OBJECTIVE: A population-based pharmacokinetic (PK) modeling approach (PopPK) was used to investigate the impact of Roux-en-Y gastric bypass (RYGB) on the PK of (R)- and (S)-carvedilol. We aimed to optimize carvedilol dosing for these patients utilizing a pharmacokinetic/pharmacodynamic (PK/PD) link model.
METHODS: PopPK models were developed utilizing data from 52 subjects, including nonobese, obese, and post- RYGB patients who received rac- carvedilol orally. Covariate analysis included anthropometric and laboratory data, history of RYGB surgery, CYP2D6 and CYP3A4 in vivo activity, and relative intestinal abundance of major drug- metabolizing enzymes and transporters. A direct effect inhibitory Emax pharmacodynamic model was linked to the PK model of (S)- carvedilol to simulate the changes in exercise- induced heart rate.
RESULTS: A 2-compartmental model with linear elimination and parallel first-order absorptions best described (S)-carvedilol PK. RYGB led to a twofold reduction in relative oral bioavailability compared to nonoperated subjects, along with delayed absorption of both enantiomers. The intestinal ABCC2 mRNA expression increases the time to reach the maximum plasma concentration. The reduced exposure (AUC) of (S)-carvedilol post-RYGB corresponded to a 33% decrease in the predicted area under the effect curve (AUEC) for the 24-hour β-blocker response. Simulation results suggested that a 50-mg daily dose in post-RYGB patients achieved comparable AUC and AUEC to 25-mg dose in nonoperated subjects.
CONCLUSIONS: Integrated PK/PD modeling indicated that standard dosage regimens for nonoperated subjects do not provide equivalent β-blocking activity in RYGB patients. This study highlights the importance of personalized dosing strategies to attain desired therapeutic outcomes in this patient cohort.

Primary gastrointestinal follicular lymphoma (PGI-FL) is a rare extra-nodal lymphoma. Its epidemiology and prognosis remain unclear. We performed a retrospective analysis of eligible patients with 1648 PGI-FL and 34 892 nodal FL (N-FL) in the Surveillance, Epidemiology and End Results (SEER) database. The age-adjusted average annual incidence of PGI-FL was 0.111/100000. The median overall survival (OS) for PGI-FL and N-FL patients was 207 and 165 months respectively. The 5-year diffuse large B-cell lymphoma (DLBCL) transformation rates were 2.1% and 2.6% respectively. Age, sex, grade, Ann Arbor stage, primary site and radiation were independent prognostic factors (p < 0.05). Nomograms were constructed to predict 1-, 5- and 10-year OS and disease-specific survival (DSS). The receiver operating characteristic curves and calibration plots showed the established nomograms had robust and accurate performance. Patients were classified into three risk groups according to nomogram score. In conclusion, the incidence of PGI-FL has increased over the past 40 years, and PGI-FL has a better prognosis and a lower DLBCL transformation rate than N-FL. The nomograms were developed and validated as an individualized tool to predict survival. Patients were divided into three risk groups to assist clinicians in identifying high-risk patients and choosing the optimal individualized treatments.

BACKGROUND: Testicular tumors are the most common malignancies in young adults and their incidence is growing. The implantation of a testicular prosthesis, for example, during orchiectomy is a standard procedure but its frequency in Germany is unknown. This study aims to analyze trends of testicular prosthesis implantation in recent years in Germany.
METHODS: The nationwide German hospital billing database and the German hospital quality reports from 2006 to 2021 were studied.
RESULTS: A total of 12,753 surgical procedures with implantation of testicular prosthesis and 1,244 procedures with testicular prosthesis explantation were included. Testicular prosthesis implantation increased in total from 699 cases in 2006 to 870 cases in 2020 (+11.4 cases/year; p < 0.001). The share of implantation of testicular prosthesis due to testicular tumor decreased from 72.6% in 2006 to 67.5% in 2020 (p < 0.001). The share of implantation due to gender affirming surgery increased from 6.8% in 2006 to 23.3% in 2020 (p < 0.001). The share of implantation due to testicular atrophy decreased from 11.4% in 2006 to 3.4% in 2020 (p < 0.001). Simultaneous implantation of testicular prosthesis during orchiectomy for testicular cancer increased from 7.8% in 2006 to 11.4% in 2020 (p < 0.001). In 2006, 146 hospitals (85%) performed < 5 testicular prosthesis implantation, while 20 hospitals (12%) performed 5-15 implantation procedures and 6 hospitals (3%) performed > 15 testicular implantation surgeries. In 2021, 115 hospitals (72%) performed < 5 testicular prosthesis implantation, while 39 hospitals (25%) performed 5-15 implantation procedures and 5 hospitals (3%) performed > 15 testicular implantation surgeries.
CONCLUSIONS: This study shows that implantation of testicular prostheses is steadily increasing. Explantation rates are low. Besides testicular cancer transgender surgeries were the main driver for increasing case numbers in recent years.

Background Randomized controlled trials showed that newer glucose-lowering agents are cardioprotective, but most participants were men. It is unknown whether benefits are similar in women. Methods and Results Among adults with type 2 diabetes mellitus not controlled with metformin with no prior use of insulin, we assessed for sex differences in the cardiovascular effectiveness and safety of sodium-glucose-like transport-2 inhibitors (SGLT-2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), dipeptidyl peptidase-4 inhibitors, initiated as second-line agents relative to sulfonylureas (reference-group). We studied type 2 diabetes mellitus American adults with newly dispensed sulfonylureas, SGLT-2i, GLP-1RA, or dipeptidyl peptidase-4 inhibitors (Marketscan-Database: 2011-2017). We used multivariable Cox proportional hazards models with time-varying exposure to compare time to first nonfatal cardiovascular event (myocardial infarction/unstable angina, stroke, and heart failure), and safety outcomes between drugs users, and tested for sex-drug interactions. Among 167 254 type 2 diabetes mellitus metformin users (46% women, median age 59 years, at low cardiovascular risk), during a median 4.5-year follow-up, cardiovascular events incidence was lower in women than men (14.7 versus 16.7 per 1000-person-year). Compared with sulfonylureas, hazard ratios (HRs) for cardiovascular events were lower with GLP-1RA (adjusted HR-women: 0.57, 95% CI: 0.48-0.68; aHR-men: 0.82, 0.71-0.95), dipeptidyl peptidase-4 inhibitors (aHR-women: 0.83, 0.77-0.89; aHR-men: 0.85, 0.79-0.91) and SGLT-2i (aHR-women: 0.58, 0.46-0.74; aHR-men: 0.69, 0.57-0.83). A sex-by-drug interaction was statistically significant only for GLP-1RA (P=0.002), suggesting greater cardiovascular effectiveness in women. Compared with sulfonylureas, risks of adverse events were similarly lower in both sexes for GLP-1RA (aHR-women: 0.81, 0.73-0.89; aHR-men: 0.80, 0.71-0.89), dipeptidyl peptidase-4 inhibitors (aHR-women: 0.82, 0.78-0.87; aHR-men: 0.83, 0.78-0.87) and SGLT-2i (aHR-women: 0.68, 0.59-0.78; aHR-men: 0.67, 0.59-0.78) (all sex-drug interactions for adverse events P>0.05). Conclusions Newer glucose-lowering drugs were associated with lower risk of cardiovascular events than sulfonylureas, with greater effectiveness of GLP-1RA in women than men. Overall, they appeared safe, with a better safety profile for SGLT-2i than for GLP-1RA regardless of sex.