Sustained Retinal Defocus Increases the Effect of Induced Myopia on the Retinal Astrocyte Template.

The aim of this article is to describe sustained myopic eye growth's effect on astrocyte cellular distribution and its association with inner retinal layer thicknesses. Astrocyte density and distribution, retinal nerve fiber layer (RNFL), ganglion cell layer, and inner plexiform layer (IPL) thicknesses were assessed using immunochemistry and spectral-domain optical coherence tomography on seventeen common marmoset retinas (Callithrix jacchus): six induced with myopia from 2 to 6 months of age (6-month-old myopes), three induced with myopia from 2 to 12 months of age (12-month-old myopes), five age-matched 6-month-old controls, and three age-matched 12-month-old controls. Untreated marmoset eyes grew normally, and both RNFL and IPL thicknesses did not change with age, with astrocyte numbers correlating to RNFL and IPL thicknesses in both control age groups. Myopic marmosets did not follow this trend and, instead, exhibited decreased astrocyte density, increased GFAP+ spatial coverage, and thinner RNFL and IPL, all of which worsened over time. Myopic changes in astrocyte density, GFAP+ spatial coverage and inner retinal layer thicknesses suggest astrocyte template reorganization during myopia development and progression which increased over time. Whether or not these changes are constructive or destructive to the retina still remains to be assessed.

Early Alterations in Inner-Retina Neural and Glial Saturated Responses in Lens-Induced Myopia.

Purpose: Myopic marmosets are known to exhibit significant inner retinal thinning compared to age-matched controls. The purpose of this study was to assess inner retinal activity in marmosets with lens-induced myopia compared to age-matched controls and evaluate its relationship with induced changes in refractive state and eye growth. Methods: Cycloplegic refractive error (Rx), vitreous chamber depth (VCD), and photopic full-field electroretinogram were measured in 14 marmosets treated binocularly with negative contact lenses compared to 9 untreated controls at different stages throughout the experimental period (from 74 to 369 days of age). The implicit times of the a-, b-, d-, and photopic negative response (PhNR) waves, as well as the saturated amplitude (Vmax), semi-saturation constant (K), and slope (n) estimated from intensity-response functions fitted with Naka-Rushton equations were analyzed. Results: Compared to controls, treated marmosets exhibited attenuated b-, d-, and PhNR waves Vmax amplitudes 7 to 14 days into treatment before compensatory changes in refraction and eye growth occurred. At later time points, when treated marmosets had developed axial myopia, the amplitudes and implicit times of the b-, d-, and PhNR waves were similar between groups. In controls, the PhNR wave saturated amplitude increased as the b + d-wave Vmax increased. This trend was absent in treated marmosets. Conclusions: Marmosets induced with negative defocus exhibit early alterations in inner retinal saturated amplitudes compared to controls, prior to the development of compensatory myopia. These early ERG changes are independent of refraction and eye size and may reflect early changes in bipolar, ganglion, amacrine, or glial cell physiology prior to myopia development. Translational Relevance: The early changes in retinal function identified in the negative lens-treated marmosets may serve as clinical biomarkers to help identify children at risk of developing myopia.

Impact of Pharmacist Transitions of Care on 30-Day Readmissions Within a Primary Care-Based Accountable Care Organization.

Previous studies in the ambulatory care setting have shown inconsistent results in regard to, or with respect to pharmacist telephonic transitions of care (TOC) encounters and reduction in 30-day readmission rates. No studies that have been completed within an accountable care organization (ACO) evaluating the impact of telephonic TOC encounters performed by a pharmacist have been identified. The objective of this study was to analyze the impact of clinical pharmacy telephonic TOC encounters on readmission rates within a primary care-based ACO. In this retrospective chart review, data for those who had a pharmacist telephonic TOC encounter and those who had an attempt were collected. The primary outcome of this study was all-cause 30-day readmission rate. Secondary outcomes included 30-day readmission rate for targeted disease states, time to readmission, and readmission reason the same as previous discharge reason. For subjects who received a telephonic TOC encounter, pharmacist intervention type and provider acceptance of intervention(s) were described. For the final analysis, 154 encounters were included, 83 encounters in the telephonic TOC encounter group, and 71 did not receive a telephonic TOC encounter. The 30-day readmission rates were similar among those who received a telephonic TOC encounter and those who did not: the difference was not significant (15.7% vs. 28.2%; P = 0.059). There was also no statistical difference in the secondary outcomes. Even so, the results of this study suggest that performing a pharmacist telephonic TOC encounter in a primary care-based ACO setting has the potential to reduce 30-day readmission rates and further research appears to be warranted in this important area of practice.

Toward a person-centered ethics framework for autonomy in spinal cord injury research and rehabilitation.

In this paper, we explore how the concepts of autonomy and autonomous choice are understood in the context of spinal cord injury in the academic literature, both in reporting on research results and more broadly on outcomes and quality of life. We find inconsistent, framework-absent portrayals of autonomy as well as an absence of discourse that draws upon ethical constructs and theory. In response, we advance a person-centered framework for spinal cord injury research that combines both lived experience and a disability ethics approach to fill this gap.

Choroidal Morphology and Photoreceptor Activity Are Related and Affected by Myopia Development.

Purpose: The choroid is critical for the regulation of eye growth and is involved in the pathogenesis of myopia-associated ocular complications. This study explores the relationship among choroidal biometry, photoreceptor activity, and myopic growth in marmosets (Callithrix jacchus) with lens-induced myopia. Methods: A total of 34 common marmosets aged 92 to 273 days old were included in this study. Axial myopia was induced in 17 marmosets using negative soft contact lenses and 17 marmosets served as untreated controls. Cycloplegic refraction (RE) and vitreous chamber depth (VCD) were measured using autorefraction and A-scan ultrasonography, respectively. Choroidal scans were obtained using spectral-domain optical coherence tomography and binarized to calculate subfoveal choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), stromal area (SA), choroidal vascularity index (CVI), and LA/SA. To assess photoreceptor activity, the a-wave of the full-field electroretinogram was measured. Regression models were used to investigate the relationship between outcome measures. Results: Eyes induced with axial myopia (RE = -7.14 ± 4.03 diopters [D], VCD = 6.86 ± 0.39 mm) showed significant reductions (4.92-21.24%) in all choroidal parameters (ChT, TCA, LA, SA, CVI, and LA/SA) compared to controls (RE = -1.25 ± 0.60 D, VCD = 6.58 ± 0.26 mm, all P < 0.05), which changed as a function of refraction and vitreous elongation, and were associated with a decrease in the a-wave amplitude. Further, multiple regression showed that a combination of ChT and CVI could well predict RE and VCD. Conclusions: This study reports the existence of significant alterations in choroidal morphology in non-human primate eyes induced with myopia. The changes in choroidal anatomy were associated with reduced light-adapted a-wave amplitude. These findings may represent early markers for reduced visual performance and chorioretinal complications known to occur in eyes with large degrees of myopia.

Normal Risk Ovarian Screening Study: 21-Year Update.

PURPOSE: The Normal Risk Ovarian Screening Study (NROSS) tested a two-stage screening strategy in postmenopausal women at conventional hereditary risk where significantly rising cancer antigen (CA)-125 prompted transvaginal sonography (TVS) and abnormal TVS prompted surgery to detect ovarian cancer. METHODS: A total of 7,856 healthy postmenopausal women were screened annually for a total of 50,596 woman-years in a single-arm study (ClinicalTrials.gov identifier: NCT00539162). Serum CA125 was analyzed with the Risk of Ovarian Cancer Algorithm (ROCA) each year. If risk was unchanged and <1:2,000, women returned in a year. If risk increased above 1:500, TVS was undertaken immediately, and if risk was intermediate, CA125 was repeated in 3 months with a further increase in risk above 1:500 prompting referral for TVS. An average of 2% of participants were referred to TVS annually. RESULTS: Thirty-four patients were referred for operations detecting 15 ovarian cancers and two borderline tumors with 12 in early stage (I-II). In addition, seven endometrial cancers were detected with six in stage I. As four ovarian cancers and two borderline tumors were diagnosed with a normal ROCA, the sensitivity for detecting ovarian and borderline cancer was 74% (17 of 23), and 70% of ROCA-detected cases (12 of 17) were in stage I-II. NROSS screening reduced late-stage (III-IV) disease by 34% compared with UKCTOCS controls and by 30% compared with US SEER values. The positive predictive value (PPV) was 50% (17 of 34) for detecting ovarian cancer and 74% (25 of 34) for any cancer, far exceeding the minimum acceptable study end point of 10% PPV. CONCLUSION: While the NROSS trial was not powered to detect reduced mortality, the high specificity, PPV, and marked stage shift support further development of this strategy.

Genetic characteristics involved in COVID-19 severity. The CARGENCORS case-control study and meta-analysis.

Pre-existing coronary artery disease (CAD), and thrombotic, inflammatory, or virus infectivity response phenomena have been associated with COVID-19 disease severity. However, the association of candidate single nucleotide variants (SNVs) related to mechanisms of COVID-19 complications has been seldom analysed. Our aim was to test and validate the effect of candidate SNVs on COVID-19 severity. CARGENCORS (CARdiovascular GENetic risk score for Risk Stratification of patients positive for SARS-CoV-2 [COVID-19] virus) is an age- and sex-matched case-control study with 818 COVID-19 cases hospitalized with hypoxemia, and 1636 controls with COVID-19 treated at home. The association between severity and SNVs related to CAD (n = 32), inflammation (n = 19), thrombosis (n = 14), virus infectivity (n = 11), and two published to be related to COVID-19 severity was tested with adjusted logistic regression models. Two external independent cohorts were used for meta-analysis (SCOURGE and UK Biobank). After adjustment for potential confounders, 14 new SNVs were associated with COVID-19 severity in the CARGENCORS Study. These SNVs were related to CAD (n = 10), thrombosis (n = 2), and inflammation (n = 2). We also confirmed eight SNVs previously related to severe COVID-19 and virus infectivity. The meta-analysis showed five SNVs associated with severe COVID-19 in adjusted analyses (rs11385942, rs1561198, rs6632704, rs6629110, and rs12329760). We identified 14 novel SNVs and confirmed eight previously related to COVID-19 severity in the CARGENCORS data. In the meta-analysis, five SNVs were significantly associated to COVID-19 severity, one of them previously related to CAD.

Use trends of chlorthalidone and hydrochlorothiazide among United States adults with hypertension: National Health and Nutrition Examination Survey 2009-2018.

OBJECTIVES: To estimate the national prevalence of chlorthalidone and hydrochlorothiazide use among adults diagnosed with hypertension by sociodemographic subgroup, healthcare access status, and clinical factors. METHODS: Data was extracted from the National Health and Nutrition Examination Survey for 2009-2010 through 2017-2018 survey waves. Patients at least 20 years old, diagnosed with hypertension, and on hydrochlorothiazide or chlorthalidone were included. Uni-variable logistic regression models estimated the odds of being on chlorthalidone compared with hydrochlorothiazide use by sociodemographic and clinical factors. Analyses were adjusted for multi-stage complex survey design and are nationally representative. RESULTS: Two thousand five hundred and eighty-five participants were included with 95.2% participants using hydrochlorothiazide and 4.8% using chlorthalidone. Participants over 65 years were more likely to be on chlorthalidone compared with younger counterparts [odds ratio (OR) 1.8; 95% confidence interval (CI) 1.12-2.88]. Participants with hypokalemia (OR 2.62; 95% CI 1.56-4.42) or hyponatremia [OR 2.298; 95% CI 1.23-4.30) were more likely to be using chlorthalidone compared with patients with normal levels. CONCLUSION: Chlorthalidone, a potent and effective first-line antihypertensive agent and thoroughly studied thiazide diuretic with substantial cardiovascular benefits, continues to be underutilized in patients with hypertension. Findings demonstrated that individuals receiving chlorthalidone were more likely to be 65 years or older and to experience hyponatremia or hypokalemia. Sociodemographic factors, healthcare access and use, clinical factors, and medical conditions did not appear to sway the choice in thiazide diuretic use.

Real-World Analysis of Long-Acting and NPH-Containing Insulins on Glycemic Control.

Introduction Affordability of insulin products has become a concern in the past several years as the average price of various insulin products has increased. While awaiting legislation at the federal level that would address issues leading to high insulin costs, providers may have shifted prescribing practices to prescribe the lowest-priced insulin products to achieve patients' treatment goals. Objective To compare the prevalence of hypoglycemic events between patients receiving lower-cost neutral protamine Hagedorn (NPH)-containing human insulins and higher-cost long-acting insulin analogs in Medicare Part D enrollees within a management services organization, as well as assessing glycemic control and changes in body mass index. Methods This was a multicenter, retrospective study conducted at three primary care clinics. The co-primary outcomes were percent difference of documented mild and severe hypoglycemic events between individuals receiving NPH-containing human insulin and long-acting insulin. Results A total of 72 patients met inclusion criteria and were receiving NPH-containing human insulins or the long-acting insulin analogs, 15 and 57 patients, respectively. Severe hypoglycemic events occurred in 3.5% vs 0% of the long-acting insulin analog and NPH-containing human insulin group, respectively (P = 0.999). Mild hypoglycemic episodes were experienced by 31.6% versus 33.3% of long-acting insulin analog and NPH, respectively (P = 0.539). For secondary outcomes, no difference was observed in glycemic control outcomes across insulin groups. Conclusion Among Medicare Part D patients with type 2 diabetes mellitus, the use of NPH-containing human insulins was not associated with an increased risk of mild or severe hypoglycemia-related episodes or reduced glycemic control compared with long-acting insulin. Study findings suggest that lower-cost, NPH-containing human insulins may be an alternative to higher-cost, long-acting insulin analogs.

Impact of Student Pharmacist-Led Transition-of-Care Services on 30-Day Hospital Readmissions at a University Call Center.

Background: Transition of care (TOC) refers to the movement of patients between different health care settings due to changes in medical conditions and needs. Pharmacists can play an important role in TOC services as polypharmacy is a common reason for hospital readmission that costs the US taxpayers an average of $17 billion annually. Objective: The purpose of this study is to evaluate the impact of TOC telehealth services provided by pharmacy students at a university-based call center on 30-day hospital readmission. Methods: In this retrospective observational study, an electronic chart review was conducted for patients who were discharged from the hospital and received a telephone call from pharmacy students. Patients were referred to the pharmacy team from a primary care provider office. The co-primary endpoints were the number of 30-day all-cause hospital readmissions (including emergency department visits) and 30-day readmission due to initial admission diagnosis in patients who received a telephonic TOC call from a pharmacy student compared with patients who declined or were unable to be reached. Types of pharmacy-related TOC interventions provided by students were also collected. Results: A total of 84 patients were included in this study. All-cause 30-day readmission was similar between groups (13% vs 15.8%), whereas 30-day readmission due to initial admission diagnosis was much lower in the intervention group (5.9% vs 11.1%). Although a positive trend was observed in favor of the intervention group, a statistically significant difference was not observed for both 30-day all-cause readmission and 30-day readmission due to initial admission diagnosis. Medication reconciliation, adherence counseling, and lifestyle education (diet, exercise) are the most common topics discussed with the patients during TOC interventions. Conclusion: Using student pharmacists to provide postdischarge TOC calls can be a benefit to the patient and the health care team while offering pharmacy students valuable learning experience prior to graduation.

Validation and clinical usefulness of the Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ) among French-speaking voice-hearers.

Auditory verbal hallucinations (AVH), also called voices, are often distressing to individuals experiencing them. Valid and reliable instruments are necessary to document the hearing voices experience across cultures. The Hamilton Program for Schizophrenia Voices Questionnaire (HPSVQ) is becoming a widely used self-administered instrument for assessing characteristics, content and subjective effect of AVH. This study investigates the psychometric characteristics of the HPSVQ French version (HPSVQ FV) in a clinical sample of voice-hearers. The results showed that the HPSVQ yields a global score (HPSVQ-Global) as well as a distress (HPSVQ-Distress) and a severity (HPSVQ-Severity) sub-score having good, acceptable and questionable internal consistency respectively. Significant correlations were found between hallucination severity (BPRS 4.0), distress (PSYRATS-AH), voices acceptance (VAAS-9), anxiety and depression (HADS). However, no significant associations were observed between Suspicion and Unusual Thoughts (BPRS 4.0). At a one-week interval, the temporal stability of the three indices was excellent. Moreover, after a brief cognitive intervention, a significant reduction was observed in all indices. Taken together, the HPSVQ FV demonstrated good construct validity, reliability and sensitivity to change. These findings support the use of the HPSVQ in francophone clinical and research settings. However, the bi-factorial solution of the HPSVQ FV should be further examined in larger samples.

Age exacerbates the effect of myopia on retinal capillaries and string vessels.

The retinal vasculature supplies oxygen and nutrition to the cells and is crucial for an adequate retinal function. In myopia, excessive eye growth is associated with various anatomical changes that can lead to myopia-related complications. However, how myopia-induced ocular growth affects the integrity of the aged retinal microvasculature at the cellular level is not well understood. Here, we studied how aging interacts with myopia-induced alteration of the retinal microvasculature in fourteen marmoset retinas (Callithrix jacchus). String vessel and capillary branchpoint were imaged and quantified in all four capillary plexi of the retinal vasculature. As marmosets with lens-induced myopia aged, they developed increasing numbers of string vessels in all four vascular plexi, with increased vessel branchpoints in the parafoveal and peripapillary retina and decreased vessel branchpoints in the peripheral retina. These myopia-induced changes to the retinal microvasculature suggest an adaptive reorganization of the retinal microvascular cellular structure template with aging and during myopia development and progression.

Evidence of vascular involvement in myopia: a review.

The benign public perception of myopia (nearsightedness) as a visual inconvenience masks the severity of its sight-threatening consequences. Myopia is a significant risk factor for posterior pole conditions such as maculopathy, choroidal neovascularization and glaucoma, all of which have a vascular component. These associations strongly suggest that myopic eyes might experience vascular alterations prior to the development of complications. Myopic eyes are out of focus because they are larger in size, which in turn affects their overall structure and function, including those of the vascular beds. By reviewing the vascular changes that characterize myopia, this review aims to provide an understanding of the gross, cellular and molecular alterations identified at the structural and functional levels with the goal to provide an understanding of the latest evidence in the field of experimental and clinical myopia vascular research. From the evidence presented, we hypothesize that the interaction between excessive myopic eye growth and vascular alterations are tipping-points for the development of sight-threatening changes.

Regulation of Atp7a RNA contributes to differentiation-dependent Cu redistribution in skeletal muscle cells.

Cu (Cu) is essential for several biochemical pathways due to its role as a catalytic cofactor or allosteric regulator of enzymes. Its import and distribution are tightly controlled by transporters and metallochaperones and Cu homeostasis is maintained by balancing Cu uptake and export. Genetic diseases are caused by impaired Cu transporters CTR1, ATP7A, or ATP7B but little is known about the regulatory mechanisms by which these proteins meet the fluctuating demands of Cu in specific tissues. Cu is required for differentiation of skeletal myoblasts to myotubes. Here, we demonstrate that ATP7A is needed for myotube formation and that its increased abundance during differentiation is mediated by stabilization of Atp7a mRNA via the 3' untranslated region. Increased ATP7A levels during differentiation resulted in increased Cu delivery to lysyl oxidase, a secreted cuproenzyme that needed for myotube formation. These studies identify a previously unknown role for Cu in regulating muscle differentiation and have broad implications for understanding Cu-dependent differentiation in other tissues.

Person Specific Parameter Heterogeneity in the 2PL IRT Model.

Following Kelderman and Molenaar's demonstration that a factor model with person specific factor loadings is almost indistinguishable from the standard factor model in terms of overall fit, we examined person specific measurement models in Item Response Theory, person specific discrimination and difficulty parameters were created by adding random variation at the item by person level. Using standard fitting algorithms for the 2PL IRT there was modest evidence of person- or item-level misfit using common diagnostic tools. The item difficulties were well-estimated, but the item discriminations were noticeably underestimated. As found by Kelderman and Molenaar, factor scores were estimated with less than expected reliability due to the underlying heterogeneity. The person specific models considered here are basically limiting cases of IRT models with multilevel, mixture, or differential item functioning structure. We conclude with some thoughts regarding real-world sources of heterogeneity that might go unacknowledged in common testing applications.

Development of a novel protocol to evaluate contact-lens related ocular surface health on marmosets (Callithrix jacchus).

Contact lens wear affects the ocular surface and can cause contact lens-induced dry eye (CLIDE). The purpose of this study was bifold: (1) to develop a novel protocol to assess the ocular surface in a non-human primate (NHP) model, the common marmoset (Callithrix jacchus), and (2) to characterize central corneal thickness (CCT), tear osmolarity, blink rate and tear meniscus height (TMH) longitudinally, in untreated marmosets (controls) compared to animals treated with contact lenses (CL). Longitudinal changes in CCT (N = 10 control; N = 10 treated with contact lenses, CL-treated), osmolarity (N = 4 control; N = 6 CL-treated), blink rate (N = 8 control; N = 10 CL-treated) and TMH (N = 8 control; N = 6 CL-treated) were assessed using high frequency A-scan ultrasound, the I-PEN Vet Tear Osmolarity System, a video recording system (745 frames/minute) and Image J respectively, from 70 days to 224 days (5 months) at approx. 9am, and again after 9hrs of CL wear (methafilcon A, 55% water content; Capricornia, Australia) after every 4 weeks of contact lens wear for a total of 22 weeks of treatment. Repeated measures ANOVA was used to compare eyes over time and student t-test was used to compare treated to control eyes at each time point. At baseline, untreated marmosets had a CCT (mean ± SD) of 0.31 ± 0.01 mm, tear osmolarity 311.67 ± 11.48 mOsms/L, blink rate 1.83 ± 1.79 blinks per minute (bpm) and TMH 0.07 ± 0.02 arbitrary units (au), all of which remained stable over 5 months, except blink rate that increased to 5.32 ± 1.58 bpm (p < 0.01) after 5 months. In CL-treated marmosets, however, CCT progressively increased with CL wear (baseline: 0.30 ± 0.01 mm; 5 months: 0.31 ± 0.02 mm, p < 0.05), while osmolarity decreased after 2 and 3 months of CL wear (baseline: 316.11 ± 13.63; 2 months: 302.63 ± 11.27, p < 0.05; 3 months: 302.92 ± 14.58, p < 0.05). The decrease in osmolarity occurred in parallel to an increase in blink rate (baseline: 0.98 ± 1.18 bpm; 2 months: 3.46 ± 3.04 bpm, p < 0.05; 3 months: 3.73 ± 1.50 bpm, p < 0.001). TMH decreased during the third month of CL wear (baseline: 0.06 ± 0.00 au; 3 months: 0.05 ± 0.01 au, p < 0.05), and increased after 4 months (0.08 ± 0.01 au, p < 0.05). As TMH decreased, tear osmolarity increased in both control (R = -0.66, p < 0.05) and CL-treated marmosets (R = -0.64, p < 0.05). The results suggest that marmosets treated with CL for 5 months experienced an increase in blink rate, CCT and TMH, along with a decrease in osmolarity within the first few months of CL treatment that differed from the unaffected stable ocular surface findings observed untreated animals. We hypothesize that CL wear in marmosets might induce an increased blink rate and TMH, in turn delaying the development of hyperosmolarity. These findings confirm that the marmoset is a good novel animal model for ocular surface research for the assessment of novel contact lens materials aimed to alleviate CLIDE.

Trait Loss in Evolution: What Cavefish Have Taught Us about Mechanisms Underlying Eye Regression.

Reduction or complete loss of traits is a common occurrence throughout evolutionary history. In spite of this, numerous questions remain about why and how trait loss has occurred. Cave animals are an excellent system in which these questions can be answered, as multiple traits, including eyes and pigmentation, have been repeatedly reduced or lost across populations of cave species. This review focuses on how the blind Mexican cavefish, Astyanax mexicanus, has been used as a model system for examining the developmental, genetic, and evolutionary mechanisms that underlie eye regression in cave animals. We focus on multiple aspects of how eye regression evolved in A. mexicanus, including the developmental and genetic pathways that contribute to eye regression, the effects of the evolution of eye regression on other traits that have also evolved in A. mexicanus, and the evolutionary forces contributing to eye regression. We also discuss what is known about the repeated evolution of eye regression, both across populations of A. mexicanus cavefish and across cave animals more generally. Finally, we offer perspectives on how cavefish can be used in the future to further elucidate mechanisms underlying trait loss using tools and resources that have recently become available.

Trends in Pain Medication Use in Patients With Type 2 Diabetes: NHANES 2005-2018.

The aim of this research was to compare pain medication use trends among adults with and without type 2 diabetes in the US. This cross-sectional study used data of adults with and without (type 2) diabetes from the National Health and Nutrition Examination Survey waves 2005-2018. Use of pain medication including opioids, prescription nonsteroidal anti-inflammatory drugs, gabapentinoids, serotonin norepinephrine reuptake inhibitors, skeletal muscle relaxants, and headache treatment agents was compared by diabetes status and within select social determinants of health and clinical factors. Adults with type 2 diabetes were twice as likely to be prescribed pain medications compared to those without a diabetes diagnosis (16.2% vs 8.6%). Females and those with a history of smoking or arthritis were more likely to be on pain medications. Opioid use was the most prevalent regardless of diabetes status, and use was twice as high among those with diabetes (10.8% vs 5.5%). Patients with type 2 diabetes in the US are twice as likely to be prescribed pain medications overall as well as opioids compared with those without diabetes. Clinical guideline recommendations are necessary to find pharmacologic and nonpharmacologic nociceptive pain management specific for patients with diabetes.

Recent trends in the prescription of opioids in the emergency department in patients with urolithiasis.

PURPOSE: Pain management is central in the treatment of urolithiasis. We aimed to estimate the impact of the 2017 Department of Health and Human Services declaration of an opioid crisis on prescribing patterns of opioids and NSAIDs in emergency department visits for urolithiasis. METHODS: The National Health Ambulatory Medical Care Survey (NHAMCS) was queried for emergency department visits of adults with a diagnosis of urolithiasis. The association between urolithiasis and narcotic and NSAIDs prescription patterns was evaluated and compared at pre-declaration (2014-2016) to post-declaration (2017-2018) periods. RESULTS: Opioids were prescribed in about 211 million (41.1%) out of 513 million emergency department visits, over a 5-year period. Diagnosis of urolithiasis accounted for 1.9% of the visits (6.0 million). The use of opioids was higher in urolithiasis (82.7%) compared to non-urolithiasis diagnosis (40.3%), as well as the use of multiple opioids per visit (p < 0.01 for all). There was an overall decrease in opioid prescriptions in the post-declaration period, - 4.3% for urolithiasis (p = 0.254) and - 5.6% for non-urolithiasis visits (p < 0.05). A decrease in the use of hydromorphone (- 47.5%. p < 0.001), an increase in the use of morphine (+ 59.7% p = 0.006), and an increase of 'other' opioids (+ 98.8%, p < 0.041), were observed. Opioids combined with NSAIDs comprised 72.6% of the opioid prescriptions and 62.3% of all analgesic prescriptions in visits with urolithiasis diagnosis. CONCLUSIONS: The use of opioids when managing urolithiasis decreased 4.3% after the crisis declaration; however, statistically are not different from pre-declaration numbers. Most often, opioids were prescribed with NSAIDs in urolithiasis patients.

DPP4-Truncated CXCL12 Alters CXCR4/ACKR3 Signaling, Osteogenic Cell Differentiation, Migration, and Senescence.

Bone marrow skeletal stem cells (SSCs) secrete many cytokines including stromal derived factor-1 or CXCL12, which influences cell proliferation, migration, and differentiation. All CXCL12 splice variants are rapidly truncated on their N-terminus by dipeptidyl peptidase 4 (DPP4). This includes the common variant CXCL12 alpha (1-68) releasing a much less studied metabolite CXCL12(3-68). Here, we found that CXCL12(3-68) significantly inhibited SSC osteogenic differentiation and RAW-264.7 cell osteoclastogenic differentiation and induced a senescent phenotype in SSCs. Importantly, pre-incubation of SSCs with CXCL12(3-68) significantly diminished their ability to migrate toward CXCL12(1-68) in transwell migration assays. Using a high-throughput G-protein-coupled receptor (GPCR) screen (GPCRome) and bioluminescent resonance energy transfer molecular interaction assays, we revealed that CXCL12(3-68) acts via the atypical cytokine receptor 3-mediated ß-arrestin recruitment and as a competitive antagonist to CXCR4-mediated signaling. Finally, a reverse phase protein array assay revealed that DPP4-cleaved CXCL12 possesses a different downstream signaling profile from that of intact CXCL12 or controls. The data presented herein provides insights into regulation of CXCL12 signaling. Importantly, it demonstrates that DPP4 proteolysis of CXCL12 generates a metabolite with significantly different and previously overlooked bioactivity that helps explain discrepancies in the literature. This also contributes to an understanding of the molecular mechanisms of osteoporosis and bone fracture repair and could potentially significantly affect the interpretation of experimental outcomes with clinical consequences in other fields where CXCL12 is vital, including cancer biology, immunology, cardiovascular biology, neurobiology, and associated pathologies.