Clinical Trial Research Articles

Association between intercellular adhesion molecule-1 to depression and blood-brain barrier penetration in cerebellar vascular disease

BACKGROUND Cerebral small vessel disease (CSVD) is a prevalent cerebrovascular disease in clinical practice that is often associated with macrovascular disease. A clear understanding of the underlying causes of CSVD remains elusive. AIM To explore the association between intercellular adhesion molecule-1 (ICAM-1) and blood-brain barrier (BBB) penetration in CSVD. METHODS This study included patients admitted to Fuyang People’s Hospital and Fuyang Community (Anhui, China) between December 2021 and March 2022. The study population comprised 142 patients, including 80 in the CSVD group and 62 in the control group. Depression was present in 53 out of 80 patients with CSVD. Multisequence magnetic resonance imaging (MRI) and dynamic contrast-enhanced MRI were applied in patients to determine the brain volume, cortical thickness, and cortical area of each brain region. Moreover, neuropsychological tests including the Hamilton depression scale, mini-mental state examination, and Montreal cognitive assessment basic scores were performed. RESULTS The multivariable analysis showed that age [P = 0.011; odds ratio (OR) = 0.930, 95% confidence interval (CI): 0.880-0.983] and ICAM-1 levels (P = 0.023; OR = 1.007, 95%CI: 1.001-1.013) were associated with CSVD. Two regions of interest (ROIs; ROI3 and ROI4) in the white matter showed significant (both P < 0.001; 95%CI: 0.419-0.837 and 0.366-0.878) differences between the two groups, whereas only ROI1 in the gray matter showed significant difference (P = 0.046; 95%CI: 0.007-0.680) between the two groups. ICAM-1 was significantly correlated (all P < 0.05) with cortical thickness in multiple brain regions in the CSVD group. CONCLUSION This study revealed that ICAM-1 levels were independently associated with CSVD. ICAM-1 may be associated with cortical thickness in the brain, predominantly in the white matter, and a significant increase in BBB permeability, proposing the involvement of ICAM-1 in BBB destruction.

Worldwide Clinical and Real-World Exposure to Baricitinib

Introduction: Baricitinib (BARI), an oral selective JAK inhibitor, is approved in many geographies for adults with rheumatoid arthritis or alopecia areata and for patients as young as age 2 years with atopic dermatitis or juvenile idiopathic arthritis. It is also approved in the US for hospitalized patients with COVID-19 infection. We report the worldwide clinical trial and real-world exposure to BARI across a range of diseases, ages and racial backgrounds. Methods: Real-world patient exposure estimates were calculated based on total mg sold, average daily dose, and average length of therapy as reported to regulatory agencies through the cumulative timeframe ending Jan. 31, 2024. Clinical trial exposures were based on actual exposures from completed trials through Feb. 13, 2024, and estimates were made for ongoing blinded trials based on the enrolment/randomization schemes Results: In the real-world setting, an estimated 1,836,600 patients have been exposed to the following BARI doses: 1 mg, ~2,000 (0.1%); 2 mg, ~524,900 (28.6%); 4 mg, ~1,309,600 (71.3%). Of these estimated exposures, ~ 57% were for COVID-19 with the remaining for all other indications combined. Across 59 clinical trials (completed and ongoing), an estimated 14,660 subjects (548 healthy volunteers and 14,112 patients) have received BARI since June 2008. Exposures from completed studies include 10,276 patients (62% female), 399 of whom were <18 yrs of age (≤1 month, N=4; 1 month - ≤2 yrs, N=24; >2 - ≤12 yrs, N=111; >12 - ≤18 yrs, N=260), 8820 were >18 to ≤65 yrs, 1027 were >65 yrs, and 30 had age unknown. An additional 467 adolescent and pediatric patients down to the age of 2 have been treated with BARI for atopic dermatitis in an ongoing clinical trial, bringing the total number of patients <18 years of age to 866 across dermatologic, rheumatologic, other autoimmunologic, and acute infectious diseases (excluding alopecia areata for which there is an ongoing pediatric trial). Clinical trial exposures by racial and ethnic background are as follows: Asian, N=2,491; Black, N=450; Caucasian, N=6,237; other, N=496; multiple, N=135; unknown, N=467. Conclusion: There has been extensive real-world exposure to BARI across indications and populations, and BARI is a well-studied molecule in clinical trials, across varied disease states, racial populations and ages. Since average daily dose and length of therapy may vary over time, real-world exposures are only an estimate of total patients receiving BARI. Exposures in clinical trials include patients as young as less than 1 month of age up to patients over the age of 65 years. While these exposures do not indicate efficacy or safety, they provide data to establish the overall profile of the drug and can inform on its performance over time across a variety of populations.

Determinants of long‐term paramagnetic rim lesion evolution in people with multiple sclerosis

AbstractObjectiveBaseline paramagnetic rim lesion (PRL) load predicts disease progression in people with multiple sclerosis (pwMS). Understanding how PRLs relate to other known MS‐related factors, and the practical utility of PRLs in clinical trials, is crucial for informing clinical decision‐making and guiding development of novel disease‐modifying treatments (DMTs).MethodsThis study included 152 pwMS enrolled in a larger prospective, longitudinal cohort study who had 3T MRI scans and clinical assessments at baseline and 5‐ or 10‐year follow‐ups. PRLs were identified on baseline 3T quantitative susceptibility maps and classified as persisting, disappearing, or newly appearing at follow‐up. The relationships between PRL evolution and clinical, radiological, environmental, and genetic characteristics were assessed, and clinical trial sample sizes were estimated using PRL appearance or disappearance as outcome measures.ResultsDMT use was associated with lower odds of new PRL appearance (for high‐efficacy DMTs: odds ratio = 0.088, p = 0.024), but not disappearance. Current smoking status was associated with greater baseline PRL number (B = 0.527 additional PRLs, p = 0.013). A 24‐month clinical trial in people with progressive MS for a DMT that doubles the rate of PRL rim disappearance would require an estimated 118 people with progressive MS per group at 80% statistical power.InterpretationEarly MS diagnosis and subsequent DMT initiation may reduce new chronic active inflammation. However, the utility of PRL disappearance or new PRL appearance as outcome measures in clinical trials is limited by potentially large sample sizes that are needed for moderate efficacy drugs.

Aldosterone synthase inhibitors for cardiorenal protection: ready for prime time?

Background: Aldosterone, through its genomic and non-genomic effects, plays an important role in cardiovascular and renal injury. Steroidal mineralocorticoid receptor antagonists (MRAs) are fundamental to offset the aldosterone-mediated cardiorenal damage, but side effects may limit their use in a substantial proportion of patients. On the other hand, non-steroidal mineralocorticoid receptor antagonists (NS-MRA) showed improved selectivity and safety profile. However, interfering with the MRA could only partially inhibit aldosterone mediated effect both because of escaping mechanisms and potential non-genomic activity. Summary: Inhibiting aldosterone synthesis could be a promising strategy to abolish aldosterone-mediated cardiovascular side effects. Aldosterone is primarily synthesized by the CYP11B2 enzyme, which is very similar to CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2 and consequent off-target effects hampered the development of first-generation aldosterone synthase inhibitors (ASIs). The subsequent development of highly specific ASIs led to successful clinical trials in patients with resistant and uncontrolled hypertension. Key Messages: A recent randomized clinical trial showed a significant benefit of ASIs in patients with chronic kidney disease and albuminuria. However, further outcome based clinical trials are needed to confirm the promising role of ASIs in cardiorenal damage.

Intracerebral hemorrhage

Background: Compared to ischemic stroke, intracerebral hemorrhage (ICH) has higher mortality and more severe disability. Asian such as Chinese and Japanese and Mexican Americans, Latin Americans, African Americans, Native Americans have higher incidences than do white Americans. So, ICH is an important cerebrovascular disease in Asia. Summary: ICH accounts for approximately 10-20% of all strokes. The incidence of ICH is higher in low- and middle-income than high-income countries and is estimated 8-15% in western countries like USA, UK and Australia, and 18-24% in Japan, Taiwan and Korea. The ICH incidence increases exponentially with age, and old age especially over 80 years is a major predictor of mortality independent of ICH severity. Females are older at the onset of ICH and have higher clinical severity than males. Modifiable risk factors include blood pressure, smoking, alcohol consumption, lipid profiles, use of anticoagulants, antiplatelet agents and sympathomimetic drugs. Non-modifiable risk factors constitute old age, male gender, Asian ethnicity, cerebral amyloid angiopathy, cerebral microbleed, and chronic kidney disease. Blood pressure is the most important risk factor of ICH. Imaging markers may help predict ICH outcome, which include black hole sign, blend sign, iodine sign, island sign, leakage sign, satellite sign, spot sign, spot-tail sign, swirl sign, and hypodensities. ICH prognostic scoring system such as ICH scoring system and ICH grading scale scoring system in Chinese and Osaka prognostic score and Naples prognostic score has been used to predict ICH outcome. Early minimally invasive removal of ICH can be recommended for lobar ICH of 30–80 mL within 24 hours after onset. Decompressive craniectomy without clot evacuation might benefit ICH patients aged 18–75 years with 30–100 mL at basal ganglia or thalamus. However, clinical studies are needed to investigate the effect of surgery on patients with smaller or larger ICH, ICH in non-lobar locations, and for older patients or patients with preexisting disability. Surgical treatment is usually associated with neurological sequels if survived. For medical treatment, blood pressure lowering should be careful titrated to secure continuous smooth and sustained control and avoid peaks and large variability in systolic blood pressure. Stroke and cancer are the most common causes of death in Asian ICH patients, compared to stroke and cardiac disease in non-Asian patients. Key Messages: The incidence and outcome are different between Asian and non-Asian patients, and more clinical studies are needed to investigate the best management for Asian ICH patients.

Efficacy and Safety of Fixed-Dose Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel in Participants with Moderate-to-Severe Acne: The Patient Journey

Introduction: The main goal of acne treatment is to clear lesions quickly to manage and/or mitigate sequelae. Topical clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (CAB) gel is the only fixed-dose, triple-combination approved for acne. In three published clinical studies of participants with moderate to severe acne, CAB gel demonstrated superior efficacy to vehicle and component dyads, with good safety/tolerability. Herein are presented detailed efficacy and safety data from 5 clinical study patients to document their CAB treatment journey. Methods: In two phase 3 (NCT04214652, NCT04214639), double-blind, 12-week studies, participants aged ≥9 years with moderate-to-severe acne were randomized to once-daily CAB or vehicle gel. Endpoints included percentage of participants achieving treatment success (≥2-grade reduction from baseline in Evaluator’s Global Severity Score and clear/almost clear skin) and percent change from baseline in inflammatory/ noninflammatory lesion counts. Dosing compliance, treatment-emergent adverse events (TEAEs) and cutaneous safety/tolerability were also assessed. Descriptive data from 5 selected cases who completed 12 weeks of CAB treatment are summarized. Results: Participants (n=5) ranged from 13-32 years. At week 12, 3 achieved treatment success, 1 achieved a 2-grade reduction from severe to mild, and 1 achieved a 1-grade reduction from moderate to mild. Reductions from baseline to week 12 in inflammatory/ noninflammatory lesion counts ranged from 74.7-100%. No participants reported TEAEs/serious AEs. Some cutaneous safety/tolerability scores increased at weeks 2, 4, or 8, but generally decreased back to/below baselines levels by week 12, similar to the overall study populations. Most scores at week 12 were 0 (none) or 1 (mild), with only one participant reporting scores of 2 (moderate) for itching, burning, and stinging. Conclusions: In the overall phase 3 clinical trials, fixed-dose, triple-combination CAB gel has demonstrated good efficacy, safety, and tolerability. All 5 cases presented here achieved substantial (>70%) acne lesion reductions, with 4/5 cases achieving treatment success or a 2-grade EGSS reduction by week 12. While patterns in cutaneous safety/tolerability were variable across cases, transient increases with CAB generally resolved to baseline values within two months of treatment. These clinical study cases reinforce the importance of patient education regarding efficacy and safety of acne treatment, including the importance of treatment adherence, managing patient expectations, and the potential for cutaneous effects, which are often transient. Support: Ortho Dermatologics

Spatially Localized Visual Perception Estimation by Means of Prosthetic Vision Simulation

Retinal prosthetic devices aim to repair some vision in visually impaired patients by electrically stimulating neural cells in the visual system. Although there have been several notable advancements in the creation of electrically stimulated small dot-like perceptions, a deeper comprehension of the physical properties of phosphenes is still necessary. This study analyzes the influence of two independent electrode array topologies to achieve single-localized stimulation while the retina is electrically stimulated: a two-dimensional (2D) hexagon-shaped array reported in clinical studies and a patented three-dimensional (3D) linear electrode carrier. For both, cell stimulation is verified in COMSOL Multiphysics by developing a lifelike 3D computational model that includes the relevant retinal interface elements and dynamics of the voltage-gated ionic channels. The evoked percepts previously described in clinical studies using the 2D array are strongly associated with our simulation-based findings, allowing for the development of analytical models of the evoked percepts. Moreover, our findings identify differences between visual sensations induced by the arrays. The 2D array showed drawbacks during stimulation; similarly, the state-of-the-art 2D visual prostheses provide only dot-like visual sensations in close proximity to the electrode. The 3D design could offer a technique for improving cell selectivity because it requires low-intensity threshold activation which results in volumes of stimulation similar to the volume surrounded by a solitary RGC. Our research establishes a proof-of-concept technique for determining the utility of the 3D electrode array for selectively activating individual RGCs at the highest density via small-sized electrodes while maintaining electrochemical safety.

Long-Term Efficacy and Safety of Risankizumab for csDMARD-IR Patients With Active Psoriatic Arthritis: 196-Week Results From the KEEPsAKE 1 Trial

Introduction & Objectives: Here, we report the long-term efficacy and safety of risankizumab (RZB) in patients with active psoriatic arthritis (PsA) through week 196 from the KEEPsAKE 1 trial. Materials & Methods: The ongoing KEEPsAKE 1 clinical trial is a global, phase 3, multicenter study to evaluate the efficacy and safety of RZB versus placebo (PBO) in patients with active PsA. Patients are at least 18 years old and demonstrated an inadequate response, intolerance or contraindication to ≥1 conventional synthetic disease modifying antirheumatic drug (csDMARD-IR). Following a 24-week double-blind, PBO-controlled, parallel-group treatment period (period 1), all patients received open-label RZB every 12 weeks thereafter (period 2). Safety assessments were based on monitoring of treatment-emergent adverse events (TEAEs) reported as events per 100 patient-years (PY). Efficacy and safety analyses were conducted in all randomized patients who received ≥1 dose of the study drug. Results: Overall efficacy results were maintained at week 196 of the KEEPsAKE 1 trial, as compared to previously reported timepoints. At week 196, 39.4% of patients receiving continuous RZB and 38.1% of PBO/RZB patients achieved ACR50; 39.6% of RZB and 35.2% of PBO/RZB patients achieved MDA. In patients with psoriasis severity of ≥ 3% of body surface area (BSA) at baseline, 65.2% on RZB and 62.9% on PBO/RZB achieved PASI90 at week 196. mNAPSI and PGA-F scores improved from baseline by 14.99 and 1.5 points, respectively, for RZB, and by 14.73 and 1.5 points for PBO/RZB patients. In patients with enthesitis at baseline, 60.1% on RZB and 63.4% on PBO/RZB achieved resolution. For patients with dactylitis at baseline, 72.3% on RZB and 77.6% on PBO/RZB achieved resolution. HAQ-DI (RZB -0.40, PBO/RZB -0.33), SF-36 PCS (RZB 8.98, PBO/RZB 7.21) and FACIT-Fatigue (RZB 7.7, PBO/RZB 5.6) scores maintained improvement from baseline to week 196. The overall rates of TEAEs (121.4 E/100PY), serious TEAEs (7.7 E/100PY) and AEs leading to discontinuation of study drug (1.8 E/100PY) have remained stable and comparable to those reported in period 1. Conclusion: The 196-week results of the ongoing KEEPsAKE 1 trial demonstrate the durable efficacy of RZB 150 mg in treating the different clinical manifestations and improving health-related quality of life in csDMARD-IR patients with PsA. RZB continued to be well-tolerated, with no new safety signals.

Allergens Causing Allergic Contact Dermatitis in Cosmetic Products: A Systematic Review

Background: The increasing use of cosmetics worldwide has led to a rise in allergic reactions, particularly due to inadequate risk assessment. Identifying common allergens in cosmetic products causing dermatitis is crucial for effective prevention and management strategies. Objectives: This systematic review aims to determine the list of allergens that most commonly cause allergic contact dermatitis in cosmetic products and to find the patch test positivity rate for cosmetic products. Methods: This systematic review, following the PRISMA guidelines, investigated patch test results on cosmetic-induced contact dermatitis from January 2013 to September 2023 on PubMed, Cochrane, and Medline databases. Inclusion criteria comprised retrospective cohort and clinical trial studies reporting patch test positivity rates and positive allergens in cosmetics, with eligibility determined through independent screening, full-text evaluation, and data extraction. Exclusion criteria comprised abstract-only publications, non-English or Indonesian languages, review articles, and studies with incomplete text. Result: 13 studies were included out of 2,162 initially screened articles, involving 111,097 participants. The selected studies encompassed ten retrospective studies and three clinical trials conducted in various locations, including India, Brazil, North America, Korea, Sweden, and the Czech Republic. The patch test positivity rate ranged from 13% to 100%. The predominant allergens identified in cosmetics were nickel sulfate, fragrance mix I, cobalt chloride, para-phenylenediamine base, potassium dichromate, and balsam of Peru. Conclusion: This systematic review highlights the diversity in patch test positivity rates and identifies key allergens responsible for allergic contact dermatitis in cosmetic products, emphasizing the need for comprehensive evaluation and awareness of cosmetic safety.

Gambaran Faktor Risiko Kejadian Stunting pada Ibu dengan Anak Balita Stunting di Wilayah Kerja Puskesmas Baregbeg

Stunting is one of the main nutritional issues that Indonesian toddlers face. The prevalence of stunting in toddlers (children under five years old) was 30.8% in 2018, according to the Basic Health Research (Riskesdas) results. This dropped to 27.67% in 2019 (Indonesian Nutrition Status Survey (SSGI), 2019), and then increased to 24.4% in 2021 (SSGI, 2021). The purpose of this study is to identify the risk factors for stunting in women in the Ciamis Regency working area of the Baregbeg Community Health Center who have stunted children under five in 2024. Descriptive research using a cross-sectional design was the methodology employed. Using a questionnaire, the study's population composed of all the mothers of 36 kids with stunting in the Baregbeg Health Center's working area. The majority of stunted toddlers had a history of exclusive breastfeeding (80.56%), middle class mothers in a middle educational level (55.56%), low parental income (86.11%), low birth weight babies (86.11%), infectious diarrheal diseases (86.11%), poor diet (77.78%), and an unvarried diet (88.88%), based to the research's results. To help to prevent potential problems with the child's growth and development, it is advised that moms of stunted children give their children greater care.

Distribution of SALT Scores with Ritlecitinib Treatment up to 24 months from the ALLEGRO Phase 2b/3 and Long-Term Phase 3 Clinical Studies in Alopecia Areata

Background:• Alopecia areata (AA) is an autoimmune disease that has an underlying immuno-inflammatorypathogenesis and is characterized by non-scarring hair loss ranging from small patches to completescalp, face, and/or body hair loss1• Ritlecitinib, an oral JAK3/TEC family kinase inhibitor, demonstrated efficacy and safety up to 48 weeks inpatients aged ≥12 years with AA in the ALLEGRO phase 2b/3 study (NCT03732807; “ALLEGRO-2b/3”)2• The long-term efficacy of ritlecitinib in patients who rolled over from ALLEGRO-2b/3 to the ongoingphase 3, open-label ALLEGRO-LT study (NCT04006457) has been reported in terms of the proportions ofpatients with Severity of Alopecia Tool (SALT) scores of ≤20 and ≤10 (≤20% or ≤10% scalp without hair)at Month 243• However, the distribution of SALT scores in the overall population, including patients not reaching theSALT score ≤20 and ≤10 thresholds, has not yet been describedOBJECTIVE• This study describes changes in the distribution of SALT scores over 24 months of ritlecitinib treatmentin the overall population and in age and disease severity subgroups Methods: Study design and patients• Key inclusion criteria in ALLEGRO-2b/3:- Age ≥12 years- Diagnosis of AA with ≥50% scalp hair loss due to AA (including alopecia totalis [AT] and alopecia universalis [AU])- Maximum duration of current episode of hair loss ≤10 years• This analysis includes patients who received ritlecitinib 50 mg once daily (QD) without a loading dose inALLEGRO-2b/3 and who subsequently rolled over into ALLEGRO-LT where they continued to receiveritlecitinib 50 mg QD (Figure 1)- Continuation criteria for adolescents (aged 12-17 years) in ALLEGRO-LT: ≥50% improvement from baseline in SALT scoreby Month 3 for rollover patients from ALLEGRO-2b/3 and SALT score ≤20 by Month 6 in ALLEGRO-LTFigure 1. Study design and patient populationCombinedritlecitinib50 mg group(N=191)ALLEGRO phase 2b/3 ALLEGRO-LTLoading(4 weeks)Maintenance(20 weeks)Extension(24 weeks)Long-term study(60 months)Group A (n=131) 200 mg 50 mg 50 mg 50 mgGroup B (n=129) 200 mg 30 mg 30 mg 50 mgGroup C (n=130) 50 mg 50 mg 50 mg 50 mgGroup D (n=132) 30 mg 30 mg 30 mg 50 mgGroup E (n=61) 10 mg 10 mg 10 mg 50 mgGroup F (n=63) Placebo Placebo 200 mg 50 mg 50 mgGroup G* (n=61) Placebo Placebo 50 mg 50 mgDe novo group (n=447) 200 mg 50 mg*Data while on placebo were not included in this analysis; data from patients in Groub G were rebaselined from the start of treatment with ritlecitinib.Assessments and statistical analysis• The distribution of patients according to SALT score (as observed) was assessed through Month 24 forthe overall population and subgroups based on age (adults [≥18 years] vs adolescents [12-17 years]) anddisease severity (patients with AT/AU vs those without AT/AU)• The data cutoff date was December 9, 2022 Results: The analysis included 191 patients (27 adolescents and 164 adults) (Table 1)• At the time of data cutoff, 71 patients had discontinued; withdrawal bypatient (n=19), adverse events (n=18), and lack of efficacy (n=14) were themost common reasons for discontinuation• The distribution of participants by SALT score (as observed) at baseline, Month12, and Month 24 are presented for the overall population (Figure 2)(Interactive dynamic plot)• Per the inclusion criteria, all participants had a SALT score of ≥50 at baseline;136/191 patients (71.2%) had SALT >90• Among patients who had a nonmissing SALT score, 56/178 (31.5%), 37/164(22.6%), and 17/120 (14.2%) were in the SALT >90-100 category at Months 6,12, and 24, respectively• Reductions in the number of patients in the other SALT >50 categories wereobserved from baseline through Month 24• At Month 12, 56/164 (34.2%) and 18/164 (11.0%) patients were in the SALT0-10 and >10-20 categories, respectively, with 61/120 (50.8%) and 12/120(10.0%) patients in these categories at Month 24• Among the patients with AT/AU at baseline, 18/69 (26.1%) and 6/69 (8.7%)were in the SALT 0-10 and >10-20 categories, respectively, at Month 12; 25/47(53.2%) and 3/47 (6.4%) were in these categories, respectively, at Month 24(Figure 3) (Interactive dynamic plot)• For the adolescent participants, 10/22 (45.5%) and 4/22 (18.2%) were in theSALT 0-10 and >10-20 categories, respectively, at Month 12, and 11/14(78.6%) and 0/14 (0%) were in these categories at Month 24 (Figure 4) Conclusions:• Over 24 months, daily treatment with ritlecitinib 50 mg resulted in fewer patients inthe highest SALT score categories• These data provide a comprehensive overview of patient response to ritlecitinibtreatment and enable us to understand treatment response and time frames whileon treatment with ritlecitinib • This information can empower clinicians when counseling patients and managingtreatment expectations based on patient characteristics• This study also shows that response to treatment improves over time, whichsuggests that adequate time should be given when assessing treatment efficacy

The establishment of reference intervals for the ClotPro thromboelastometry device in healthy dogs

AbstractObjectiveTo establish reference intervals using a new point‐of‐care thromboelastometry device in dogs for the extrinsically activated test (EX‐test), intrinsically activated test (IN‐test), fibrin polymerization test (FIB‐test), ecarin test (ECA‐test), and tissue plasminogen activator test (TPA‐test) and to investigate the effects of storage time on the results.DesignProspective clinical study in 2022.SettingUniversity teaching hospital.AnimalsForty‐eight healthy privately or university‐owned dogs were prospectively enrolled and included on the basis of normal physical examination and normal baseline laboratory results (CBC, biochemistry profile, prothrombin time, and activated partial thromboplastin time [aPTT]).InterventionsAfter a 30‐minute storage time, the EX‐test, IN‐test, FIB‐test, ECA‐test, and TPA‐test were performed on citrated blood samples. To determine the effect of storage time, 11 samples had the EX‐test, FIB‐test, and IN‐test repeated 90 and 150 minutes after sample collection.Measurements and Main ResultsTen thromboelastometry parameters were evaluated for each test. Reference intervals were calculated using the robust method for parametric data, and the robust Box–Cox transformed or nonparametric methods were used for nonparametric data. Increasing storage time resulted in more hypocoagulable tracings. A correlation was found between the IN‐test and aPTT (r = 0.62, P < 0.0001). Other weak to moderate correlations were seen between thromboelastometry parameters and platelet count and hematocrit.Conclusions and Clinical ImportanceThe development of reference intervals for the thromboelastometry device allows for the clinical use of this technology. Analyzing samples after a prolonged storage time of more than 30 minutes may result in erroneous results. Results may also be affected by an abnormal hematocrit or platelet count.

Gut Microbe-Generated Metabolite Trimethylamine-N-Oxide and Ischemic Stroke

Trimethylamine-N-oxide (TMAO) is a gut microbiota-derived metabolite, the production of which in vivo is mainly regulated by dietary choices, gut microbiota, and the hepatic enzyme flavin monooxygenase (FMO), while its elimination occurs via the kidneys. The TMAO level is positively correlated with the risk of developing cardiovascular diseases. Recent studies have found that TMAO plays an important role in the development of ischemic stroke. In this review, we describe the relationship between TMAO and ischemic stroke risk factors (hypertension, diabetes, atrial fibrillation, atherosclerosis, thrombosis, etc.), disease risk, severity, prognostic outcomes, and recurrence and discuss the possible mechanisms by which they interact. Importantly, TMAO induces atherosclerosis and thrombosis through lipid metabolism, foam cell formation, endothelial dysfunction (via inflammation, oxidative stress, and pyroptosis), enhanced platelet hyper-reactivity, and the upregulation and activation of vascular endothelial tissue factors. Although the pathogenic mechanisms underlying TMAO’s aggravation of disease severity and its effects on post-stroke neurological recovery and recurrence risk remain unclear, they may involve inflammation, astrocyte function, and pro-inflammatory monocytes. In addition, this paper provides a summary and evaluation of relevant preclinical and clinical studies on interventions regarding the gut-microbiota-dependent TMAO level to provide evidence for the prevention and treatment of ischemic stroke through the gut microbe–TMAO pathway.

Proposed Mechanisms of Cell Therapy for Alzheimer’s Disease

Alzheimer’s disease is a progressive neurodegenerative disorder characterized by mitochondria dysfunction, accumulation of beta-amyloid plaques, and hyperphosphorylated tau tangles in the brain leading to memory loss and cognitive deficits. There is currently no cure for this condition, but the potential of stem cells for the therapy of neurodegenerative pathologies is actively being researched. This review discusses preclinical and clinical studies that have used mouse models and human patients to investigate the use of novel types of stem cell treatment approaches. The findings provide valuable insights into the applications of stem cell-based therapies and include the use of neural, glial, mesenchymal, embryonic, and induced pluripotent stem cells. We cover current studies on stem cell replacement therapy where cells can functionally integrate into neural networks, replace damaged neurons, and strengthen impaired synaptic circuits in the brain. We address the paracrine action of stem cells acting via secreted factors to induce neuroregeneration and modify inflammatory responses. We focus on the neuroprotective functions of exosomes as well as their neurogenic and synaptogenic effects. We look into the shuttling of mitochondria through tunneling nanotubes that enables the transfer of healthy mitochondria by restoring the normal functioning of damaged cells, improving their metabolism, and reducing the level of apoptosis.

Efficacy of Autofluorescence in Detection of Tobacco-associated Oral Mucosal Lesions - A Systematic Review

Abstract Background: This study was conducted with the aim to systematically review the efficacy of autofluorescence in the detection of tobacco-associated oral mucosal lesions. Objectives and Data Sources: Clinical studies with patients that focused on the autofluorescence method in the detection, visualisation, or management of tobacco-associated oral mucosal lesions were included in the literature search across bibliographic databases. Results: Autofluorescence visualisation showed positive results, with high sensitivity scores when compared with the gold standard of histopathology in the clinical evaluation of common tobacco-associated oral mucosal lesions. However, the low specificity values indicate its limited ability to distinguish between dysplasia and other benign conditions. Conclusions and Implications: This review provides promising evidence for the application of autofluorescence in the detection of tobacco-associated oral mucosal lesions where autofluorescence is used in conjunction with conventional examination with the gold standard of histopathological examination. Registration number: PROSPERO 2023 CRD42023442292.

Efficacy and Safety of Fixed-Dose Clindamycin Phosphate 1.2%/Adapalene 0.15%/Benzoyl Peroxide 3.1% Gel in Black Participants with Moderate-to-Severe Acne

Introduction: Topical clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (CAB) gel is the first fixed-dose, triple-combination formulation approved for the treatment of acne, and is indicated in patients 12 years of age and older. In 3 clinical studies of participants with moderate-to-severe acne, CAB gel demonstrated superior efficacy to vehicle and component dyads, with good safety/tolerability. To better understand the efficacy and safety of CAB gel in patients with darker skin phototypes, this post hoc analysis included participants who self-identified as ‘Black or African American’ (hereafter referred to as Black). Methods: Data were pooled from a phase 2 (N=741) and two phase 3 (N=183; N=180), double-blind, randomized, 12-week studies. Participants aged ≥9 years with moderate to severe acne were randomized to receive once-daily CAB or vehicle gel. Endpoints included ≥2-grade reduction from baseline in Evaluator’s Global Severity Score and clear/almost clear skin (treatment success) and least-squares mean percent change from baseline in inflammatory/ noninflammatory lesion counts. Treatment-emergent adverse events (TEAEs) were also assessed. Results: Of 657 participants randomized to CAB or vehicle gel, 104 (15.8%) self-identified as Black (n=64 CAB, n=40 vehicle). At week 12, 31.5% of Black participants treated with CAB achieved treatment success, compared to 17.3% with vehicle. Inflammatory lesion reductions with CAB were significantly greater than with vehicle (69.0% vs 53.6%, P<0.01), and noninflammatory lesion reductions were numerically greater with CAB than with vehicle (58.3% vs 51.9%). The rate of TEAEs with CAB treatment in Black participants was generally lower than in the overall study population (23.4% vs 24.6-36.2%), and most TEAEs were of mild-to-moderate severity. Conclusions: Fixed-dose, triple-combination CAB gel was efficacious and well tolerated in Black participants with moderate-to-severe acne. Despite the limited number of self-identified Black participants across the clinical studies of CAB gel, these post hoc analyses add valuable information to the limited literature describing treatment effects of fixed-dose combination acne treatments in Black individuals. Funding: Ortho Dermatologics

Permissive weight bearing versus restrictive weight bearing in surgically treated trauma patients with displaced intra-articular calcaneal fractures (the PIONEER study): study protocol for a multicenter randomized controlled trial

Abstract Background Following successful treatment, displaced intra-articular calcaneal fractures (DIACFs) necessitate an extensive rehabilitation regimen, significantly influencing functional and socio-economic outcomes. Apart from surgical intervention, the implementation of a comprehensive rehabilitation protocol is crucial to optimize foot stability and functional recovery. The objective of this study is to ascertain the optimal rehabilitation protocol for patients with surgically treated DIACFs, either permissive weight bearing (PWB) or Restricted Weight Bearing, focusing on functional outcomes, health-related quality of life (HRQoL), radiographic parameters, cost-effectiveness, and incidence of complications. Methods Study design: A prospective multicenter randomized controlled trial. Study population: Presence of surgically (extended lateral, sinus tarsi, or percutaneous approach) treated unilateral DIACFs (Sanders type II to IV), aged 18–67 years (labor force). Patients must be able to understand and follow weight bearing instructions. N = 115 patients with DIACFs will be included. Interventions: Patients with DIACFs will be randomly allocated to one of the rehabilitation protocols, either PWB or RWB. Primary outcome measure: Functional outcome, measured with the American Orthopaedic Foot & Ankle Society Score (AOFAS)). Secondary outcomes: Functional outcome (Maryland Foot Score, MFS), HRQoL (EuroQol-5D, EQ-5D), differences in radiographic parameters, cost-effectiveness, and complications. Nature and extent of burden: The PWB protocol is aimed to be non-inferior to the RWB protocol. Previous analysis of this protocol in other lower extremity fractures has shown a safe complication rate. Follow-up is standardized according to current trauma guidelines, namely at time points 2, 6, 12 weeks, and 6 months. The radiation exposure for both groups will differ from standard care (one extra CT scan of the foot will be made). Therefore, the burden for participants is considered minimal, with no significant health risks. Discussion This study will be the first study to define an optimal rehabilitation regime for surgically treated patients with DIACFs. The limitations of this study include the absence of patient blinding, as this is impossible in rehabilitation. Additionally, the primary outcome measure (AOFAS) has limited validity for DIACFs. However, it is the most commonly used questionnaire in the literature on DIACFs. There is an apparent need since current literature is lacking on this specific topic. Trial registration ClinicalTrials.gov NCT05721378, accepted on February 7, 2023.

Postinsertion Management of Cholecystostomy Tubes for Acute Cholecystitis: A Systematic Review

Background: Percutaneous gallbladder drainage (PGD) is indicated to treat high-risk patients with acute cholecystitis. Trends suggest increasing use of PGD over time as the population ages and lives longer with multiple comorbidities. There is no consensus on the management of cholecystostomies tube once inserted. This review aims to synthesize and describe the most common protocols in terms of the need and timing of follow-up imaging, management of a destination tube, timing of tube removal, and optimal interval time from tube positioning to delayed cholecystectomy. Methods: The study protocol has been registered on the International Prospective Register of Systematic Reviews–PROSPERO. Studies on adult patients diagnosed with acute cholecystitis who underwent a PGD from 2000 to November 2023 were included. The databases searched were MEDLINE, Embase, and Cochrane. The quality assessment tools provided by the NHLBI (National Heart, Lung, and Blood Institute) were applied and descriptive statistics were performed. Results: We included 22,349 patients from 94 studies with overall fair quality (6 prospective and 88 retrospective). In 92.7% of papers, the authors checked by imaging all patients with a PGD (41 studies included). Depending on protocol time, 30% of studies performed imaging within the first 2 weeks and 35% before tube removal (40 studies included). In the case of a destination tube, 56% of studies reported removing the tube (25 studies included). In the case of tube removal, the mean time after insertion was more than 4 weeks in 24 of the 33 included studies (73%). Interval cholecystectomies are more frequently performed after 5 weeks from PGD (32/38 included studies, 84%). Limitations included high clinical heterogeneity and prevalent retrospective studies. Conclusions: A standard management for percutaneous cholecystostomy after insertion is difficult to define based on existing evidence, and currently we can only rely on the most common existing protocols.

Effectiveness of a single burr hole as a surgical technique for the management of chronic subdural hematoma: A clinical case series study

Effectiveness of a single burr hole as a surgical technique for the management of chronic subdural hematoma: A clinical case series study

Food Costs of a Low-Fat Vegan Diet vs a Mediterranean Diet

This ad hoc secondary analysis of a randomized clinical trial compares the food costs in the United States of a low-fat vegan diet and a Mediterranean diet.