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MicroRNA-17-92 Regulates Skin Langerhans Cell Embryonic Development by Targeting Cell Proliferation Pathways
No full textAn evidence-driven classification of nonfiltering ingredients for topical photoprotection
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Semaglutide in Adults with Type 1 Diabetes and Obesity
No full textBACKGROUND: Once-weekly semaglutide is approved for the management of type 2 diabetes and obesity. The efficacy and safety of semaglutide in adults with type 1 diabetes are not established.
METHODS: In this 26-week, double-blind trial, we randomly assigned 72 adults with type 1 diabetes using an automated insulin delivery (AID) system and with a body mass index of 30 or higher in a 1:1 ratio to receive once-weekly semaglutide up to 1 mg or placebo. The primary composite end point consisted of achieving all of the following elements: continuous glucose monitoring (CGM)-based time between 70 and 180 mg/dl of greater than 70% and time below 70 mg/dl of less than 4%; and weight reduction of at least 5%.
RESULTS: A significantly greater percentage of patients in the semaglutide group than in the placebo group achieved the primary composite outcome (36% vs. 0%; between-group difference, 36 percentage points; 95% confidence interval [CI], 20.6 to 52.2; P\u3c 0.001). The difference in the least-squares mean change from baseline to week 26 for the semaglutide versus placebo group for glycated hemoglobin was -0.3 percentage points (95% CI, -0.6 to -0.05), for percentage of time with CGM glucose levels between 70 and 180 mg/dl it was 8.8 percentage points (95% CI, 3.9 to 13.7), and for body weight it was -8.8 kg (95% CI, -10.6 to -7.0). There were two severe hypoglycemia events in each group, and no diabetic ketoacidosis was reported.
CONCLUSIONS: In adults with type 1 diabetes and obesity, semaglutide treatment, compared with AID use alone, significantly improved achievement of a composite of time in range of greater than 70%, with time below range of less than 4%, and a 5% body weight reduction. (Funded by Breakthrough T1D [Type 1 Diabetes]; ADJUST-T1D trial ; Clinicaltrials.gov number, NCT05537233)
AGP Reports for Glucose and Insulin Devices Qualitative Study: What Patients and Clinicians Want
No full textPurpose: The purpose of the 2-phase study was to determine patient/family and clinician design preference, usability, and comprehension of ambulatory glucose profile (AGP) reports.
Methods: A cross-sectional research design employing 2 phases was conducted. Patients and parents (n = 139) reviewed an educational guide and AGP report during a clinician consultation. They were directed to identify glucose trends before answering a design preferences and usability survey. Clinicians (n = 17) completed questionnaires about patients and personal experiences, design preferences, and expected future usability. Further study of the AGP (n = 21) evaluated a draft display AGP continuous glucose monitoring (CGM) + pump report, enhanced after the aforementioned blood glucose monitoring (BGM) and CGM survey through interviews using both scripted and unscripted questions.
Results: Patients identified glucose trends/patterns in all AGP reports (100% BGM; 98% CGM; 95% CGM + pump). Patients and clinicians felt that the single-page report added value both in and outside of the clinic, preferred this standardized data view compared to traditional device-specific reports, and saw value in the AGP combination of statistics and graphs. Insulin data were seen as useful but increased the difficulty of report interpretation; only 38% were able to accurately interpret the data and make self-treatment recommendations.
Conclusions: Patients feel that the AGP report (BGM, CGM, CGM + pump) is useful for identifying new glucose patterns/trends. Patients report more confidence in making self-care adjustments (behavioral, lifestyle, and treatments) using the AGP report. For shared decision-making, the AGP report serves both patients\u27 and clinicians\u27 needs
Pre-Diagnosis Alkaline Phosphatase and Antimitochondrial Antibody Positivity Vary by Race/Ethnicity Among Patients With Primary Biliary Cholangitis
No full textBACKGROUND: Diagnosis of primary biliary cholangitis (PBC) is made using alkaline phosphatase (ALP) and positive antimitochondrial antibody (AMA), but these biomarkers may vary by race. There is also little known about changes in ALP in the years prior to PBC diagnosis.
METHODS: Using data from the Fibrotic Liver Disease Consortium, we used matched pairs to evaluate racial differences in ALP for up to 5 years prior to diagnosis. We also compared rates of AMA positivity by race.
RESULTS: 1335 confirmed PBC patients were included: 769 (58%) non-Hispanic white (NHW); 110 (8%) Black; 138 (11%) Asian American Pacific Islander (AAPI); and 318 (24%) Hispanic. 774 patients had AMA test results. Black patients had significantly lower AMA positivity than NHWs. Black patients were less likely to be AMA-positive compared to NHW patients (OR = 0.50, 95% CI 0.29-0.86, p = 0.012). There were no significant differences in rates of AMA positivity between AAPI or Hispanic versus NHW patients. All patient groups had elevated ALP for 2-5 years prior to diagnosis. ALP differed between Black and NHW patients only at specific times before diagnosis. There were no significant differences in ALP between Hispanic and NHW patients. AAPI patients had significantly lower ALP compared to NHWs.
CONCLUSION: In a diverse sample of PBC patients, we observed significant differences in AMA positivity and pre-diagnosis ALP levels by race. Future studies to better characterize PBC across racial/ethnic groups are warranted
Garsorasib, a KRAS G12C inhibitor, with or without cetuximab, an EGFR antibody, in colorectal cancer cohorts of a phase II trial in advanced solid tumors with KRAS G12C mutation
No full textMutations in the KRAS gene have long been implicated in the pathogenesis of colorectal cancer (CRC). KRAS G12C inhibitors overcome the undruggable challenge, enabling precision therapy. Garsorasib (D-1553), a highly potent and selective KRAS G12C inhibitor, has demonstrated promising anti-tumor activity and favorable safety profile in early clinical trials. We conducted an open-label, nonrandomized phase II trial (ClinicalTrials.gov, NCT04585035) to assess the safety and efficacy of garsorasib with or without cetuximab in KRAS G12C-mutated CRC. In the monotherapy cohort (n = 26), objective response rate (ORR) was 19.2% (95% CI, 6.6-39.4), disease control rate (DCR) was 92.3% (95% CI, 74.9-99.1), median progression-free survival (PFS) was 5.5 months (95% CI, 2.9-11.6) and median overall survival (OS) was 13.1 months (95% CI, 9.5-NE). In the combination cohort (n = 42), ORR was 45.2% (95% CI, 29.8-61.3), DCR was 92.9% (95% CI, 80.5-98.5), median PFS was 7.5 months (95% CI, 5.5-8.1), and median OS was not reached. Grade ≥3 treatment-related adverse events occurred in 5 (19.2%) and 6 (14.3%) patients in monotherapy and combination cohort, respectively. Garsorasib with or without cetuximab showed a promising efficacy and manageable safety profiles in heavily pretreated patients with KRAS G12C-mutated CRC, providing a potential new treatment approach for such population
Effects of antiretrovirals on major adverse cardiovascular events in the REPRIEVE trial: a longitudinal cohort analysis
No full textBACKGROUND: In the REPRIEVE trial of statin therapy in people with HIV, pitavastatin reduced major adverse cardiovascular events (MACE) among those with low-to-moderate risk of cardiovascular disease (CVD). We aimed to investigate associations between former and current use of antiretroviral therapy (ART) on entry into the REPRIEVE trial and the development of MACE.
METHODS: This longitudinal cohort analysis was a prespecified secondary analysis of the REPRIEVE trial, a double-blind, placebo-controlled, multicentre, phase 3 randomised trial conducted at 137 sites in 12 countries. REPRIEVE enrolled people with HIV aged 40-75 years, currently on ART, with a CD4 count of more than 100 cells per μL and low-to-moderate CVD risk, and randomly assigned them to receive pitavastatin or placebo. For this secondary analysis, participants\u27 history of ART use, including lifetime exposure to selected agents, was collected at baseline. The primary outcome of interest was time-to-first MACE. Stratified Cox proportional hazards models were used to estimate the relative hazards of MACE associated with ART exposures. Effects of no previous exposure, former exposure, and current exposure to ART at entry to the study were compared using models unadjusted and adjusted for entry risk factors and ART regimen at entry. All analyses were conducted in the intention-to-treat population. The REPRIEVE trial is registered at ClinicalTrials.gov, NCT02344290, and is complete.
FINDINGS: Between March 26, 2015, and July 31, 2019, 7769 participants were enrolled into the REPRIEVE trial. 2419 (31·1%) of 7769 participants were assigned female at birth and 5350 (68·9%) were assigned male at birth. 3208 (41·3%) of 7769 participants were Black or African American, 2704 (34·8%) were White, 1138 (14·6%) were Asian, and 719 (9·3%) were of other races. Participants had a median age of 50·0 years (IQR 45·0-55·0), LDL cholesterol concentration of 106 mg/dL (86-128), 10-year atherosclerotic cardiovascular disease risk score of 4·5% (2·1-7·0), and CD4 cell count of 621 cells per μL (448-827). 5867 (97·8%) of 5997 participants for whom data on this measure were available had an HIV-1 viral load of less than 400 copies per mL. The median duration of ART use at entry was 9·6 years (5·3-14·8). Overall, 1702 (21·9%) of 7769 participants reported previous exposure to abacavir, 6681 (86·0%) to tenofovir disoproxil fumarate, 3832 (49·3%) to thymidine analogues (zidovudine or stavudine), and 3683 (47·4%) to protease inhibitors. At study entry, 984 (12·6%) participants were using abacavir, 4743 (61·0%) were using tenofovir disoproxil fumarate, 756 (9·7%) were using thymidine analogues, and 1990 (25·6%) were using protease inhibitors. In adjusted analyses, former exposure (hazard ratio 1·62, 95% CI 1·14-2·30) and current exposure (1·41, 1·01-1·96) to abacavir was associated with a higher hazard of MACE than in participants who were never exposed. Associations between former or current exposure to other ART agents and MACE were not consistently apparent.
INTERPRETATION: Previous and current use of abacavir increases the hazard of MACE among people with HIV at low-to-moderate CVD risk, suggesting that abacavir should be avoided and previous exposure considered when assessing the risk of MACE in this population.
FUNDING: National Institutes of Health, Kowa Pharmaceuticals America, Gilead Sciences, and ViiV Healthcare
Risk Factors for Seeking Medical Care Following Nirmatrelvir-Ritonavir (Paxlovid) Treatment for COVID-19: Symptom Rebound
No full textNirmatrelvir plus ritonavir (NPR) has been approved for treating mild to moderate COVID-19 in high-risk adults but concerns about rebound effects have limited its use. This study aimed to identify individuals at risk of seeking medical care among high-risk non-hospitalized patients treated with NPR from 1 January 2022 to 31 December 2022, at our institution. Our outcome variable was the composite of subsequent evaluation in the Emergency Department or inpatient admission within four weeks of their NPR treatment. Of 369 patients who received NPR treatment, the mean (SD) age was 59.3 (±13.8) years; 64% (236) were female, and 77.7% (281) were white. The incidence of the composite event was 6.8% (25/369). In multivariable logistic regression, factors for seeking medical care following NPR treatment were female sex (OR 4.6; 95% CI 1.4-15.3; p = 0.013), myocardial infarction (OR 4.1; 95% CI 1.4-11.8; p = 0.011), chronic lung disease (CLD) except asthma and chronic obstructive pulmonary disease (COPD) (OR = 3.9, 95% CI 1.1-13.5; p = 0.03), and diabetes mellitus with complications (OR 6.9; 95% CI 2.0-23.3; p = 0.002) while alcohol users (OR 0.39; 95% CI 0.2-0.9; p = 0.038) were less likely to seek medical care. Larger cohorts are necessary to further assess and confirm these risk factors
New Frontiers in Multiple Sclerosis Treatment: From Targeting Costimulatory Molecules to Bispecific Antibodies
No full textMultiple sclerosis (MS) is an autoimmune demyelinating disease of the central nervous system. The therapeutic landscape for MS has evolved significantly since the 1990s, with the development of more than 20 different disease-modifying therapies (DMTs). These therapies effectively manage relapses and inflammation, but most have failed to meaningfully prevent disease progression. While classically understood as a T cell-mediated condition, the most effective DMTs in slowing progression also target B cells. Novel classes of MS therapies in development, including anti-CD40L monoclonal antibodies, CD19 chimeric antigen receptor (CAR) T cells, and Bruton\u27s tyrosine kinase (BTK) inhibitors show greater capacity to target and eliminate B cells in the brain/CNS, as well as impacting T-cell and innate immune compartments. These approaches may help tackle the disease at its immunopathological core, addressing both peripheral and central immune responses that drive MS progression. Another emerging therapeutic strategy is to use bispecific antibodies, which have the potential for dual-targeting various disease aspects such as immune activation and neurodegeneration. As such, the next generation of MS therapies may be the first to reduce both inflammatory demyelination and disease progression in a clinically meaningful way. Their ability to target specific immune cell populations while minimizing broad immune suppression could also lead to better safety profiles. Here, we explore the biological rationale, advantages, limitations, and clinical progress of these emerging immunotherapies for relapsing-remitting and progressive forms of MS