Role of parathyroid hormone in regeneration of irradiated bone in a murine model of mandibular distraction osteogenesis

BackgroundThe purpose of this study was to measure the histologic and histomorphometric effects of parathyroid hormone (PTH) treatment on irradiated bone undergoing distraction osteogenesis (DO).MethodsThirty‐four rats were divided into 3 groups. The control group underwent DO and the radiation control group underwent radiotherapy (RT) before DO. The PTH group underwent RT and received PTH during DO. Quantitative histology and histomorphometry were performed.ResultsRT resulted in a depletion of osteocytes and increase in empty lacunae. Treatment with PTH resulted in an increase in osteocyte counts and decrease in empty lacunae (p < .05), restoring osteocytes to levels seen in nonradiated bone (p = .121). RT decreased bone volume to tissue volume (BV‐TV) ratio and increased osteoid volume to tissue volume (OV‐TV) ratio, signifying increased immature bone formation. PTH treatment restored OV‐TV ratio to that observed in nonradiated bone.ConclusionPTH treatment of irradiated bone enhanced bone regeneration and restored osteocyte counts and OV‐TV ratio to levels comparable to nonradiated bone. © 2016 Wiley Periodicals, Inc. Head Neck 39: 464–470, 2017Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/136287/1/hed24612.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/136287/2/hed24612_am.pd

Minimal information for studies of extracellular vesicles 2018 (MISEV2018):a position statement of the International Society for Extracellular Vesicles and update of the MISEV2014 guidelines

The last decade has seen a sharp increase in the number of scientific publications describing physiological and pathological functions of extracellular vesicles (EVs), a collective term covering various subtypes of cell-released, membranous structures, called exosomes, microvesicles, microparticles, ectosomes, oncosomes, apoptotic bodies, and many other names. However, specific issues arise when working with these entities, whose size and amount often make them difficult to obtain as relatively pure preparations, and to characterize properly. The International Society for Extracellular Vesicles (ISEV) proposed Minimal Information for Studies of Extracellular Vesicles (“MISEV”) guidelines for the field in 2014. We now update these “MISEV2014” guidelines based on evolution of the collective knowledge in the last four years. An important point to consider is that ascribing a specific function to EVs in general, or to subtypes of EVs, requires reporting of specific information beyond mere description of function in a crude, potentially contaminated, and heterogeneous preparation. For example, claims that exosomes are endowed with exquisite and specific activities remain difficult to support experimentally, given our still limited knowledge of their specific molecular machineries of biogenesis and release, as compared with other biophysically similar EVs. The MISEV2018 guidelines include tables and outlines of suggested protocols and steps to follow to document specific EV-associated functional activities. Finally, a checklist is provided with summaries of key points

Genomic Relationships, Novel Loci, and Pleiotropic Mechanisms across Eight Psychiatric Disorders

Genetic influences on psychiatric disorders transcend diagnostic boundaries, suggesting substantial pleiotropy of contributing loci. However, the nature and mechanisms of these pleiotropic effects remain unclear. We performed analyses of 232,964 cases and 494,162 controls from genome-wide studies of anorexia nervosa, attention-deficit/hyper-activity disorder, autism spectrum disorder, bipolar disorder, major depression, obsessive-compulsive disorder, schizophrenia, and Tourette syndrome. Genetic correlation analyses revealed a meaningful structure within the eight disorders, identifying three groups of inter-related disorders. Meta-analysis across these eight disorders detected 109 loci associated with at least two psychiatric disorders, including 23 loci with pleiotropic effects on four or more disorders and 11 loci with antagonistic effects on multiple disorders. The pleiotropic loci are located within genes that show heightened expression in the brain throughout the lifespan, beginning prenatally in the second trimester, and play prominent roles in neurodevelopmental processes. These findings have important implications for psychiatric nosology, drug development, and risk prediction.Peer reviewe

Glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter 2 inhibitor use among adults with diabetes mellitus by cardiovascular-kidney disease risk: National Health and Nutrition Examination Surveys, 2015–2020

Objective: Glucagon-like peptide-1 receptor agonists (GLP1-RAs) and sodium-glucose cotransporter 2 inhibitors (SGLT2Is) lower adverse cardiac and kidney events among high-risk patients with diabetes mellitus (DM) and are now guideline-recommended as first-line therapy alongside metformin. However, the adoption of these new treatments from 2015 to 2020 among the highest-risk adults with DM remains unclear. Methods: We performed a cross-sectional analysis of the National Health and Nutrition Examination Surveys (NHANES) 2015–2020 to estimate the use of GLP1-RAs and SGLT2Is among adults with DM overall and by level of cardiovascular and kidney risk (CKR). We defined high CKR by history of atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD), heart failure, or age ≥55 years with at least 2 ASCVD risk factors (i.e., obesity, hypertension, hyperlipidemia, or current smoker). Results: Overall, 2,432 participants with DM (mean age 60.6 years, 46.8 % female, 58.8 % Non-Hispanic White) were included, of which 1,869 and 563 were with and without high CKR, respectively. Participants with vs. without high CKR were more likely to be older, have higher systolic blood pressure, lower estimated glomerular filtration rate, use oral antidiabetic agents, and have health insurance. Overall, the weighted prevalence of GLP1-RA or SGLT2I was 9.0 % (95 % confidence interval [CI] 6.9–11.0): 4.8 % (95 % CI 3.6–6.1) took GLP1-RAs, and 5.1 % (95 % CI 3.3–7.0) took SGLT2Is. Use of GLP1-RAs or SGLT2Is did not differ between participants with vs. without high CKR (adjusted prevalence ratio [aPR] 1.00; 95 % CI 0.98–1.02). Participants with ASCVD were more likely to be on a GLP1-RA or SGLT2I (aPR 1.28; 95 % CI 1.25–1.31), while adults with CKD were less likely (aPR 0.84; 95 % CI 0.82–0.86). Conclusion: Among US adults with DM, GLP1-RA and SGLT2I use was low regardless of CKR. Data since 2020 analyzing the utilization of GLP1-RAs and SGLT2Is among high-CKR patients with DM is needed to identify implementation strategies for increased utilization

Lipid-lowering therapy use and intensification among United States veterans following myocardial infarction or coronary revascularization between 2015 and 2019

Background: Understanding how statins, ezetimibe, and PCSK9i (proprotein convertase subtilisin/kexin type 9 serine protease inhibitors) are prescribed after a myocardial infarction (MI) or elective coronary revascularization may improve lipid-lowering therapy (LLT) intensification and reduce recurrent atherosclerotic cardiovascular disease events. We described the use and intensification of LLT among US veterans who had a MI or elective coronary revascularization between July 24, 2015, and December 9, 2019, within 12 months of hospital discharge.Methods: LLT intensification was defined as increasing statin dose, or initiating a statin, ezetimibe, or a PCSK9i, overall and among those with an LDL-C (low-density lipoprotein cholesterol) ≥70 or 100 mg/dL. Poisson regression was used to determine patient characteristics associated with a greater likelihood of LLT intensification following hospitalization for MI or elective coronary revascularization. Results: Among 81 372 index events (mean age, 69.0 years, 2.3% female, mean LDL-C 89.6 mg/dL, 33.8% with LDL-C /dL), 39.7% were not taking any LLT, and 22.0%, 37.2%, and 0.6% were taking a low-moderate intensity statin, a high-intensity statin, and ezetimibe, respectively, before MI/coronary revascularization during the study period. Within 14 days, 3 months, and 12 months posthospitalization, 33.3%, 41.9%, and 47.3%, respectively, of veterans received LLT intensification. LLT intensification was most common among veterans taking no LLT (82.5%, n=26 637) before MI/coronary revascularization. Higher baseline LDL-C, having a lipid test, and attending a cardiology visit were each associated with a greater likelihood of LLT intensification, while age ≥75 versus posthospitalization. Conclusions: Less than half of veterans received LLT intensification in the year after MI or coronary revascularization suggesting a missed opportunity to reduce atherosclerotic cardiovascular disease risk

New Users of Angiotensin II Receptor Blocker–Versus Angiotensin‐Converting Enzyme Inhibitor–Based Antihypertensive Medication Regimens and Cardiovascular Disease Events: A Secondary Analysis of ACCORD‐BP and SPRINT

BACKGROUND Angiotensin II receptor blockers (ARBs) and angiotensin‐converting enzyme inhibitors (ACEIs) block distinct components of the renin‐angiotensin system. Whether this translates into differential effects on cardiovascular disease events remains unclear. METHODS AND RESULTS We used the ACCORD‐BP (Action to Control Cardiovascular Risk in Diabetes–Blood Pressure) trial and the SPRINT (Systolic Blood Pressure Intervention Trial) to emulate target trials of new users of ARBs versus ACEIs on cardiovascular disease events (primary outcome) and death (secondary outcome). We estimated marginal cause‐specific hazard ratios (HRs) and treatment‐specific cumulative incidence functions with inverse probability of treatment weights. We identified 3298 new users of ARBs or ACEIs (ACCORD‐BP: 374 ARB versus 884 ACEI; SPRINT: 727 ARB versus 1313 ACEI). For participants initiating ARBs versus ACEIs, the inverse probability of treatment weight rate of the primary outcome was 3.2 versus 3.5 per 100 person‐years in ACCORD‐BP (HR, 0.91 [95% CI, 0.63–1.31]) and 1.8 versus 2.2 per 100 person‐years in SPRINT (HR, 0.81 [95% CI, 0.56–1.18]). There were no appreciable differences in pooled analyses, except that ARBs versus ACEIs were associated with a lower death rate (HR, 0.56 [95% CI, 0.37–0.85]). ARBs were associated with a lower rate of the primary outcome among subgroups of male versus female participants, non‐Hispanic Black versus non‐Hispanic White participants, and those randomly assigned to standard versus intensive blood pressure (Pinteraction: <0.01, 0.05, and <0.01, respectively). CONCLUSIONS In this secondary analysis of ACCORD‐BP and SPRINT, new users of ARB‐ versus ACEI‐based antihypertensive medication regimens experienced similar cardiovascular disease events rates, with important subgroup differences and lower rates of death overall. REGISTRATION URL: https://www.clinicaltrials.gov; Unique identifiers: NCT01206062, NCT00000620

Association Between Self‐Reported Medication Adherence and Therapeutic Inertia in Hypertension: A Secondary Analysis of SPRINT (Systolic Blood Pressure Intervention Trial)

Background Therapeutic inertia (TI), failure to intensify antihypertensive medication when blood pressure (BP) is above goal, remains prevalent in hypertension management. The degree to which self‐reported antihypertensive adherence is associated with TI with intensive BP goals remains unclear. Methods and Results Cross‐sectional analysis was performed of the 12‐month visit of participants in the intensive arm of SPRINT (Systolic Blood Pressure Intervention Trial), which randomized adults to intensive (120 mm Hg at the 12‐month visit (mean age, 69.6 years; 35.2% female, 28.8% non‐Hispanic Black), TI occurred in 50.8% of participants. Participants with low adherence (versus high) were younger and more likely to be non‐Hispanic Black or smokers. The prevalence of TI among patients with low, medium, and high adherence was 45.0%, 53.5%, and 50.4%, respectively. After adjustment, neither low nor medium adherence (versus high) were associated with TI (PR, 1.11 [95% CI, 0.87–1.42]; PR, 1.08 [95% CI, 0.84–1.38], respectively). Conclusions Although clinician uncertainty about adherence is often cited as a reason for why antihypertensive intensification is withheld when above BP goals, we observed no evidence of an association between self‐reported adherence and TI

Angiotensin II receptor blocker or angiotensin-converting enzyme inhibitor use and COVID-19-related outcomes among US Veterans.

BackgroundAngiotensin II receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs) may positively or negatively impact outcomes in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. We investigated the association of ARB or ACEI use with coronavirus disease 2019 (COVID-19)-related outcomes in US Veterans with treated hypertension using an active comparator design, appropriate covariate adjustment, and negative control analyses.Methods and findingsIn this retrospective cohort study of Veterans with treated hypertension in the Veterans Health Administration (01/19/2020-08/28/2020), we compared users of (A) ARB/ACEI vs. non-ARB/ACEI (excluding Veterans with compelling indications to reduce confounding by indication) and (B) ARB vs. ACEI among (1) SARS-CoV-2+ outpatients and (2) COVID-19 hospitalized inpatients. The primary outcome was all-cause hospitalization or mortality (outpatients) and all-cause mortality (inpatients). We estimated hazard ratios (HR) using propensity score-weighted Cox regression. Baseline characteristics were well-balanced between exposure groups after weighting. Among outpatients, there were 5.0 and 6.0 primary outcomes per 100 person-months for ARB/ACEI (n = 2,482) vs. non-ARB/ACEI (n = 2,487) users (HR 0.85, 95% confidence interval [CI] 0.73-0.99, median follow-up 87 days). Among outpatients who were ARB (n = 4,877) vs. ACEI (n = 8,704) users, there were 13.2 and 14.8 primary outcomes per 100 person-months (HR 0.91, 95%CI 0.86-0.97, median follow-up 85 days). Among inpatients who were ARB/ACEI (n = 210) vs. non-ARB/ACEI (n = 275) users, there were 3.4 and 2.0 all-cause deaths per 100 person months (HR 1.25, 95%CI 0.30-5.13, median follow-up 30 days). Among inpatients, ARB (n = 1,164) and ACEI (n = 2,014) users had 21.0 vs. 17.7 all-cause deaths, per 100 person-months (HR 1.13, 95%CI 0.93-1.38, median follow-up 30 days).ConclusionsThis observational analysis supports continued ARB or ACEI use for patients already using these medications before SARS-CoV-2 infection. The novel beneficial association observed among outpatients between users of ARBs vs. ACEIs on hospitalization or mortality should be confirmed with randomized trials