATP, ADP, UTP, UDP, UDP-glucose and adenosine. The eight mammalian P2Y receptors are activated by distinct nucleotides: P2Y1, P2Y11, P2Y12 and P2Y13 are activated by adenosine-nucleotides; P2Y2, P2Y4 can be activated by both adenosine and uridine nucleotides, with some species-specific differences; P2Y6 is mainly activated by UDP; P2Y14 is preferentially activated by sugar-uracil nucleotides. The missing numbers in the receptor nomenclature refer either to non-mammalian orthologs or receptors having some sequence homology to P2Y receptors but for which there is no functional evidence of responsiveness to nucleotides [380]. Based on their G protein coupling P2Y receptors can be divided into two subfamilies: P2Y1, P2Y2, P2Y4, P2Y6 and P2Y11 receptors couple via Gq proteins to stimulate phospholipase C followed by increases in inositol phosphates and mobilization of Ca2+ from intracellular stores. P2Y11 receptors couple in addition to Gs proteins followed by increased adenylate cyclase activity. In contrast, P2Y12, P2Y13, and P2Y14 receptors signal primarily through activation of Gi proteins and inhibition of adenylate cyclase activity or control of ion channel activity [380]. Clinically used drugs acting on these receptors include the dinucleoside polyphosphate diquafosol, agonist of the P2Y2 receptor subtype, approved in Japan and South Korea for the management of dry eye disease [238], and the P2Y12 receptor antagonists prasugrel, ticagrelor and cangrelor, all approved as antiplatelet drugs [52, 320].