Faculty Bibliography

INTRODUCTION/BACKGROUND:Disturbances in microvascular flow dynamics are hypothesized to precede the symptomatic phase of Alzheimer's disease (AD). However, evidence in presymptomatic AD remains elusive, underscoring the need for therapies targeting these early vascular changes. METHODS:We employed a multimodal approach, combining in vivo optical imaging, molecular techniques, and ex vivo magnetic resonance imaging, to investigate early capillary dysfunction in C57BL/6-Tg(Thy1-APPSwDutIowa)BWevn/Mmjax (Tg-SwDI) mice without memory impairment. We also assessed the efficacy of carbonic anhydrase inhibitors (CAIs) in preventing capillary flow disturbances. RESULTS:Our study revealed capillary flow disturbances associated with alterations in capillary morphology, adhesion molecule expression, and amyloid beta (Aβ) load in 9- to 10-month-old Tg-SwDI mice without memory impairment. CAI treatment ameliorated these capillary flow disturbances, enhanced oxygen availability, and reduced Aβ load. DISCUSSION/CONCLUSIONS:These findings underscore the importance of capillary flow disturbances as early biomarkers in presymptomatic AD and highlight the potential of CAIs for preserving vascular integrity in the early stages of AD. HIGHLIGHTS/CONCLUSIONS:Uncovered early capillary dysfunction in a presymptomatic Alzheimer's disease (AD) mouse model. Evidence linking capillary stalls and capillary dysfunction with oxygen delivery issues in AD. Novel use of carbonic anhydrase inhibitors to prevent early capillary flow disturbances in AD.

BACKGROUND:Randomized trials of chronic total occlusion (CTO) revascularization vs medical therapy have yielded inconsistent results. OBJECTIVES/OBJECTIVE:The aim of this study was to evaluate outcomes with an initial invasive strategy (INV) vs an initial conservative strategy (CON) in patients with coronary computed tomographic angiography (CCTA)-determined CTO in the ISCHEMIA (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) trial. METHODS:Participants in ISCHEMIA who underwent CCTA evaluated for CTO by the core laboratory (3,113 of 5,179 randomized patients [60%]) were categorized into subgroups with (100% stenosis) and without (<100% stenosis) CTO. Primary analysis compared outcomes in those randomized to INV vs CON using an intention-to-treat approach. Secondary analyses compared outcomes using inverse probability weighting to model successful CTO revascularization (REV) in all INV participants vs CON participants. RESULTS:Of the 3,113 CCTA-evaluable participants, 1,470 had at least 1 CTO (752 INV and 718 CON). INV did not reduce cardiovascular (CV) death or myocardial infarction (MI) (5-year difference -3.5%; 95% CI: -7.8% to 0.8%) and resulted in more procedural MIs (2.5%; 95% CI: 1.0%-4.0%) but fewer spontaneous MIs (-6.3%; 95% CI: -9.7% to -3.2%) than CON. CTO REV modeled across INV had a high probability (>90%) of any lower CV death or MI, MI, spontaneous MI, unstable angina, and heart failure counterbalanced by a higher rate of procedural MI. CTO REV significantly improved angina-related quality of life (mean difference 4.6 points), Rose Dyspnea Scale score (rescaled) (mean difference 5.3 points), and EQ-5D visual analog scale score (4.6 points). CONCLUSIONS:In the ISCHEMIA trial, the risks and benefits of INV compared with CON were similar among patients with and without CCTA-determined CTO (more frequent procedural MI, less frequent spontaneous MI, and significantly improved angina and dyspnea-related quality of life). In an observational comparison, successful CTO REV was associated with a high probability of lower CV death or MI (driven by lower MI) compared with CON. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

RGS8-associated paraneoplastic neurologic syndrome (PNS) is a recently-described disorder associated with lymphomas and typically presenting with severe, rapidly-progressing cerebellar dysfunction. We describe a patient who presented with mild signs of cerebellar dysfunction, including ocular motor abnormalities and impaired tandem gait. CSF showed elevated protein and a neural-restricted antibody pattern. Mesenteric lymphadenopathy on abdominal CT was biopsied and diagnosed as follicular B-cell lymphoma. After four years, the previously-detected antibody pattern was identified as RGS8 antibodies. This case describes the first RGS8-PNS patient presenting with a subtle and ocular motor predominant cerebellar syndrome with low-grade lymphoma.

PURPOSE OF REVIEW/OBJECTIVE:Fiber restriction has been a long-standing strategy for patients with inflammatory bowel disease (IBD), ostensibly to improve symptoms and reduce complications. Fiber though has a well-documented trophic effect on gut barrier defenses and the intestinal microbiome. This report discusses how texture modification may allow the safe and effective provision of much needed fiber to this patient population. RECENT FINDINGS/RESULTS:The effect of dietary fiber is characterized by maintenance of gut integrity, support of the microbiome, and immune modulation. Low-fiber diets in patients with IBD result in greater dysbiosis, intestinal permeability, and mucosal inflammation. New recommendations from international IBD guidelines now promote texture modification to allow for inclusion of fiber in certain conditions of IBD. For patients flaring with acute inflammation, or those with ileostomy, intestinal stricture, or ileal pouch anastomosis, continued fiber intake with softer textures and mechanical modification should be prioritized when feasible. For patients recovering from surgery, diet advancement should include reintroduction of soluble and insoluble fibers, while those in remission should have little or no dietary restrictions. Texture modification of high fiber foods may be accomplished by a variety of strategies involved in the selection, preparation, and cooking of fruits and vegetables. Greater effort to include dietary soluble and insoluble fiber should result in clinical benefit to the IBD patient, avoiding the adverse consequences of a low-fiber diet.

Low-dose oral minoxidil (LDOM) has emerged as a widely used off-label treatment for different types of alopecia, showing a favorable safety profile and effectiveness. Despite its growing use, it is essential to understand the possible associated adverse events (AEs) and their appropriate management to optimize this therapy. The aim of this article was to comprehensively review the AEs of LDOM treatment, describing their frequency, risk factors, affected anatomical sites, and management strategies. A search in the PubMed and EMBASE databases was performed for studies published before 31 December 2024, reporting the treatment of any type of hair loss with oral minoxidil. The most frequent AE is hypertrichosis, occurring in approximately 15% of patients, with a higher incidence in women and patients with higher doses. Fluid retention affects 1.3-10% of patients, particularly women, and typically occurs within 1-3 months of treatment. Other cardiovascular AEs, such as tachycardia or dizziness, occur in fewer than 5% of cases and are usually mild and transient. Severe AEs, including pericardial effusion, are extremely rare and often linked to compounding errors comprising an excessive dose. Management strategies include dose reduction, pharmacological interventions like diuretics for edema, and lifestyle measures such as sodium restriction. In most cases, AEs resolve without the need for treatment discontinuation. The favorable safety profile of LDOM makes it a valuable therapeutic option for alopecia, though careful patient selection, dose titration, and monitoring are essential to minimize risks.

OBJECTIVE:Controversy persists regarding the optimal management of gout in routine primary care. There is a lack of clarity on whether treating to a target serum urate (TTT-SU) versus treating to avoid symptoms (TTASx) is more effective. METHODS:We designed a randomized controlled comparative effectiveness trial aimed at patients in primary care who have known gout, have elevated SU levels, and had at least one flare in the previous 12 months. The trial was designed to be pragmatic and incorporated structured input from primary care physicians, rheumatologists, and patients. The TTASx strategy group will receive weeklong courses of typical therapies for gout flares, such as colchicine, naproxen, or an oral glucocorticoid. The TTT-SU strategy group will receive urate-lowering therapy (primarily allopurinol) with dose titration to maintain an SU level <6 mg/dL, colchicine (or naproxen) prophylaxis for the first six months of urate-lowering therapy, and access to the same flare therapies as the TTASx group. Two clinicians (nurses or physicians) per site will be trained in each strategy to manage the patients in each arm without contamination. Gout flares are the primary outcome and are assessed every two weeks by trained study staff masked to treatment assignment using a validated questionnaire. The secondary outcome is quality of life. Blood pressure control, kidney function, glycemic control, and coronary atherosclerosis are exploratory secondary outcomes. RESULTS:Several sites have started prescreening using automated search strategies in their patients' electronic health records. Of the first 1,381 patients found in primary care practices with a history of gout, 691 patients (50%) passed prescreening checks. These potentially eligible participants have a median age of 67 years, 85% are men, median SU levels are 7.2 mg/dL, and 18% are taking low dosages of allopurinol. These patients have been targeted for recruitment efforts that are underway now. CONCLUSION/CONCLUSIONS:This randomized controlled active comparator strategy trial will answer a key question in the treatment of patients with gout in primary care: the comparative effectiveness of TTT-SU versus TTASx in gout. Secondary and exploratory outcomes will add important information regarding the broader extra-articular and quality-of-life effects of lowering SU levels.

Although platelets play a critical pathogenic role in myocardial infarction (MI), few studies have characterized the MI platelet transcriptome in the acute or chronic setting in women. We report that transcripts associated with the actin cytoskeleton, Rho family GTPases, mitochondrial dysfunction, and inflammatory signaling are enriched in platelets from MI patients in the acute setting (n = 40, MI; n = 38, control) and do not significantly change over time. Furthermore, 79 platelet genes chronically elevated or suppressed after MI are associated with future cardiovascular events in an independent high-risk cohort (n = 135). Compared with women with MI with nonobstructive coronary arteries, platelets from women with MI and obstructive coronary artery disease were enriched in neutrophil activation and proinflammatory signaling pathways driven by increased tumor necrosis factor (TNF)-α signaling. Hierarchic clustering of the MI transcriptomic profile identified 3 subgroups with distinctive biological pathways and MI correlates. Our data demonstrate that platelets from MI patients are phenotypically different from MI-naïve patients in the acute and chronic settings and reveal a platelet transcriptomic signature with distinct clinical features.

BACKGROUND:The purpose of this systematic review was to evaluate the clinical and radiological outcomes at short-term follow-up following suture button fixation for the management of ligamentous Lisfranc injuries. AIM/OBJECTIVE:To assess the effectiveness of suture button fixation in managing ligamentous Lisfranc injuries through a systematic evaluation of short-term clinical and radiological outcomes. METHODS:During March 2024, the PubMed, EMBASE, and Cochrane library databases were systematically reviewed to identify clinical studies examining outcomes following suture button fixation for the management of ligamentous Lisfranc injuries. Data regarding patient demographics, pathological characteristics, subjective clinical outcomes, radiological outcomes, complications, and failure rates were extracted and analyzed. RESULTS:Eight studies were included. In total, 94 patients (94 feet) underwent suture button fixation for the management of ligamentous Lisfranc injuries at a weighted mean follow-up of 27.2 ± 10.2 months. The American Orthopaedic Foot and Ankle Society score improved from a weighted mean pre-operative score of 39.2 ± 11.8 preoperatively to a post-operative score of 82.8 ± 5.4. The weighted mean visual analogue scale score improved from a weighted mean pre-operative score of 7.7 ± 0.6 preoperatively to a post-operative score of 2.0 ± 0.4. In total, 100% of patients returned to sport at a mean time of 16.8 weeks. The complication rate was 5%, the most common complication of which was residual midfoot stiffness (3.0%). No failures nor secondary surgical procedures were recorded. CONCLUSION/CONCLUSIONS:This systematic review demonstrated that suture button fixation for ligamentous Lisfranc injuries produced improved clinical outcomes at short-term follow-up. In addition, there was an excellent return-to-sport rate (100%) at a weighted mean time of 16.8 weeks. This review highlights that suture button fixation is a potent surgical treatment strategy for ligamentous Lisfranc injuries; however, caution should be taken when evaluating this data in light of the lack of high quality, comparative studies, and short-term follow-up.

NCT06203600.

BACKGROUND:Four-dimensional computed tomography is routinely used to localize parathyroid disease, with consistently excellent parathyroid gland localization rates reported. This study evaluated whether pairing 4-dimensional computed tomography results with preoperative clinical variables can accurately predict single-gland disease in primary hyperparathyroidism. METHODS:Patients with primary hyperparathyroidism who underwent both 4-dimensional computed tomography imaging and parathyroidectomy between January 2019 and September 2021 at a large academic health system were included. Patient demographics, preoperative characteristics, and peri- and postoperative data were collected. The accuracy of 4-dimensional computed tomography in correctly identifying patients with single-gland disease with and without preoperative calcium and parathyroid hormone levels was calculated. Single-gland disease was defined by intraoperative parathyroid hormone decrease >50% and a hypercellular gland on pathology. RESULTS:One hundred seventy-five patients had 4-dimensional computed tomography results suggestive of single gland disease. One hundred fifty-two patients (87%) were predicted correctly to have single-gland disease. The predictive accuracy increased when stratifying by preoperative calcium (≥10.5 mg/dL, ≥11 mg/dL, and ≥12 mg/dL) and parathyroid hormone levels (≥65 pg/mL, ≥100 pg/mL, and ≥200 pg/dL). The accuracy further increased when stratifying by age (≤50 years). Accuracy for single gland disease was 100% when combined with any of the following: (1) calcium ≥12 mg/dL, (2) parathyroid hormone ≥200 pg/dL, or (3) calcium ≥11 mg/dL in patients ≤50 years. CONCLUSION/CONCLUSIONS:Four-dimensional computed tomography alone accurately predicted single gland disease in 87% of patients with primary hyperparathyroidism. When combined with preoperative calcium, parathyroid hormone and age thresholds, predictive accuracy for single-gland disease approached 100%. Given the high likelihood of single-gland disease in these scenarios, clinicians may consider offering focused unilateral parathyroidectomy without intraoperative parathyroid hormone monitoring in selected patients.