Shorter-acting glucagon-like peptide-1 receptor agonists are associated with increased development of gastro-oesophageal reflux disease and its complications in patients with type 2 diabetes mellitus: a population-level retrospective matched cohort study.

BACKGROUND: Shorter half-life glucagon-like peptide-1 receptor agonists (GLP-1 RAs) delay gastric emptying (DGE) more than GLP-1 RAs with longer half-lives. DGE is a known risk factor for gastro-oesophageal reflux disease (GERD) and its complications. AIM: To determine whether short-acting or long-acting GLP-1 RAs are associated with an increased risk of new GERD or GERD-related complications DESIGN: We used the TriNetX global database to identify adult patients with type 2 diabetes mellitus and generated two cohorts totalling 1 543 351 patients on (1) GLP-1 RA or (2) other second-line diabetes medication. Using propensity-score matching, Kaplan-Meier Analysis and Cox-proportional hazards ratio (HR), we analysed outcomes and separately examined outcomes in patients starting short-acting (≤1 day) and long-acting (≥5 days) GLP-1 RAs. RESULTS: 177 666 patients were in each propensity-matched cohort. GLP-1 RA exposure was associated with an increased risk (HR 1.15; 95% CI 1.09 to 1.22) of erosive reflux disease (ERD). However, this was solely due to short-acting (HR 1.215; 95% CI 1.111 to 1.328), but not long-acting (HR 0.994; 95% CI 0.924 to 1.069) GLP-1 RA exposure. Short-acting GLP-1 RAs were also associated with increased risk of oesophageal stricture (HR 1.284; 95% CI 1.135 to 1.453), Barrett's without dysplasia (HR 1.372; 95% CI 1.217 to 1.546) and Barrett's with dysplasia (HR 1.505; 95% CI 1.164 to 1.946) whereas long-acting GLP-1 RAs were not. This association persisted in sensitivity analyses, and when individually examining the short-acting GLP-1 RAs liraglutide, lixisenatide and exenatide. CONCLUSION: Starting shorter-acting GLP-1 RAs is associated with increased risks of GERD and its complications.

Spontaneous coronary artery dissection is infrequent in individuals with heritable thoracic aortic disease despite partially shared genetic susceptibility.

Spontaneous coronary artery dissection (SCAD) is a potential precipitant of myocardial infarction and sudden death for which the etiology is poorly understood. Mendelian vascular and connective tissue disorders underlying thoracic aortic disease (TAD), have been reported in ~5% of individuals with SCAD. We therefore hypothesized that patients with TAD are at elevated risk for SCAD. We queried registries enrolling patients with TAD to define the incidence of SCAD. Of 7568 individuals enrolled, 11 (0.15%) were found to have SCAD. Of the sequenced cases (9/11), pathogenic variants were identified (N = 9), including COL3A1 (N = 3), FBN1 (N = 2), TGFBR2 (N = 2), TGFBR1 (N = 1), and PRKG1 (N = 1). Individuals with SCAD had an increased frequency of iliac artery dissection (25.0% vs. 5.1%, p = 0.047). The prevalence of SCAD among individuals with TAD is low. The identification of pathogenic variants in genes previously described in individuals with SCAD, particularly those underlying vascular Ehlers-Danlos, Marfan syndrome, and Loeys-Dietz syndrome, is consistent with prior reports from clinical SCAD series. Further research is needed to identify specific genetic influences on SCAD risk.

A Novel Recurrent COL5A1 Genetic Variant Is Associated With a Dysplasia-Associated Arterial Disease Exhibiting Dissections and Fibromuscular Dysplasia.

OBJECTIVE: While rare variants in the COL5A1 gene have been associated with classical Ehlers-Danlos syndrome and rarely with arterial dissections, recurrent variants in COL5A1 underlying a systemic arteriopathy have not been described. Monogenic forms of multifocal fibromuscular dysplasia (mFMD) have not been previously defined. Approach and Results: We studied 4 independent probands with the COL5A1 pathogenic variant c.1540G>A, p.(Gly514Ser) who presented with arterial aneurysms, dissections, tortuosity, and mFMD affecting multiple arteries. Arterial medial fibroplasia and smooth muscle cell disorganization were confirmed histologically. The COL5A1 c.1540G>A variant is predicted to be pathogenic in silico and absent in gnomAD. The c.1540G>A variant is on a shared 160.1 kb haplotype with 0.4% frequency in Europeans. Furthermore, exome sequencing data from a cohort of 264 individuals with mFMD were examined for COL5A1 variants. In this mFMD cohort, COL5A1 c.1540G>A and 6 additional relatively rare COL5A1 variants predicted to be deleterious in silico were identified and were associated with arterial dissections (P=0.005). CONCLUSIONS: COL5A1 c.1540G>A is the first recurring variant recognized to be associated with arterial dissections and mFMD. This variant presents with a phenotype reminiscent of vascular Ehlers-Danlos syndrome. A shared haplotype among probands supports the existence of a common founder. Relatively rare COL5A1 genetic variants predicted to be deleterious by in silico analysis were identified in ≈2.7% of mFMD cases, and as they were enriched in patients with arterial dissections, may act as disease modifiers. Molecular testing for COL5A1 should be considered in patients with a phenotype overlapping with vascular Ehlers-Danlos syndrome and mFMD.

Evidence for distinct rate-limiting steps in the cleavage of alkenes by carotenoid cleavage dioxygenases.

Carotenoid cleavage dioxygenases (CCDs) use a nonheme Fe(II) cofactor to split alkene bonds of carotenoid and stilbenoid substrates. The iron centers of CCDs are typically five-coordinate in their resting states, with solvent occupying an exchangeable site. The involvement of this iron-bound solvent in CCD catalysis has not been experimentally addressed, but computational studies suggest two possible roles. 1) Solvent dissociation provides a coordination site for O2, or 2) solvent remains bound to iron but changes its equilibrium position to allow O2 binding and potentially acts as a proton source. To test these predictions, we investigated isotope effects (H2O versus D2O) on two stilbenoid-cleaving CCDs, Novosphingobium aromaticivorans oxygenase 2 (NOV2) and Neurospora crassa carotenoid oxygenase 1 (CAO1), using piceatannol as a substrate. NOV2 exhibited an inverse isotope effect (kH/kD ∼ 0.6) in an air-saturated buffer, suggesting that solvent dissociates from iron during the catalytic cycle. By contrast, CAO1 displayed a normal isotope effect (kH/kD ∼ 1.7), suggesting proton transfer in the rate-limiting step. X-ray absorption spectroscopy on NOV2 and CAO1 indicated that the protonation states of the iron ligands are unchanged within pH 6.5-8.5 and that the Fe(II)-aquo bond is minimally altered by substrate binding. We pinpointed the origin of the differential kinetic behaviors of NOV2 and CAO1 to a single amino acid difference near the solvent-binding site of iron, and X-ray crystallography revealed that the substitution alters binding of diffusible ligands to the iron center. We conclude that solvent-iron dissociation and proton transfer are both associated with the CCD catalytic mechanism.

The Association of Intracranial Aneurysms in Women with Renal Artery Aneurysms.

BACKGROUND: Renal artery aneurysms (RAAs) may reflect a systemic dysplastic arteriopathy, independent of a recognized connective tissue disease. It is hypothesized that RAAs are associated with an increased risk of intracranial aneurysms (IcAs). The objective of this study was to better define the association of IcAs in women with RAAs. METHODS: Women aged 20 to 60 years who presented with RAAs at the University of Michigan from 2001 to 2016 were included in the study. Their clinical status and radiologic images were retrospectively reviewed, with particular attention directed to the prevalence of IcAs. Phenotypic characteristics predictive of associated cerebrovascular lesions were assessed using various statistical analyses, including binomial logistic regression. RESULTS: Among 83 women with RAAs, the average age at the time of RAA detection was 45.3 ± 9.9 years (range, 20-60 years). Hypertension affected 56 (67.5%) patients and poorly controlled hypertension prompted imaging for suspected renal arterial disease in 12 (14.5%) patients. Multifocal fibromuscular dysplasia occurred in 12 (14.8%) of patients, and unifocal stenosis affected 7 (8.4%) patients. Imaging of the intracranial vasculature (n = 31) documented 12 aneurysms in 9 women, with the cavernous internal carotid artery being the most commonly affected artery. Among the study's patients, 20 (24.1%) had an "at-risk disorder for IcA formation," although the frequency of relevant "at-risk disorders" in those with and without IcAs was not statistically different (P = 0.21). Rupture risk defined by PHASES score was less than 1% for 10 IcAs, but 2 IcAs carried a 2.4% and 7.2% rupture risk, respectively, over a 5-year time period. Surgical management was pursued in 6 (50%) of the study's IcAs. CONCLUSIONS: Coexisting RAAs and IcAs may reflect a systemic arteriopathy. IcAs appear to occur with greater frequency in women with RAAs than the general population. This observation warrants prospective investigation as to the clinical appropriateness and relevance of cerebrovascular imaging in women with RAAs. Furthermore, this study's findings prompt further investigation of the underlying pathogenesis of what appears to be a broader and more complex arterial disease than previously recognized.

Preparation and characterization of metal-substituted carotenoid cleavage oxygenases.

Carotenoid cleavage oxygenases (CCO) are non-heme iron enzymes that catalyze oxidative cleavage of alkene bonds in carotenoid and stilbenoid substrates. Previously, we showed that the iron cofactor of CAO1, a resveratrol-cleaving member of this family, can be substituted with cobalt to yield a catalytically inert enzyme useful for trapping active site-bound stilbenoid substrates for structural characterization. Metal substitution may provide a general method for identifying the natural substrates for CCOs in addition to facilitating structural and biophysical characterization of CCO-carotenoid complexes under normal aerobic conditions. Here, we demonstrate the general applicability of cobalt substitution in a prototypical carotenoid cleaving CCO, apocarotenoid oxygenase (ACO) from Synechocystis. Among the non-native divalent metals investigated, cobalt was uniquely able to stably occupy the ACO metal binding site and inhibit catalysis. Analysis by X-ray crystallography and X-ray absorption spectroscopy demonstrate that the Co(II) forms of both ACO and CAO1 exhibit a close structural correspondence to the native Fe(II) enzyme forms. Hence, cobalt substitution is an effective strategy for generating catalytically inert but structurally intact forms of CCOs.

Cinnamon Sugar Scrub Dermatitis: "Natural" Is Not Always Best.

Children are at risk of developing allergic contact dermatitis to fragrances. Personal hygiene products, even those labeled hypoallergenic or considered all natural, may be a significant source of fragrance exposure in this population.

Shin-Guard Dermatitis-Detection and Protection.

With the popularity of soccer among American youth and the associated use of protective shin guards, dermatitis from the guard components has emerged. Awareness and protective measures may help prevent irritation and the development of contact sensitization from the guards.

Benzoate Allergy in Children--From Foods to Personal Hygiene Products.

Benzoate allergy may be an overlooked allergen in children and one that may be of increasing importance with its increasing role as a preservative in pediatric personal hygiene formulations. The cases herein report an association with cola and benzoate allergy and discusses the implications of replacement of formaldehyde by benzoates in personal hygiene products.

The Association between Hormone Replacement Therapy and Gastroparesis in Post-Menopausal Women: A Worldwide Database Analysis.

Female sex hormones have been hypothesized to influence the higher prevalence of gastroparesis in females. This study investigated the effects of hormone replacement therapy (HRT) on gastroparesis and its related symptoms, medication use, and diagnostic testing in post-menopausal women. Utilizing the TriNetX platform, we conducted a population-based cohort study involving post-menopausal women aged 50 or older, with and without HRT. One-to-one propensity score matching was performed to adjust for age, race, ethnicity, diabetes, body mass index (BMI), and hemoglobin A1c. The exclusion criteria included functional dyspepsia, cyclic vomiting syndrome, and surgical procedures. After applying the exclusion criteria, we identified 78,192 post-menopausal women prescribed HRT and 1,604,822 not prescribed HRT. Post-propensity matching, each cohort comprised 67,874 patients. A total of 210 of the post-menopausal women prescribed HRT developed an ICD encounter diagnosis of gastroparesis at least 30 days after being prescribed HRT compared to post-menopausal women not prescribed HRT (OR = 1.23, 95% CI [1.01-1.51] p-value = 0.0395). These associations persisted in sensitivity analysis over 5 years (OR = 1.65, 95% CI [1.13-2.41] p-value = 0.0086). HRT was associated with increased GI symptoms, including early satiety (OR = 1.22, 95% CI [1.03-1.45] p-value = 0.0187), domperidone use (OR = 2.40, 95% CI [1.14-5.02] p-value = 0.0163), and undergoing gastric emptying studies (OR = 1.67, 95% CI [1.39-2.01] p-value < 0.0001). HRT is linked to an increased risk of developing an ICD encounter diagnosis of gastroparesis.

Standardizing the Dosage and Timing of Dexamethasone for Postoperative Nausea and Vomiting Prophylaxis at a Safety-Net Hospital System.

BACKGROUND: A single dose of dexamethasone is routinely given during general anesthesia for postoperative nausea and vomiting (PONV) prophylaxis, although the exact dosage and timing of administration may vary between practitioners. The authors aimed to standardize the dosage and timing of this medication when given to adult patients undergoing general anesthesia for elective surgery. METHODS: Baseline data for 7,483 preintervention cases were analyzed. The researchers attempted to use a standard dose of 8 to 10 mg induction of anesthesia, which, based on a literature review, was effective for PONV prophylaxis, had a similar safety profile as a 4 to 5 mg dose (including in diabetic patients), and may confer additional benefits such as improved prophylaxis and quality of recovery. The interventions included standardizing the medication concentration vials, altering electronic health record quick-select button options, simplifying the intraoperative charting process, and educating the anesthesia providers. The research team then tracked compliance with the standard of care for 2,167 cases after the interventions. RESULTS: Overall compliance with the standard of care increased from 21.2% preintervention to 53.7% postintervention. The number of patients not receiving dexamethasone was reduced from 29.7% to 19.4%. Patients receiving a compliant dose at a noncompliant time increased from 16.3% to 23.8%. Postanesthesia care unit antiemetic administration also decreased after the interventions. CONCLUSION: This study showed improvements in compliance with the dosage of medication with the interventions. However, compliance with the timing of administration remains challenging.

Scanning the aged to minimize missed injury: An EAST multicenter study.

BACKGROUND: Despite the high incidence of blunt trauma in older adults, there is a lack of evidence-based guidance for computed tomography (CT) imaging in this population. We aimed to identify an algorithm to guide use of a Pan-Scan (Head/C-spine/Torso) or a Selective Scan (Head/C-spine ± Torso). We hypothesized that a patient's initial history and exam could be used to guide imaging. METHODS: We prospectively studied blunt trauma patients aged 65+ at 18 Level I/II trauma centers. Patients presenting >24 h after injury or who died upon arrival were excluded. We collected history and physical elements and final injury diagnoses. Injury diagnoses were categorized into CT body regions of Head/C-spine or Torso (chest, abdomen/pelvis, and T/L spine). Using machine learning and regression modeling as well as a priori clinical algorithms based, we tested various decision rules against our dataset. Our priority was to identify a simple rule which could be applied at the bedside, maximizing sensitivity (Sens) and negative predictive value (NPV) to minimize missed injuries. RESULTS: We enrolled 5,498 patients with 3,082 injuries. Nearly half (47.1%, n = 2,587) had an injury within the defined CT body regions. No rule to guide a Pan-Scan could be identified with suitable Sens/NPV for clinical use. A clinical algorithm to identify patients for Pan-Scan, using a combination of physical exam findings and specific high-risk criteria, was identified and had a Sens of 0.94 and NPV of 0.86 This rule would have identified injuries in all but 90 patients (1.6%) and would theoretically spare 11.9% (655) of blunt trauma patients a torso CT. CONCLUSIONS: Our findings advocate for Head/Cspine CT in all geriatric patients with the addition of torso CT in the setting of positive clinical findings and high-risk criteria. Prospective validation of this rule could lead to streamlined diagnostic care of this growing trauma population. LEVEL OF EVIDENCE: Level 2, Diagnostic Tests or Criteria.

Physical activity has a stronger correlation with arterial stiffness than strength, balance, or BMI in an older population.

Background: Arterial stiffness is associated with an array of debilitating health conditions. While exercise typically has beneficial effects on both arterial stiffness and overall health, more research is needed to understand the associations of different types of fitness indices with arterial stiffness. Aim: To investigate the relationship between balance, strength, cardiovascular fitness and physical activity with arterial stiffness (as measured by pulse wave velocity (PWV)) in older adults. Method: Eighty retirement-village residents (24 males, 56 females, age: 78.2 ± 6.4 years, weight: 69.4 ± 12.5 kg, height: 162.9 ± 8.5 cm) completed the Yale Physical Activity Survey, PWV measurement, 30-s sit-to-stand leg strength test, hand grip strength assessment, 4-stage balance test, and a 6-min walk fitness test. The number of exiting risk factors (smoking, previous heart incidents, previous stroke(s), having hypertension, or taking anti-hypertension medication) were tallied. Pearson's correlations were used to assess the relationship between PWV and health and fitness parameters. Results were interpreted using qualitative inference. Results: The number of risk factors (r = 0.57, p < 0.001), age (r = 0.51, p < 0.001) and systolic blood pressure (r = 0.50, p = 0.001) had strong, harmful associations with PWV. Total physical activity minutes/week (r = -0.31 p = 0.01), total energy expenditure Kcal/week (r = -0.30, p = 0.01), and the 6-min walk test (r = -0.29, p = 0.01) had a moderate, beneficial association with PWV, while sit-to-stand (r = -0.27, p = 0.02) and balance (r = -0.27, p = 0.01) had a weak, beneficial association with PWV. Hand grip strength (r = 0.02, p = 0.94) and body mass index (r = -0.04, p = 0.75) had no significant associations with PWV. Discussion: All measured fitness indices had beneficial associations with PWV. However, having more risk factors, increased age, and higher systolic blood pressure had significant (harmful) associations with PWV in our older population. Conclusion: Controlling cardiovascular risk factors, especially high systolic blood pressure, is likely to have the largest beneficial effect on PWV. Improving general physical activity, including walking capacity, may prove beneficial in improving PWV in an older population.

Raloxifene increases the risk of gastroesophageal reflux disease, Barrett's esophagus, and esophageal stricture in postmenopausal women with osteoporosis.

BACKGROUND AND AIMS: Estrogen-based therapies may increase the risk of gastroesophageal reflux (GERD) and its complications. We aimed to determine the effect of raloxifene on the development of GERD, Barrett's esophagus, and esophageal stricture in postmenopausal women with osteoporosis. METHODS: This was a population-based, propensity-matched cohort study using the TriNetX platform. Patients 50 years and older with a diagnosis of "menopause" and "osteoporosis" were included in this study. Odds ratios (OR) and 95% confidence intervals (CI) were calculated for new GERD, esophageal stricture and Barrett's esophagus after raloxifene exposure. The control cohort consisted of patients who did not start any hormonal replacement therapy. We conducted a multivariable logistic regression analysis to evaluate the effect of confounding variables and also addressed common confounding medications with 1:1 propensity score-matching. Internal validity was confirmed by comparing to negative controls (lisinopril, atorvastatin) and positive controls (metformin, ibuprofen, aspirin). RESULTS: Five thousand four hundred and seventy two postmenopausal women with osteoporosis were on raloxifene of which 1908 (34.86%) developed GERD, compared to 296,067 postmenopausal who were not on raloxifene of which 90,643 (30.62%) developed GERD (OR 1.2; 95% CI 1.10-1.31, p < 0.0001). This persisted after adjusting for common medications known to affect GERD. Raloxifene was identified as a risk factor for GERD in a multivariate analysis, controlling for factors including age, obesity, smoking, and alcohol use (OR 1.51, 95% Wald CI 1.47-1.53). Raloxifene was associated with esophageal stricture (OR 1.60; 95% Wald CI 1.51-1.69) and Barrett's esophagus (OR 1.50; 95% Wald CI 1.37-1.63) in multivariate analysis. These associations persisted using sensitivity analyses. CONCLUSION: Raloxifene increases the risk of GERD, esophageal stricture and Barrett's esophagus in postmenopausal women with osteoporosis. Further studies are needed to confirm our findings.