Fellowship-Trained Surgeons Experience a Learning Curve Performing Revision Total Joint Arthroplasty.

BACKGROUND: Revision hip (rTHA) and knee (rTKA) arthroplasties require considerable surgical proficiency, but are frequently delegated to the least experienced surgeons. This study examined the influence of surgeon experience on revision outcomes. METHODS: Prospective data on confirmed aseptic rTHAs (n=122) and rTKAs (n=195) performed by four fellowship-trained surgeons in the same practice were retrospectively analyzed. Surgeons were grouped based on years in practice (inexperienced [IE] first two years, early experience [EE) 4 to 6 years, senior experience [SE] 15 to 17 years). Procedure duration, estimated blood loss (EBL), and reoperation rates were compared, controlling for potential covariates. RESULTS: Procedure durations varied based on surgeon experience for three of four rTHA diagnoses (P≤0.001). Relative to the SE surgeon, procedure duration was 80.0 (95% CI [confidence interval] 61.7 to 98.4, P<0.001) minutes longer for IE surgeons and 30.9 (95% CI 17.5 to 44.3, P < 0.001) minutes longer for the EE surgeon. Procedure durations also varied based on surgeon experience for three of four rTKA diagnoses (P<0.001), with the longest durations for IE surgeons. Procedure durations varied based on the interaction of surgeon experience, patient age, and body mass index (BMI). The EBL did not differ in rTHA based on surgeon experience (P=0.978), but did differ for rTKA (P=0.004). There were 25% of rTHAs performed by IE surgeons compared to 15.5% for the EE surgeon and 3.6% for the SE surgeon that underwent reoperation within a year of the index procedure (P=0.064), with significantly more reoperations for the same indication among IE and EE surgeons (P=0.046). CONCLUSIONS: Complex procedures completed by less experienced surgeons may result in longer procedures, higher EBL, and more early reoperations. Study findings implicate a learning curve for revision arthroplasty that continues for several years, warranting consideration of existing patient allocation and referral patterns.

Diabetes-associated Genetic Variation in MTNR1B and Its Effect on Islet Function.

Context: Multiple common genetic variants have been associated with type 2 diabetes, but the mechanism by which they predispose to diabetes is incompletely understood. One such example is variation in MTNR1B, which implicates melatonin and its receptor in the pathogenesis of type 2 diabetes. Objective: To characterize the effect of diabetes-associated genetic variation at rs10830963 in the MTNR1B locus on islet function in people without type 2 diabetes. Design: The association of genetic variation at rs10830963 with glucose, insulin, C-peptide, glucagon, and indices of insulin secretion and action were tested in a cohort of 294 individuals who had previously undergone an oral glucose tolerance test (OGTT). Insulin sensitivity, ß-cell responsivity to glucose, and Disposition Indices were measured using the oral minimal model. Setting: The Clinical Research and Translation Unit at Mayo Clinic, Rochester, MN. Participants: Two cohorts were utilized for this analysis: 1 cohort was recruited on the basis of prior participation in a population-based study in Olmsted County. The other cohort was recruited on the basis of TCF7L2 genotype at rs7903146 from the Mayo Biobank. Intervention: Two-hour, 7-sample OGTT. Main Outcome Measures: Fasting, nadir, and integrated glucagon concentrations. Results: One or 2 copies of the G-allele at rs10830963 were associated with increased postchallenge glucose and glucagon concentrations compared to subjects with the CC genotype. Conclusion: The effects of rs10830963 on glucose homeostasis and predisposition to type 2 diabetes are likely to be partially mediated through changes in α-cell function.

A fine-scale examination of parturition timing in temperate ungulates.

Parturition timing has long been a topic of interest in ungulate research. However, few studies have examined parturition timing at fine scale (e.g., <1 day). Predator activity and environmental conditions can vary considerably with diel timing, which may result in selective pressure for parturition to occur during diel times that maximize the likelihood of neonate survival. We monitored parturition events and early-life survival of elk (Cervus canadensis) and mule deer (Odocoileus hemionus) in Utah, USA to better understand diel timing of parturition in temperate ungulates. Diel timing of parturition was moderately synchronous among conspecifics and influenced by environmental variables on the date of parturition. For elk, parturition events were most common during the morning crepuscular period and generally occurred later (i.e., closer to 12:00) when a relatively large proportion of the moon was illuminated. For mule deer, parturition events were most common during the diurnal period and generally occurred later (i.e., closer to 15:00) on cold, wet dates. Diel timing of parturition did not influence neonate survival, but larger datasets may be required to verify the apparent lack of influence. Although additional work could evaluate alternative variables that might affect parturition timing, our data provide an improved and finer scale understanding of reproductive ecology and phenology in ungulates.

Effect of disclosing a polygenic risk score for coronary heart disease on adverse cardiovascular events: 10-year follow-up of the MI-GENES randomized clinical trial.

Background: The MI-GENES clinical trial (NCT01936675), in which participants at intermediate risk of coronary heart disease (CHD) were randomized to receive a Framingham risk score (FRSg, n=103), or an integrated risk score (IRSg, n=104) that additionally included a polygenic risk score (PRS), demonstrated that after 6 months, participants randomized to IRSg had higher statin initiation and lower low-density lipoprotein cholesterol (LDL-C). Objectives: In a post hoc 10-year follow-up analysis of the MI-GENES trial, we investigated whether disclosure of a PRS for CHD was associated with a reduction in adverse cardiovascular events. Methods: Participants were followed from randomization beginning in October 2013 until September 2023 to ascertain adverse cardiovascular events, testing for CHD, and changes in risk factors, by blinded review of electronic health records. The primary outcome was the time from randomization to the occurrence of the first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction, coronary revascularization, and non-fatal stroke. Statistical analyses were conducted using Cox proportional hazards regression and linear mixed-effects models. Results: We followed all 203 participants who completed the MI-GENES trial, 100 in FRSg and 103 in IRSg (mean age at the end of follow-up: 68.2±5.2, 48% male). During a median follow-up of 9.5 years, 9 MACEs occurred in FRSg and 2 in IRSg (hazard ratio (HR), 0.20; 95% confidence interval (CI), 0.04 to 0.94; P=0.042). In FRSg, 47 (47%) underwent at least one test for CHD, compared to 30 (29%) in IRSg (HR, 0.51; 95% CI, 0.32 to 0.81; P=0.004). IRSg participants had a longer duration of statin therapy during the first four years post-randomization and a greater reduction in LDL-C for up to 3 years post-randomization. No significant differences between the two groups were observed for hemoglobin A1C, systolic and diastolic blood pressures, weight, and smoking cessation rate during follow-up. Conclusions: The disclosure of an IRS that included a PRS to individuals at intermediate risk for CHD was associated with a lower incidence of MACE after a decade of follow-up, likely due to a higher rate of initiation and longer duration of statin therapy, leading to lower LDL-C levels.

Effects of ondansetron on symptoms during a gastric emptying study and enteral lipid challenge and on daily symptoms in diabetic gastroenteropathy.

BACKGROUND: This study compared the effects of ondansetron and placebo in patients with diabetes mellitus and symptoms of dyspepsia (diabetic gastroenteropathy [DGE]). METHODS: We performed a randomized, double-blinded, placebo-controlled study of ondansetron tablets (8 mg) three times daily for 4 weeks in DGE patients. Symptoms were assessed with the Gastroparesis Cardinal Symptom Index daily diaries. Gastric emptying (GE) of solids (scintigraphy) and duodenal lipid infusions (300 kcal over 2 h) were each assessed twice, with placebo and ondansetron. Drug effects on GE, symptoms during the GE study and during lipid infusion, and daily symptoms were analyzed. KEY RESULTS: Of 41 patients, 37 completed both GE studies and one completed 1; 31 completed both lipid infusions and four only placebo; and all 35 randomized patients completed 4 weeks of treatment. Compared to placebo, ondansetron reduced the severity of fullness (p = 0.02) and belching (p = 0.049) during lipid infusion but did not affect GE T1/2. Both ondansetron and placebo improved daily symptoms versus the baseline period (p < 0.05), but the differences were not significant. In the analysis of covariance of daily symptoms during the treatment period, the interaction term between treatment and the acute effect of ondansetron on symptoms during lipid challenge was significant (p = .024). CONCLUSIONS & INFERENCES: Ondansetron significantly reduced fullness during enteral lipid infusion in patients with DGE. Overall, ondansetron did not improve daily symptoms versus placebo. But patients in whom ondansetron improved symptoms during enteral lipid challenge were perhaps more likely to experience symptom relief during daily treatment.

The Longitudinal Effect of Diabetes-Associated Variation in TCF7L2 on Islet Function in Humans.

The T allele at rs7903146 in TCF7L2 increases the rate of conversion from prediabetes to type 2 diabetes. This has been associated with impaired ß-cell function and with defective suppression of α-cell secretion by glucose. However, the temporal relationship of these abnormalities is uncertain. To study the longitudinal changes in islet function, we recruited 128 subjects, with 67 homozygous for the diabetes-associated allele (TT) at rs7903146 and 61 homozygous for the protective allele. Subjects were studied on two occasions, 3 years apart, using an oral 75-g glucose challenge. The oral minimal model was used to quantitate ß-cell function; the glucagon secretion rate was estimated from deconvolution of glucagon concentrations. Glucose tolerance worsened in subjects with the TT genotype. This was accompanied by impaired postchallenge glucagon suppression but appropriate ß-cell responsivity to rising glucose concentrations. These data suggest that α-cell abnormalities associated with the TT genotype (rs7903146) occur early and may precede ß-cell dysfunction in people as they develop glucose intolerance and type 2 diabetes.

Concordance of Blood Glucose and CGM During a Pilot Trial of Automated Insulin Delivery in Type 1 Diabetes Pregnancies.

Background: Customized and standard automated insulin delivery (AID) systems for use in pregnancies of women with preexisting type 1 diabetes (T1D) are being developed and tested to achieve pregnancy appropriate continuous glucose monitoring (CGM) targets. Guidance on the use of CGM for treatment decisions during pregnancy in the United States is limited. Methods: Ten pregnant women with preexisting T1D participated in a trial evaluating at-home use of a pregnancy-specific AID system. Seven-point self-monitoring of blood glucose (SMBG) was compared to the closest sensor glucose (Dexcom G6 CGM) value biweekly to assess safety and reliability based on the 20%/20 mg/dL criteria. Results: All participants completed the study with 7 participants satisfying the safety and reliability criteria with a mean absolute relative difference of 10.3%. Three participants did not fulfill the criteria, mainly because the frequency of SMBG did not meet the requirements. Conclusion: Dexcom G6 CGM is safe and accurate in the real-world setting for use in pregnant women with preexisting T1D with reduced SMBG testing as part of a pregnancy-specific AID system.

Cardiac Resynchronization Therapy for Patients With Mild to Moderately Reduced Ejection Fraction and Left Bundle Branch Block.

BACKGROUND: It is unknown whether cardiac resynchronization therapy (CRT) would improve or halt the progression of heart failure (HF) in patients with mild to moderately reduced ejection fraction (HFmmrEF) and left bundle branch block (LBBB). OBJECTIVE: This study aimed to investigate the outcomes of CRT in patients with HFmmrEF and left ventricular conduction delay. METHODS: A prospective, randomized clinical trial sponsored by the National Heart, Lung, and Blood Institute included 76 patients who met the study inclusion criteria (left ventricular ejection fraction [LVEF] of 36%-50% and LBBB). Patients received CRT-pacemaker and were randomized to CRT-OFF (right ventricular pacing 40 beats/min) or CRT-ON (biventricular pacing 60-150 beats/min). At a 6-month follow-up, pacing programming was changed to the opposite settings. New York Heart Association class, N-terminal pro-brain natriuretic peptide levels, and echocardiographic variables were collected at baseline, 6 months, and 12 months. The primary study end point was the left ventricular end-systolic volume (LVESV) change from baseline, and the primary randomized comparison was the comparison of 6-month to 12-month changes between randomized groups. RESULTS: The mean age of the patients was 68.4 ± 9.8 years (male, 71%). Baseline characteristics were similar between the 2 randomized groups (all P > .05). In patients randomized to CRT-OFF first, then CRT-ON, LVESV was reduced from baseline only after CRT-ON (baseline, 116.1 ± 36.5 mL; CRT-ON, 87.6 ± 26.0 mL; P < .0001). The randomized analysis of LVEF showed a significantly better change from 6 to 12 months in the OFF-ON group (P = .003). LVEF was improved by CRT (baseline, 41.3% ±.7%; CRT-ON, 46.0% ± 8.0%; P = .002). In patients randomized to CRT-ON first, then CRT-OFF, LVESV was reduced after both CRT-ON and CRT-OFF (baseline, 109.8 ± 23.5 mL; CRT-ON, 91.7 ± 30.5 mL [P < .0001]; CRT-OFF, 99.3 ± 28.9 mL [P = .012]). However, the LVESV reduction effect became smaller between CRT-ON and CRT-OFF (P = .027). LVEF improved after both CRT-ON and CRT-OFF (baseline, 42.7% ± 4.3%; CRT-ON, 48.5% ± 8.6% [P < .001]; CRT-OFF, 45.9% ± 7.7% [P = .025]). CONCLUSION: CRT for patients with HFmmrEF significantly improves LVEF and ventricular remodeling after 6 months of CRT. The study provides novel evidence that early CRT benefits patients with HFmmrEF with LBBB.

Changes in thyroid hormone concentrations over time in dogs with autoimmune thyroiditis.

OBJECTIVE: The objective of this study was to follow long-term changes in the concentration of thyroid hormones in dogs with subclinical thyroiditis. SAMPLES: Samples were obtained from 125 dogs with subclinical thyroiditis. The study population included 70 female and 55 male dogs. The mean testing interval was 3.9 years from initial testing (SD, 2.3 years; range, 1 to 9 years). METHODS: Dogs with subclinical thyroiditis were identified retrospectively using results from the Orthopedic Foundation for Animals Canine Thyroid Profile performed by the Endocrinology Section of the Michigan State University Veterinary Diagnostic Lab. Owners were invited to submit follow-up serum samples with their veterinarian along with a medical history form, including subsequent treatments. RESULTS: At the time of retesting, 30% of the dogs had progressed to hypothyroidism and/or were treated with thyroxine. Fifty percent maintained positive or equivocal thyroglobulin autoantibody (TgAA) results while remaining euthyroid. Fourteen percent of the dogs became TgAA negative and remained euthyroid. In 6% of the cases tested, proper medical histories were not available, and a final classification could not be determined. CLINICAL RELEVANCE: These results indicate that most dogs with elevated thyroglobulin autoantibodies either exhibit persistent autoimmune thyroiditis with continued risk of hypothyroidism or progress to hypothyroidism when monitored for more than 1 year. Thyroid function in dogs with subclinical thyroiditis should be monitored every 12 months or if there is change in the clinical presentation.

INHIBITORS OF INORGANIC POLYPHOSPHATE AND NUCLEIC ACIDS ATTENUATE IN VITRO THROMBIN GENERATION IN PLASMA FROM TRAUMA PATIENTS.

ABSTRACT: Background: Inorganic polyphosphate (polyP) is a procoagulant polyanion. We assessed the impact of polyP inhibition on thrombin generation after trauma using the novel polyP antagonists, macromolecular polyanion inhibitor 8 (MPI 8), and universal heparin reversal agent 8 (UHRA-8). Methods: Plasma thrombin generation (calibrated automated thrombogram, CAT), in 56 trauma patients and 39 controls +/- MPI 8 and UHRA-8 (50 µg/mL), was expressed as lag time (LT, minutes), peak height (PH, nM), and time to peak (ttPeak, minutes), with change in LT (ΔLT) and change in ttPeak (ΔttPeak) quantified. Results expressed in median and quartiles [Q1, Q3], Wilcoxon matched-pairs testing, P < 0.05 significant. Results: Trauma patients had greater baseline PH than controls (182.9 [121.0, 255.2]; 120.5 [62.1, 174.8], P < 0.001). MPI 8 treatment prolonged LT and ttPeak in trauma (7.20 [5.88, 8.75]; 6.46 [5.45, 8.93], P = 0.020; 11.28 [8.96, 13.14]; 11.00 [8.95, 12.94], P = 0.029) and controls (7.67 [6.67, 10.50]; 6.33 [5.33, 8.00], P < 0.001; 13.33 [11.67, 15.33]; 11.67 [10.33, 13.33], P < 0.001). UHRA-8 treatment prolonged LT and ttPeak and decreased PH in trauma (9.09 [7.45, 11.33]; 6.46 [5.45, 8.93]; 14.02 [11.78, 17.08]; 11.00 [8.95, 12.94]; 117.4 [74.5, 178.6]; 182.9 [121.0, 255.2]) and controls (9.83 [8.00, 12.33]; 6.33 [5.33, 8.00]; 16.67 [14.33, 20.00]; 11.67 [10.33, 13.33]; 55.3 [30.2, 95.9]; 120.5 [62.1, 174.8]), all P < 0.001. Inhibitor effects were greater for controls (greater ΔLT and ΔttPeak for both inhibitors, P < 0.001). Conclusion: PolyP inhibition attenuates thrombin generation, though to a lesser degree in trauma than in controls, suggesting that polyP contributes to accelerated thrombin generation after trauma.

Small intestinal bacterial overgrowth in diabetic gastroenteropathy.

BACKGROUND: Although diabetic gastroenteropathy (DGE) is associated with small intestinal bacterial overgrowth (SIBO), most studies have evaluated SIBO with a hydrogen breath test, which may be affected by altered transit in DGE. The risk factors for the consequences of SIBO in DGE are poorly understood. We aimed to evaluate the prevalence of, risk factors for, and gastrointestinal symptoms associated with SIBO in patients with DGE. METHODS: In 75 patients with DGE and dyspepsia, we tested for SIBO (≥105 colony forming units /mL of aerobic and/or anaerobic bacteria in a duodenal aspirate) and assessed gastric emptying (GE) of solids, symptoms during a GE study and during an enteral lipid challenge (300 kcal/2 h), and daily symptoms with a Gastroparesis Cardinal Symptom Index diary for 2 weeks. Symptoms and GE were compared in patients with versus without SIBO. KEY RESULTS: Of 75 patients, 34 (45%) had SIBO, which was not associated with the use of proton pump inhibitors, daily symptoms, GE, or symptoms during a GE study. During enteral lipid challenge, severe nausea (p = 0.006), fullness (p = 0.02) and bloating (p = 0.009) were each associated with SIBO. Twenty patients (59%) with versus 13 (32%) without SIBO had at least one severe symptom during the lipid challenge (p = 0.006). CONCLUSIONS & INFERENCES: Among patients with DGE 45% had SIBO, which was associated with symptoms during enteral lipid challenge but not with delayed GE, symptoms during a GE study, or daily symptoms. Perhaps bacterial products and even fatty acids are recognized by and activate mast cells that drive the increased lipid sensitivity in SIBO.

A Mindfulness-Based Intervention for Acute Care Nursing Staff: A Pilot Study.

Purpose:The purpose of this study was to determine if a mindfulness-based smartphone application, used for 5 minutes a day for 30 days, could address burnout among acute care nursing staff. Methods: A pretest-posttest design with a midpoint evaluation was utilized. The sample included 31 nursing staff from cardiovascular acute care units. The Copenhagen Burnout Inventory, Cognitive and Affective Mindfulness Scale-Revised, Perceived Stress Scale, and Brief Resilience Scale were used to measure the impact of the intervention on participants. Findings: In a repeated measures analysis, there were no statistically significant changes in scores on the Brief Resilience Scale across the three timeframes (F = 0.64, df = 1.42, p = .49). There were significant reductions over time for perceived stress (F = 10.56, df = 1.74, p = .002) and personal burnout (F = 11.8, df = 1.10, p = .007), and increased scores on mindfulness (F = 4.76, df = 1.57, p = .039). Conclusions: The utilization of a mindfulness-based smartphone application may promote the health and well-being of cardiovascular nurses in acute care units. Mindfulness-based smartphone apps should be considered as a method of self-care, along with other holistic approaches to improve well-being.

Effect of clinical decision support for severe hypercholesterolemia on low-density lipoprotein cholesterol levels.

Severe hypercholesterolemia/possible familial hypercholesterolemia (FH) is relatively common but underdiagnosed and undertreated. We investigated whether implementing clinical decision support (CDS) was associated with lower low-density lipoprotein cholesterol (LDL-C) in patients with severe hypercholesterolemia/possible FH (LDL-C ≥ 190 mg/dL). As part of a pre-post implementation study, a CDS alert was deployed in the electronic health record (EHR) in a large health system comprising 3 main sites, 16 hospitals and 53 clinics. Data were collected for 3 months before ('silent mode') and after ('active mode') its implementation. Clinicians were only able to view the alert in the EHR during active mode. We matched individuals 1:1 in both modes, based on age, sex, and baseline lipid lowering therapy (LLT). The primary outcome was difference in LDL-C between the two groups and the secondary outcome was initiation/intensification of LLT after alert trigger. We identified 800 matched patients in each mode (mean ± SD age 56.1 ± 11.8 y vs. 55.9 ± 11.8 y; 36.0% male in both groups; mean ± SD initial LDL-C 211.3 ± 27.4 mg/dL vs. 209.8 ± 23.9 mg/dL; 11.2% on LLT at baseline in each group). LDL-C levels were 6.6 mg/dL lower (95% CI, -10.7 to -2.5; P = 0.002) in active vs. silent mode. The odds of high-intensity statin use (OR, 1.78; 95% CI, 1.41-2.23; P < 0.001) and LLT initiation/intensification (OR, 1.30, 95% CI, 1.06-1.58, P = 0.01) were higher in active vs. silent mode. Implementation of a CDS was associated with lowering of LDL-C levels in patients with severe hypercholesterolemia/possible FH, likely due to higher rates of clinician led LLT initiation/intensification.

County Rurality and Incidence and Prevalence of Diagnosed Diabetes in the United States.

OBJECTIVE: To examine differences in the incidence and prevalence of diagnosed diabetes by county rurality. PATIENTS AND METHODS: This observational, cross-sectional study used US Centers for Disease Control and Prevention data from 2004 through 2019 for county estimates of incidence and prevalence of diagnosed diabetes. County rurality was based on 6 levels (large central metro counties [most urban] to noncore counties [most rural]). Weighted least squares regression was used to relate rurality with diabetes incidence rates (IRs; per 1000 adults) and prevalence (percentage) in adults aged 20 years or older after adjusting for county-level sociodemographic factors (eg, food environment, health care professionals, inactivity, obesity). RESULTS: Overall, in 3148 counties and county equivalents, the crude IR and prevalence of diabetes were highest in noncore counties. In age and sex ratio-adjusted models, the IR of diabetes increased monotonically with increasing rurality (P<.001), whereas prevalence had a weak, nonmonotonic but statistically significant increase (P=.002). Further adjustment for sociodemographic factors including food environment, health care professionals, inactivity, and obesity attenuated differences in incidence across rurality levels, and reversed the pattern for prevalence (prevalence ratios [vs large central metro] ranged from 0.98 [95% CI, 0.97 to 0.99] for large fringe metro to 0.94 [95% CI, 0.93 to 0.96] for noncore). In region-stratified analyses adjusted for sociodemographic factors including inactivity and obesity, increasing rurality was inversely associated with incidence in the Midwest and West only and inversely associated with prevalence in all regions. CONCLUSION: The crude incidence and prevalence of diagnosed diabetes increased with increasing county rurality. After accounting for sociodemographic factors including food environment, health care professionals, inactivity, and obesity, county rurality showed no association with incidence and an inverse association with prevalence. Therefore, interventions targeting modifiable sociodemographic factors may reduce diabetes disparities by region and rurality.

Structure of Amyloid Peptide Ribbons Characterized by Electron Microscopy, Atomic Force Microscopy, and Solid-State Nuclear Magnetic Resonance.

Polypeptides often self-assemble to form amyloid fibrils, which contain cross-ß structural motifs and are typically 5-15 nm in width and micrometers in length. In many cases, short segments of longer amyloid-forming protein or peptide sequences also form cross-ß assemblies but with distinctive ribbon-like morphologies that are characterized by a well-defined thickness (on the order of 5 nm) in one lateral dimension and a variable width (typically 10-100 nm) in the other. Here, we use a novel combination of data from solid-state nuclear magnetic resonance (ssNMR), dark-field transmission electron microscopy (TEM), atomic force microscopy (AFM), and cryogenic electron microscopy (cryoEM) to investigate the structures within amyloid ribbons formed by residues 14-23 and residues 11-25 of the Alzheimer's disease-associated amyloid-ß peptide (Aß14-23 and Aß11-25). The ssNMR data indicate antiparallel ß-sheets with specific registries of intermolecular hydrogen bonds. Mass-per-area values are derived from dark-field TEM data. The ribbon thickness is determined from AFM images. For Aß14-23 ribbons, averaged cryoEM images show a periodic spacing of ß-sheets. The combined data support structures in which the amyloid ribbon growth direction is the direction of intermolecular hydrogen bonds between ß-strands, the ribbon thickness corresponds to the width of one ß-sheet (i.e., approximately the length of one molecule), and the variable ribbon width is a variable multiple of the thickness of one ß-sheet (i.e., a multiple of the repeat distance in a stack of ß-sheets). This architecture for a cross-ß assembly may generally exist within amyloid ribbons.

Evaluating movement-based methods for estimating the frequency and timing of parturition in mule deer.

BACKGROUND: Information on reproduction of harvested species such as mule deer (Odocoileus hemionus) is vital for conservation and management. Furthermore, parturition in ungulates may be detected using patterns of movement logged by GPS transmitters. Several movement-based methods have been developed to detect parturition in ungulates including the Peterson method, behavioral change point analysis (BCPA), rolling minimum convex polygons (rMCP), individual-based method (IBM), and population-based method (PBM). Our objectives were to (1) test the accuracy and the precision of each previously described method and (2) develop an improved method optimized for mule deer that incorporated aspects of the other methods. METHODS: We determined parturition timing and status for female mule deer fitted with GPS collars and implanted with vaginal implant transmitters (VITs). We used movement patterns before and after parturition to set movement thresholds for each movement-based method. Following model training, we used location and birth date data from an external dataset to test the effectiveness of each movement-based method. Additionally, we developed a novel method for detecting parturition called the analysis of parturition indicators (API). We used two regression analyses to determine the accuracy and precision of estimates generated by each method. RESULTS: The six methods we employed varied in accuracy, with the API, rMCP, and BCPA being most accurate. Precision also varied among methods, with the API, rMCP, and PBM generating the most precise estimates of parturition dates. The API and the rMCP performed similarly and better overall than any of the other existing methods. CONCLUSIONS: We found that movement-based methods could be used to accurately and precisely detect parturition in mule deer. Further, we determined that the API and rMCP methods had the greatest overall success at detecting parturition in mule deer. The relative success of the API and rMCP may be attributed to the fact that both methods use home range size to detect parturition and are validated using known parturition dates of collared deer. We present the API as an efficient method of estimating birth status and timing of parturition of mule deer fitted with GPS transmitters, as well as affirm the effectiveness of a previously developed method, rMCP.

A murine multiple-injury model for the study of thromboinflammation.

INTRODUCTION: Neutrophil extracellular traps (NETs) contribute to trauma-induced coagulopathy. We aimed to develop a murine multiple-injury model that induces thrombo-inflammatory response, that is, NETosis and accelerated thrombin generation. METHODS: Wild-type male mice (n = 10, aged 8-12 weeks) underwent multiple injuries (gastrocnemius crush, femur fracture, and laparotomy) and were compared with an uninjured control group (n = 10). Mice were euthanized by cardiac puncture performed 3 hours after injury. Whole blood samples were immediately processed to platelet poor plasma for thrombin generation kinetics (calibrated automated thrombogram), myeloperoxidase (MPO), and von Willebrand factor quantification. Immunohistochemistry of lung tissue was performed to assess for citrullinated histone 3 (CitH3) and MPO. A NETosis cluster was defined as 3+ neutrophils staining for CitH3 at 400× magnification (CitH3 cluster). Data were presented either as mean (SD) or median (interquartile range) with p < 0.05 significant. Sham and trauma treated animals were compared by the two-sample Wilcoxon rank-sum test. RESULTS: Animals subjected to multiple injuries had accelerated thrombin generation compared with controls with greater peak height (61.3 [41.2-73.2] vs. 28.4 [19.5-37.5] nM, p = 0.035) and shorter time to peak (3.37 [2.81-3.81] vs. 4.5 [4.08-4.75] minutes, p = 0.046). Markers of neutrophil activation were greater following multiple injuries than in controls (MPO, 961.1 [858.1-1116.8] vs. 481.3 [438.0-648.9] ng/mL; p = 0.004). NETosis, as evidenced by the aforementioned defined number of CitH3 clusters in the lung, was greater in multiple-injury animals than in controls (mean [SD], 3 [2.9] vs. 0.2 [0.7]; p = 0.009). CONCLUSION: This is the first study to demonstrate that NETosis and accelerated thrombin generation can be induced using a murine multiple-injury model, as early as 3 hours following injury.

A randomized double-blind trial of clonidine and colesevelam for women with fecal incontinence.

BACKGROUND: Diarrhea and rectal urgency are risk factors for fecal incontinence (FI). The effectiveness of bowel modifiers for improving FI is unclear. METHODS: In this double-blind, parallel-group, randomized trial, women with urge FI were randomly assigned in a 1:1 ratio to a combination of oral clonidine (0.1 mg twice daily) with colesevelam (1875 mg twice daily) or two inert tablets for 4 weeks. The primary outcome was a ≥50% decrease in number of weekly FI episodes. KEY RESULTS: Fifty-six participants were randomly assigned to clonidine-colesevelam (n = 24) or placebo (n = 32); 51 (91%) completed 4 weeks of treatment. At baseline, participants had a mean (SD) of 7.5 (8.2) FI episodes weekly. The primary outcome was met for 13 of 24 participants (54%) treated with clonidine-colesevelam versus 17 of 32 (53%) treated with placebo (p = 0.85). The Bristol stool form score decreased significantly, reflecting more formed stools with clonidine-colesevelam treatment (mean [SD], 4.5 [1.5] to 3.2 [1.5]; p = 0.02) but not with placebo (4.2 [1.9] to 4.1 [1.9]; p = 0.47). The proportion of FI episodes for semiformed stools decreased significantly from a mean (SD) of 76% (8%) to 61% (10%) in the clonidine-colesevelam group (p = 0.007) but not the placebo group (61% [8%] to 67% [8%]; p = 0.76). However, these treatment effects did not differ significantly between groups. Overall, clonidine-colesevelam was well tolerated. CONCLUSIONS AND INFERENCES: Compared with placebo, clonidine-colesevelam did not significantly improve FI despite being associated with more formed stools and fewer FI episodes for semiformed stools.

Atrial fibrillation ablation in heart failure patients: Where do we stand in 2023? - State of the art review.

Atrial fibrillation (AF) and heart failure are common overlapping cardiovascular disorders. Despite important therapeutic advances over the past several decades, controversy persists about whether a rate control or rhythm control approach constitutes the best option in this population. There is also considerable debate about whether antiarrhythmic drug therapy or ablation is the best approach when rhythm control is pursued.  A brief historical examination of the literature addressing this issue will be performed. An analysis of several important clinical outcomes observed in the prospective, randomized studies, which have compared AF ablation to non-ablation treatment options, will be discussed. This review will conclude with recommendations to guide clinicians on the status of AF ablation as a treatment option when considering management options in heart failure patients with atrial fibrillation.

Most patients with disorders of gut-brain interaction receive pharmacotherapy with major or moderate drug-gene interactions.

BACKGROUND: How variations predicted by pharmacogenomic testing to alter drug metabolism and therapeutic response affect outcomes for patients with disorders of gut- brain interaction is unclear. AIMS: To assess the prevalence of pharmacogenomics-predicted drug-gene interactions and symptom outcomes for patients with disorders of gut-brain interaction. METHODS: Patients who were treated in our clinical practice for functional dyspepsia/bowel disorder underwent pharmacogenomic testing. The change in symptoms from baseline to 6 months was compared for patients with variations in CYP2D6 and CYP2C19, which metabolize neuromodulators, and SLC6A4, which encodes the sodium- dependent serotonin transporter. RESULTS: At baseline, 79 of 94 participants (84%) had at least one predicted major drug- gene interaction, and all 94 (100%) had at least one predicted moderate interaction. For the 44 participants who completed a survey of their symptoms at 6 months, the mean (SD) irritable bowel syndrome-symptom severity score decreased from 284 (71) at baseline to 231 (95) at 6 months (p < 0.001). Among patients taking selective serotonin reuptake inhibitors, the decrease in symptom severity (p = 0.03) and pain (p = 0.002) scores from baseline to 6 months was greater for patients with a homozygous SLC6A4 long/long genotype (n = 30) (ie, increased serotonin transporter activity) than for patients with homozygous short/short or heterozygous long/short genotypes (n = 64). Symptom outcomes were not affected by CYP2D6 or CYP2C19 variations. CONCLUSIONS: The homozygous SLC6A4 long/long genotype confers better symptom resolution for patients with disorders of gut-brain interaction who take selective serotonin reuptake inhibitors than do the homozygous short/short or heterozygous long/short genotypes.