Association of Blood Pressure With Brain White Matter Microstructural Integrity Assessed With MRI Diffusion Tensor Imaging in Healthy Young Adults.

BACKGROUND: High blood pressure (BP) in middle-aged and older adults is associated with a brain white matter (WM) microstructural abnormality. However, little evidence is available in healthy young adults. We investigated the associations between high BP and WM microstructural integrity in young adults. METHODS: This study included 1015 healthy young adults (542 women, 22-37 years) from the Human Connectome Project. Brachial systolic and diastolic BP were measured using a semiautomatic or manual sphygmomanometer. Diffusion-weighted magnetic resonance imaging was acquired to obtain diffusion tensor imaging metrics of free water (FW) content, FW-corrected WM fractional anisotropy, axial diffusivity, radial diffusivity, and mean diffusivity. Using whole-brain voxel-wise linear regression models and ANCOVA, we examined associations of BP and hypertension stage with diffusion tensor imaging metrics after adjusting for age, sex, education, body mass index, smoking status, alcohol consumption history, and differences in the b value used for diffusion magnetic resonance imaging. RESULTS: Systolic and diastolic BP of the sample (mean±SD) were 122.8±13.0 and 76.0±9.9 mm Hg, respectively. Associations of BP with diffusion tensor imaging metrics revealed regional heterogeneity for FW-corrected fractional anisotropy. High BP and high hypertension stage were associated with higher FW and lower FW-corrected axial diffusivity, FW-corrected radial diffusivity, and FW-corrected mean diffusivity. Moreover, associations of high diastolic BP and hypertension stage with high FW were found only in men not in women. CONCLUSIONS: High BP in young adults is associated with altered brain WM microstructural integrity, suggesting that high BP may have damaging effects on brain WM microstructural integrity in early adulthood, particularly in men.

Training Medical Student Counselors for the Rochester Model, a Hospital Tobacco Treatment Program.

Purpose: Providing effective tobacco dependence treatments to hospitalized patients remains a challenge. Prior to 2021, the Rochester Model program used staff nurses for both bedside and post-discharge counseling necessary to maintain abstinence. When nurse shortages and elevated job stress occurred during the COVID Pandemic, we proposed that medical students learn to counsel patients at the bedside and after discharge. Patients and Methods: Due to COVID restrictions, first- and second-year medical students trained using remote Zoom sessions. The total training time was 2.5 hr without role-play or additional evaluations. A survey measured the students' satisfaction, confidence, and counseling barriers. A smoking patient on a participating hospital unit can enroll in the program. Students delivered bedside counseling, then provided follow-up treatment and outcome calls along with New York State Quitline counselors. Results: The survey demonstrated that 89% of the students were satisfied with the training. The bedside counseling confidence was greater than the phone counseling confidence. All students felt the program experience has value to them as future physicians. 124 smoking patients enrolled, and outcomes followed out to 6 months. The 7-day point prevalence quit rates using the as-treated (patients contacted) analysis were 57% at 4 weeks, 48% at 3 months, and 43% at 6 months. The 7-day point prevalence quit rates using the intent-to-treat (all patients) analysis were 31% at 4 weeks, 16% at 3 months and 14% at 6 months. Conclusion: Medical students given minimal training are effective tobacco cessation counselors at no cost to the hospital system. The Rochester Model program using student counseling benefits patients, the students, and the health-care system.

Etrasimod as induction and maintenance therapy for ulcerative colitis (ELEVATE): two randomised, double-blind, placebo-controlled, phase 3 studies.

BACKGROUND: Etrasimod, a once-daily, oral, sphingosine 1-phosphate (S1P) receptor modulator that selectively activates S1P receptor subtypes 1, 4, and 5, with no detectable activity on S1P2,3, is in development for the treatment of immune-mediated diseases, including ulcerative colitis. In these two phase 3 trials, we aimed to evaluate the safety and efficacy of etrasimod in adult patients with moderately to severely active ulcerative colitis. METHODS: In two independent randomised, multicentre, double-blind, placebo-controlled, phase 3 trials, ELEVATE UC 52 and ELEVATE UC 12, adults with active moderate-to-severe ulcerative colitis and an inadequate or loss of response or intolerance to at least one approved ulcerative colitis therapy were randomly assigned (2:1) to once-daily oral etrasimod 2 mg or placebo. Patients in ELEVATE UC 52 were enrolled from 315 centres in 40 countries. Patients in ELEVATE UC 12 were enrolled from 407 centres in 37 countries. Randomisation was stratified by previous exposure to biologicals or Janus kinase inhibitor therapy (yes vs no), baseline corticosteroid use (yes vs no), and baseline disease activity (modified Mayo score [MMS]; 4-6 vs 7-9). ELEVATE UC 52 comprised a 12-week induction period followed by a 40-week maintenance period with a treat-through design. ELEVATE UC 12 independently assessed induction at week 12. The primary efficacy endpoints were the proportion of patients with clinical remission at weeks 12 and 52 in ELEVATE UC 52 and week 12 in ELEVATE UC 12. Safety was evaluated in both trials. ELEVATE UC 52 and ELEVATE UC 12 were registered with ClinicalTrials.gov, NCT03945188 and NCT03996369, respectively. FINDINGS: Patients in ELEVATE UC 52 were enrolled between June 13, 2019, and Jan 28, 2021. Patients in ELEVATE UC 12 were enrolled between Sept 15, 2020, and Aug 12, 2021. ELEVATE UC 52 and ELEVATE UC 12 screened 821 patients and 606 patients, respectively, with 433 and 354 subsequently undergoing random assignment. The full analysis set of ELEVATE UC 52 comprised 289 patients assigned to etrasimod and 144 to placebo. In ELEVATE UC 12, 238 patients were assigned to etrasimod and 116 to placebo. In ELEVATE UC 52, a significantly greater proportion of patients in the etrasimod group achieved clinical remission compared with patients in the placebo group at completion of the 12-week induction period (74 [27%] of 274 patients vs ten [7%] of 135 patients; p<0·0001) and at week 52 (88 [32%] of 274 patients vs nine [7%] of 135 patients; p<0·0001). In ELEVATE UC 12, 55 (25%) of 222 patients in the etrasimod group had clinical remission compared with 17 (15%) of 112 patients in the placebo group at the end of the 12-week induction period (p=0·026). Adverse events were reported in 206 (71%) of 289 patients in the etrasimod group and 81 (56%) of 144 patients in the placebo group in ELEVATE UC 52 and 112 (47%) of 238 patients in the etrasimod group and 54 (47%) of 116 patients in the placebo group in ELEVATE UC 12. No deaths or malignancies were reported. INTERPRETATION: Etrasimod was effective and well tolerated as an induction and maintenance therapy in patients with moderately to severely active ulcerative colitis. Etrasimod is a treatment option with a unique combination of attributes that might address the persistent unmet needs of patients with ulcerative colitis. FUNDING: Arena Pharmaceuticals.

Idiopathic lingual mandibular sequestration and its relationship to medication-related osteonecrosis of the jaws (MRONJ): mini review.

OBJECTIVE: Idiopathic lingual mandibular sequestration is an uncommon condition that affects the lingual aspect of the mandible and may result in a necrosis of the jaw that is clinically indistinguishable from medication-related osteonecrosis of the jaw. This condition, however, is not associated with the intake of antiresorptive medication and may not require the same safeguards for extended periods of time. The etiology of idiopathic lingual mandibular sequestration is still unknown although trauma has been shown to play an important role. METHOD AND MATERIALS: PubMed and the Cochrane Library were used to retrieve papers written in English through the years 1970 to 2021 using the key words "idiopathic osteonecrosis," "lingual sequestration," and "idiopathic jaw sequestration." In addition, clinical presentation of the lesion was included. RESULTS: Idiopathic lingual mandibular sequestration is a benign, mostly self-limiting condition distinct from medication- related osteonecrosis of the jaw. CONCLUSION: The dental clinician should be familiar with this condition and include it in their differential diagnosis when exposed bone is present with no history of radiation to the area or intake of antiresorptive medication. The course of the condition is usually very mild and may be self-limiting and usually does not require surgical intervention.

Concurrent Improvement in Both Binge Eating and Depressive Symptoms with Naltrexone/Bupropion Therapy in Overweight or Obese Subjects with Major Depressive Disorder in an Open-Label, Uncontrolled Study.

INTRODUCTION: Binge eating disorder (BED) is associated with obesity and major depressive disorder (MDD). Naltrexone extended-release (ER)/bupropion ER (NB) is approved as an adjunct to diet and physical activity for chronic weight management. In a prospectively designed 24-week open-label, single-arm, single-site trial of 25 women with MDD and overweight/obesity, NB reduced weight and depressive symptoms. METHODS: This post hoc analysis investigated the relationship between change in self-reported binge eating behavior (evaluated with the Binge Eating Scale [BES]) and changes in weight, control of eating, and depressive symptoms. RESULTS: At baseline, 91% of subjects had moderate or severe BES scores, suggesting BED. BES scores were significantly improved from week 4, and by week 24, 83% reported "little or no problem." Improvement in BES scores correlated with improvement in depressive symptoms and control of eating. CONCLUSION: NB may be effective in reducing binge eating symptoms associated with MDD and overweight/obesity. Evaluation of NB in BED appears warranted. FUNDING: Orexigen Therapeutics, Inc.

Model-based spike sorting with a mixture of drifting t-distributions.

BACKGROUND: Chronic extracellular recordings are a powerful tool for systems neuroscience, but spike sorting remains a challenge. A common approach is to fit a generative model, such as a mixture of Gaussians, to the observed spike data. Even if non-parametric methods are used for spike sorting, such generative models provide a quantitative measure of unit isolation quality, which is crucial for subsequent interpretation of the sorted spike trains. NEW METHOD: We present a spike sorting strategy that models the data as a mixture of drifting t-distributions. This model captures two important features of chronic extracellular recordings-cluster drift over time and heavy tails in the distribution of spikes-and offers improved robustness to outliers. RESULTS: We evaluate this model on several thousand hours of chronic tetrode recordings and show that it fits the empirical data substantially better than a mixture of Gaussians. We also provide a software implementation that can re-fit long datasets in a few seconds, enabling interactive clustering of chronic recordings. COMPARISON WITH EXISTING METHODS: We identify three common failure modes of spike sorting methods that assume stationarity and evaluate their impact given the empirically-observed cluster drift in chronic recordings. Using hybrid ground truth datasets, we also demonstrate that our model-based estimate of misclassification error is more accurate than previous unit isolation metrics. CONCLUSIONS: The mixture of drifting t-distributions model enables efficient spike sorting of long datasets and provides an accurate measure of unit isolation quality over a wide range of conditions.

Method-of-use study of naltrexone sustained release (SR)/bupropion SR on body weight in individuals with obesity.

OBJECTIVE: This study assessed the effects of 32 mg naltrexone sustained release (SR)/360 mg bupropion SR (NB) on body weight in adults with obesity, with comprehensive lifestyle intervention (CLI), for 78 weeks. METHODS: In this phase 3b, randomized, open-label, controlled study, subjects received NB + CLI or usual care (standard diet/exercise advice) for 26 weeks. NB subjects not achieving 5% weight loss at week 16 were discontinued, as indicated by product labeling. After week 26, usual care subjects began NB + CLI. Assessments continued through week 78. The primary end point was percent change in weight from baseline to week 26 in the per protocol population. Other end points included percentage of subjects achieving ≥5%, ≥10%, and ≥15% weight loss, percent change in weight at week 78, and adverse events (AEs) necessitating study medication discontinuation. RESULTS: NB + CLI subjects lost significantly more weight than usual care subjects at week 26 (8.52% difference; P < 0.0001). Weight loss persisted through 78 weeks. In total, 20.7% of subjects discontinued medication for AEs, including 7.0% for nausea. CONCLUSIONS: Treatment with NB, used as indicated by prescribing information and with CLI, significantly improved weight loss over usual care alone. NB-facilitated weight loss was sustained for 78 weeks and was deemed safe and well tolerated.

Spatial tuning and brain state account for dorsal hippocampal CA1 activity in a non-spatial learning task.

The hippocampus is a brain area crucial for episodic memory in humans. In contrast, studies in rodents have highlighted its role in spatial learning, supported by the discovery of place cells. Efforts to reconcile these views have found neurons in the rodent hippocampus that respond to non-spatial events but have not unequivocally dissociated the spatial and non-spatial influences on these cells. To disentangle these influences, we trained freely moving rats in trace eyeblink conditioning, a hippocampally dependent task in which the animal learns to blink in response to a tone. We show that dorsal CA1 pyramidal neurons are all place cells, and do not respond to the tone when the animal is moving. When the animal is inactive, the apparent tone-evoked responses reflect an arousal-mediated resumption of place-specific firing. These results suggest that one of the main output stages of the hippocampus transmits only spatial information, even in this non-spatial task.

Effects of pramlintide in patients with type 2 diabetes mellitus: an analysis using daily insulin dose tertiles.

OBJECTIVE: The purpose of the analysis was to investigate if the efficacy and tolerability of 6 months of pramlintide therapy in patients with type 2 diabetes mellitus (T2DM) differed with increasing levels of concomitant insulin doses, using data from 3 previously described clinical trials. METHODS: In this post hoc analysis, data from 2 pooled, placebo-controlled pivotal trials and 1 clinical practice trial were evaluated by baseline insulin use tertile in patients with T2DM. RESULTS: In the pivotal trials, both glycated hemoglobin (A1C) and body weight decreased similarly across tertiles with pramlintide. A1C decreased slightly and body weight remained relatively unchanged across tertiles with placebo. Similarly, in the clinical practice trial, pramlintide was associated with decreases in A1C, body weight, and total daily insulin use across the tertiles. Overall, the most common adverse events were gastrointestinal in nature, and the rate of severe hypoglycemia was low. CONCLUSION: These results suggest that pramlintide therapy was associated with improved A1C and decreased body weight, with a low rate of severe hypoglycemia, among patients with T2DM, regardless of baseline insulin use.

Pramlintide improved measures of glycemic control and body weight in patients with type 1 diabetes mellitus undergoing continuous subcutaneous insulin infusion therapy.

OBJECTIVE: To assess the safety and efficacy of the addition of pramlintide to continuous subcutaneous insulin infusion (CSII) therapy in patients with type 1 diabetes mellitus (T1DM). RESEARCH DESIGN AND METHODS: We conducted a post hoc analysis of 2 studies: a 29-week, multicenter, randomized, double-blind, placebo-controlled trial (referred to as RCT) (pramlintide, n = 82; placebo, n = 73) and an open-ended, multicenter, open-label, single-arm, observational study (referred to as clinical practice trial) (n = 150), which assessed the addition of pramlintide to CSII therapy in patients with T1DM. Pramlintide was initiated at 15 µg and titrated to 30 or 60 µg with major meals. The mealtime insulin dose was reduced by 30% to 50% at initiation, and then adjusted to optimize glycemic control. Endpoints at 29 weeks (RCT) and 6 months (clinical practice trial) included change in glycated hemoglobin (HbA1c) level, insulin dose, body weight, pre- and postprandial blood glucose level, and tolerability and safety. RESULTS: In both studies, mean baseline age was approximately 42 years, duration of diabetes was 20 to 24 years, and HbA1c level was approximately 8%. Pramlintide reduced blood glucose excursions and improved the percentage of recorded postprandial blood glucose levels < 180 mg/dL. Mean (± standard deviation) reduction in HbA1c level in the clinical practice trial was -0.3% ± 0.1% (P < 0.0001), and in the RCT was similar between pramlintide- and placebo-treated patients (-0.4% ± 0.1% and -0.3% ± 0.1%, respectively). Glycemic improvements were accomplished, with reductions in mealtime insulin doses (RCT: pramlintide, -23.8% ± 5.2%; placebo, -3.2% ± 4.1%; P < 0.0005; clinical practice trial: -27.5% ± 2.9%; P < 0.0001) and body weight (RCT: pramlintide, -2.2 kg ± 0.5 kg; placebo, +1.4 kg ± 0.3 kg; P < 0.0001; clinical practice trial: -3.2 kg ± 0.4 kg; P < 0.0001). Short-lived nausea, primarily mild to moderate in intensity, was the most common adverse event associated with pramlintide therapy. Severe hypoglycemic events occurred at a rate of 0.56 and 0.34 events per patient-year in pramlintide- and placebo-treated patients, respectively, in the RCT, and at a rate of 0.12 events per patient-year in the clinical practice trial. CONCLUSION: Addition of pramlintide to CSII therapy was safe and effective in patients with T1DM. Pramlintide should be considered for patients who are not able to optimize glycemic control with CSII therapy alone, particularly those with difficulty controlling postprandial blood glucose levels and/or body weight. TRIAL REGISTRATION: www.ClinicalTrials.gov identifiers: NCT00042458, NCT00108004.

Increased variability and abnormalities in pancreatic enzyme concentrations in otherwise asymptomatic subjects with type 2 diabetes.

BACKGROUND: Recent studies have demonstrated an increased incidence of pancreatitis in patients with type 2 diabetes compared with obese nondiabetic individuals. Serum lipase and pancreatic amylase concentrations are used in conjunction with clinical findings to diagnose pancreatitis. METHODS: In two large clinical trials of overweight/obese nondiabetic and type 2 diabetic subjects, lipase and pancreatic amylase were measured at screening and 2-5 weeks later at baseline (prior to treatment with study medication). RESULTS: Lipase and pancreatic amylase concentrations were above the upper limit of normal (ULN) in 13% and 6% of type 2 diabetic subjects, respectively, and were approximately three-fold (3 ×) higher than the proportion of nondiabetic subjects with levels above ULN. Elevations exceeding ULN were seen in many subjects asymptomatic for pancreatitis; however, elevations >2 × ULN and >3 × ULN were uncommon, and elevations >3 × ULN were often associated with a history of dyslipidemia, hyperlipidemia, and gastrointestinal disorders. Additionally, enzyme concentrations varied within this 2-5-week screening period, including shifts between elevated and normal levels. CONCLUSION: Results from this post hoc analysis suggest that, although pancreatic enzymes can be a useful marker for pancreatitis within the proper clinical context, diagnosis of pancreatitis may be confounded in populations known to have asymptomatic elevations associated with disease, such as type 2 diabetes. Further effort is needed to clarify the etiology and epidemiology of pancreatic enzyme elevations in type 2 diabetes.

Climbing for credit: applying Kurt Hahn's principles for promoting holistic lifestyles.

Climbing is a sport, a hobby, and metaphor for life's lessons. A climbing course for undergraduate students was designed on the basis of the principles of rock climber and educator Kurt Hahn, who transferred lessons learned from physical activity into lessons for life and whose philosophy underpins the Outward Bound program. Hahn's 10 principles for sound mind-body-spirit are described.

Enhanced weight loss with pramlintide/metreleptin: an integrated neurohormonal approach to obesity pharmacotherapy.

The neurohormonal control of body weight involves a complex interplay between long-term adiposity signals (e.g., leptin), and short-term satiation signals (e.g., amylin). In diet-induced obese (DIO) rodents, amylin/leptin combination treatment led to marked, synergistic, fat-specific weight loss. To evaluate the weight-lowering effect of combined amylin/leptin agonism (with pramlintide/metreleptin) in human obesity, a 24-week, randomized, double-blind, active-drug-controlled, proof-of-concept study was conducted in obese or overweight subjects (N = 177; 63% female; 39 +/- 8 years; BMI 32.0 +/- 2.1 kg/m(2); 93.3 +/- 13.2 kg; mean +/- s.d.). After a 4-week lead-in period with pramlintide (180 microg b.i.d. for 2 weeks, 360 microg b.i.d. thereafter) and diet (40% calorie deficit), subjects achieving 2-8% weight loss were randomized 1:2:2 to 20 weeks of treatment with metreleptin (5 mg b.i.d.), pramlintide (360 microg b.i.d.), or pramlintide/metreleptin (360 microg/5 mg b.i.d.). Combination treatment with pramlintide/metreleptin led to significantly greater weight loss from enrollment to week 20 (-12.7 +/- 0.9%; least squares mean +/- s.e.) than treatment with pramlintide (-8.4 +/- 0.9%; P < 0.001) or metreleptin (-8.2 +/- 1.3%; P < 0.01) alone (evaluable, N = 93). The greater reduction in body weight was significant as early as week 4, and weight loss continued throughout the study, without evidence of a plateau. The most common adverse events with pramlintide/metreleptin were injection site events and nausea, which were mostly mild to moderate and decreased over time. These results support further development of pramlintide/metreleptin as a novel, integrated neurohormonal approach to obesity pharmacotherapy.