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Efficacy and safety of switch to bictegravir/emtricitabine/tenofovir alafenamide from dolutegravir/abacavir/lamivudine: Results from an open-label extension of a phase 3 randomized, double-blind, multicenter, active-controlled, non-inferiority study
No full textBACKGROUND: The phase 3 randomized, active-controlled GS-US-380-1844 (NCT02603120) study evaluated switching to the single-tablet regimen bictegravir, emtricitabine, and tenofovir alafenamide (B/F/TAF) from dolutegravir (DTG), abacavir (ABC), and lamivudine (3TC) among people with HIV-1. Previously, results from the 48-week double-blind phase showed that switching to B/F/TAF was noninferior to remaining on DTG/ABC/3TC and that B/F/TAF was well tolerated. Here, we show the long-term safety and efficacy of switching to B/F/TAF from DTG/ABC/3TC among people with HIV-1.
METHODS: Participants were virologically suppressed people with HIV-1 (HIV-1 RNA \u3c 50 copies/mL for ≥ 3 months prior to screening) receiving DTG/ABC/3TC at baseline. Participants were randomized 1:1 to switch to B/F/TAF or remain on DTG/ABC/3TC. Following 48 weeks of treatment with B/F/TAF or DTG/ABC/3TC in the double-blind phase, participants had the option to enter an open-label extension phase, during which they received B/F/TAF. Virologic, immunologic, and safety outcomes during treatment with B/F/TAF through the open-label extension up to 168 weeks, including preexisting and treatment-emergent resistance, were analyzed.
RESULTS: Among 547 participants in the all-B/F/TAF analysis set, virologic suppression (HIV-1 RNA \u3c 50 copies/mL) was maintained in 99% to 100% of participants up to 168 weeks into B/F/TAF treatment, including in those with preexisting resistance; no treatment-emergent resistance was detected. CD4 cell counts remained stable during B/F/TAF treatment, with median (interquartile range) changes from baseline of -17 (-120, 65) cells/µL at week 48 and -9 (-100, 108) cells/µL at week 96. Safety and tolerability findings were consistent with previously reported findings up to week 48; most drug-related adverse events were grade 1 or 2 in severity; no new safety signals were identified.
CONCLUSION: Switching to B/F/TAF from DTG/ABC/3TC was associated with continued high rates of virologic suppression up to week 168, with no treatment-emergent resistance. B/F/TAF was well tolerated throughout the study period
Advancing health equity: evaluating AI translations of kidney donor information for Spanish speakers
No full textBACKGROUND: Health equity and access to essential medical information remain significant challenges, especially for the Spanish-speaking Hispanic population, which faces barriers in accessing living kidney donation opportunities. ChatGPT, an AI language model with sophisticated natural language processing capabilities, has been identified as a promising tool for translating critical health information into Spanish. This study aims to assess ChatGPT\u27s translation efficacy to ensure the information provided is accurate and culturally relevant.
METHODS: This study utilized ChatGPT versions 3.5 and 4.0 to translate 27 frequently asked questions (FAQs) from English to Spanish, sourced from Donate Life America\u27s website. The translated content was reviewed by native Spanish-speaking nephrologists using a standard rubric scale (1-5). The assessment focused on linguistic accuracy and cultural sensitivity, emphasizing retention of the original message, appropriate vocabulary and grammar, and cultural relevance.
RESULTS: The mean linguistic accuracy scores were 4.89 ± 0.32 for GPT-3.5 and 5.00 ± 0.00 for GPT-4.0 (p = 0.08). The percentage of excellent-quality translations (score = 5) in linguistic accuracy was 89% for GPT-3.5 and 100% for GPT-4.0 (p = 0.24). The mean cultural sensitivity scores were 4.89 ± 0.32 for both GPT-3.5 and GPT-4.0 (p = 1.00). Similarly, excellent-quality translations in cultural sensitivity were achieved in 89% of cases for both versions (p = 1.00).
CONCLUSION: ChatGPT 4.0 demonstrates strong potential to enhance health equity by improving Spanish-speaking Hispanic patients\u27 access to LKD information through accurate and culturally sensitive translations. These findings highlight the role of AI in mitigating healthcare disparities and underscore the need for integrating AI-driven tools into healthcare systems. Future efforts should focus on developing accessible platforms and establishing guidelines to maximize AI\u27s impact on equitable healthcare delivery and patient education
The effect of AKT inhibition in α-synuclein-dependent neurodegeneration
No full textParkinson\u27s disease (PD) is a progressive neurodegenerative disorder affecting millions of individuals worldwide. A hallmark of PD pathology is the accumulation of α-synuclein (α-Syn), a small protein known to support neuronal development and function. However, in PD, α-Syn cumulatively misfolds into toxic aggregates that disrupt cellular processes and contribute to neuronal damage and neurodegeneration. Previous studies implicated the AKT signaling pathway in α-Syn toxicity in cellular models of PD, suggesting AKT as a potential therapeutic target. Here, we investigated the effect of AKT inhibition in a Drosophila model of synucleinopathy. We observed that administration of the AKT inhibitor, A-443654 led to mild improvements in both survival and motor function in flies expressing human α-Syn. Genetic studies revealed that reduction of AKT levels decreased α-Syn protein levels, concomitant with improved physiological outcomes. The protective effects of AKT reduction appear to operate through the fly ortholog of NF-κB, Relish, suggesting a link between AKT and NF-κB in regulating α-Syn levels. These findings highlight the AKT cascade as a potential therapeutic target for synucleinopathies and provide insights into mechanisms that could be utilized to reduce α-Syn toxicity in PD and related disorders, such as multiple system atrophy
Identification and validation of LINC02381 as a biomarker associated with lymph node metastasis in esophageal squamous cell carcinoma
No full textBACKGROUND: The treatment of esophageal squamous cell carcinoma (ESCC) patients varies considerably depending upon whether lymph node metastasis (LNM) is present. Patients with ESCC can particularly benefit from neoadjuvant therapy if LNM is accurately diagnosed before surgery. Long noncoding RNA (lncRNA) has been confirmed to be closely related to the development of metastases in ESCC, but much remains unknown regarding the relationship between LNM and lncRNA. The purpose of our study was to investigate relationship between LNM and lncRNA, and create a diagnostic model for predicting LNM in ESCC before surgery.
METHODS: We used quantitative real-time polymerase chain reaction (qRT-PCR) to detect the expression of LINC02381. We also verified the in vitro effect of LINC02381 on the growth and metastasis of ESCC in the KYSE510 and KYSE180 cell lines. We used the Kaplan-Meier (KM) method and the log-rank test to confirm the differences of overall survival (OS) and disease-free survival (DFS) in LINC02381 expression. We used univariate and multivariate logistic regression analyses to screen for clinical characteristics and assessed their clinical diagnostic efficacy using receiver operating characteristic (ROC) curves. The model was validated with the area under the curve (AUC) and calibration curves and visualized through a nomogram.
RESULTS: qRT-PCR suggested a significant elevation of LINC02381 expression in ESCC tissues compared with normal esophageal epithelial tissues (P \u3c 0.001) and in ESCC tissues with LNM (P \u3c 0.001). Analysis of OS and DFS indicated that the high expression of LINC02381 and lymph node positivity were associated with poor prognosis. Combined analysis showed that patients with both a high expression of LINC02381 and lymph node positivity had the worst prognosis. High expression of LINC02381 was associated with poor differentiation, tumor-node-metastasis (TNM) staging, and LNM in ESCC. Presence of LNM was also closely associated with tumor differentiation and primary tumor staging. Univariate and multivariate logistic regression analyses identified that primary tumor staging, tumor differentiation, and LINC02381 expression were independent influencing factors. In the ROC curve analysis of the risk model, the AUC for LINC02381 expression was 0.822 and increased to 0.913 when primary tumor staging and tumor differentiation were added. We further conducted calibration curve analysis to display the calibration of our final model. A nomogram was used to display the predictive variables. The in vitro experiments demonstrated that the knockdown of LINC02381 could inhibit the growth and metastasis of ESCC.
CONCLUSIONS: LINC02381 may serve as a biomarker for predicting LNM. Our risk model can assist in predicting LNM in clinical practice, inform the decision to implement neoadjuvant therapy before surgery, and therefore improve prognosis
Genome-wide association study meta-analysis provides insights into the etiology of heart failure and its subtypes
No full textHeart failure (HF) is a major contributor to global morbidity and mortality. While distinct clinical subtypes, defined by etiology and left ventricular ejection fraction, are well recognized, their genetic determinants remain inadequately understood. In this study, we report a genome-wide association study of HF and its subtypes in a sample of 1.9 million individuals. A total of 153,174 individuals had HF, of whom 44,012 had a nonischemic etiology (ni-HF). A subset of patients with ni-HF were stratified based on left ventricular systolic function, where data were available, identifying 5,406 individuals with reduced ejection fraction and 3,841 with preserved ejection fraction. We identify 66 genetic loci associated with HF and its subtypes, 37 of which have not previously been reported. Using functionally informed gene prioritization methods, we predict effector genes for each identified locus, and map these to etiologic disease clusters through phenome-wide association analysis, network analysis and colocalization. Through heritability enrichment analysis, we highlight the role of extracardiac tissues in disease etiology. We then examine the differential associations of upstream risk factors with HF subtypes using Mendelian randomization. These findings extend our understanding of the mechanisms underlying HF etiology and may inform future approaches to prevention and treatment
Efficacy and safety of fixed-dose clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% gel in Hispanic participants with moderate-to-severe acne: a pooled analysis
No full textINTRODUCTION: Clindamycin phosphate 1.2%/adapalene 0.15%/benzoyl peroxide 3.1% (CAB) gel is the only fixed-dose, triple-combination approved for acne. In phase 2 and 3 studies, CAB demonstrated superior efficacy to vehicle and component dyads. This post hoc analysis examined efficacy/tolerability of CAB in 147 self-identified Hispanic/Latino participants (referred to as Hispanic).
METHODS: Data were pooled from one phase 2 (NCT03170388) and two phase 3 (NCT04214652, NCT04214639) double-blind, 12-week studies. Eligible participants aged ≥9 years with moderate to severe acne were randomized to once-daily CAB or vehicle. Endpoints included ≥2-grade reduction from baseline in Evaluator\u27s Global Severity Score with clear/almost clear skin (treatment success) and inflammatory/noninflammatory lesion counts. Treatment-emergent adverse events (TEAEs) were assessed.
RESULTS: At week 12, 56.2% of CAB-treated participants achieved treatment success vs 18.4% with vehicle (p \u3c 0.001). Reductions in inflammatory/noninflammatory lesions were 77.1%/76.2% with CAB vs 56.4%/45.0% with vehicle, respectively (p \u3c 0.001, all). CAB TEAE rates were similar to overall study populations (27.0% vs 24.6%-36.2%). Baseline hyperpigmentation scores decreased from 0.6 to 0.3 (1 = mild) at week 12 with CAB. CAB gel was efficacious, safe, and well tolerated in Hispanic participants. Limitations include lack of Fitzpatrick skin phototype and short study duration.
CONCLUSIONS: This study provides support for acne treatment with CAB in ethnically diverse populations
Gender-Based Disparities in Academic Orthopaedic Surgery Physician Compensation in 2023
No full textBACKGROUND: Orthopaedic surgery remains one of the least diverse specialties in medicine. Parity in opportunity and recognition are key factors in attracting and retaining a diverse group of individuals in the field. The primary purpose of this study was to assess gender-based discrepancies in total salary compensation by rank for academic orthopaedic surgery faculty.
METHODS: Aggregate data were obtained from the Association of American Medical Colleges for fiscal year 2023. Mean compensation was compared for orthopaedic surgery faculty and total surgery faculty at all academic ranks based on gender and race.
RESULTS: Men received markedly higher total compensation for all ranks except chair within orthopaedic surgery. At the instructor level, men earned an average annual income of 229,204, demonstrating a significant pay gap ( P = 0.0019). At the assistant professor (men: 475,857), associate professor (men: 575,877), and professor (men: 472,140) levels, there existed significant pay disparities ( P \u3c 0.0001 for all three academic levels, respectively). At the chief position, men earned an average of 596,270 ( P = 0.0006). Aggregate data for other surgical specialties demonstrated similar results, with women receiving lower total compensation at all ranks compared with men.
CONCLUSION: This analysis of the 2023 American Medical Colleges Faculty Salary Report demonstrates a notable pay differential between men and women in orthopaedic surgery and surgical specialties, in general, across multiple academic levels including instructor, assistant professor, associate professor, professor, and chief of division. Although there has been increasing awareness of gender-based compensation disparities within surgical specialties, particularly in orthopaedic surgery, these disparities are still clearly present
Preoperative depression screening using PHQ-2 is associated with worse outcomes after ACL reconstruction
No full textPURPOSE: To determine how screening positive for depression preoperatively can affect patient reported outcomes after anterior cruciate ligament reconstruction (ACLR).
METHODS: Primary ACLR patients between May 2020-September 2022 with a PHQ-2 score prior to their surgery were retrospectively reviewed. Patients older than 13 years of age and with minimum 6-months of follow-up were included for analysis. Patients were categorized as PHQ(+) (PHQ-2 ≥2) or PHQ2(-) (PHQ-2 \u3c 2). Demographics, preoperative and postoperative Patient Reported Outcome Information System (PROMIS) -Physical Function (PF) and Pain Interference (PI) scores, Patient Acceptable Symptomatic State (PASS), surgical clinical outcomes, and complications were collected and compared. Chi-square tests and independent t-tests were used for categorical and continuous variables, respectively.
RESULTS: A total of 127 patients were analyzed, with 32 PHQ2(+) and 95 PHQ2(-). The PHQ2(+) group had a lower proportion responding yes to PASS preoperatively (6.5 % vs. 25.3 %, p = 0.03), at 9 months (47.4 % vs. 72.4 %, p = 0.05), and 12 months postoperatively (42.9 % vs 79.5 %, p = 0.009). PHQ2(+) reported worse PROMIS-PI scores preoperatively, at 6 months, and at 9 months. The PHQ2(+) group reported worse PROMIS-PF preoperatively, at 6 months, at and 12 months. The PHQ2(+) group had worse IKDC scores preoperatively at 9 months and at 12 months. Those screening positive for depression also demonstrated a higher incidence of postoperative complications (34.4 % vs. 9.5 %, p = 0.001) and reoperation rates (21.9 % vs. 4.2 %; p = 0.002).
CONCLUSION: A brief preoperative survey, such as the PHQ-2, can provide prognostic value for patient outcomes after ACLR.
LEVEL OF EVIDENCE: III-Retrospective cohort study
Case Report: Prepubertal-type testicular teratoma with local metastasis in a postpubertal patient
No full textINTRODUCTION: We report for the first time a case of a postpubertal patient presenting with a metastatic prepubertal-type testicular teratoma.
CASE DISCUSSION: A 29-year-old male with a history of corrected unilateral cryptorchidism presented with progressive bilateral lower extremity edema. Imaging revealed an inferior vena cava thrombus associated with a complex mass. A left testicular ultrasound identified a solid lesion suggestive of a germ cell tumor, leading to a left radical orchiectomy, which revealed a mature pure teratoma with no evidence of germ cell neoplasia in situ (GCNIS). Excision of the retroperitoneal mass confirmed the presence of mature teratomatous elements without evidence of non-teratomatous germ cell tumor elements or cytological atypia. Fluorescence in situ hybridization (FISH) showed no evidence of gain of 12p, and next-generation sequencing showed no alterations in genes known to be associated with GCT.
CONCLUSION: This case illustrates that pure mature teratomas lacking chromosome 12p abnormalities, GCNIS, and other dysgenetic features, occurring in postpubertal males, cannot invariably be classified into the benign prepubertal-type teratoma category. Contrary to current paradigm, in rare cases these may represent tumors with metastatic potential