Mortality after Use of Paclitaxel-Coated Balloons Correlates with Total Cumulative Dosage of Paclitaxel in Real-World Analysis

This study used independent, real-world, patient-level data to examine whether the dosage or frequency of paclitaxel exposure correlated with mortality during follow up. We conducted a retrospective analysis of patients treated with a drug-coated balloon (DCB) for an atherosclerotic femoropopliteal lesion from February 2013 to December 2018, excluding patients with non-atherosclerotic lesions or restenosis after DCB treatment in another hospital. We investigated the causes of death, comorbidities (including cancer status), and the initial and total cumulative dosages and frequency of paclitaxel use. To determine whether the dosage or frequency of paclitaxel exposure affected mortality during follow up, we analyzed the risk factors for all-cause death by conducting a time-dependent Cox regression analysis that considered demographics, comorbidities, lesion and procedural characteristics, and paclitaxel exposure data (dosage and frequency). Our analysis examined 225 patients (mean age 71 ± 9 years, range 38–93 years, male 81%). During a mean follow-up duration of 35 months (range 1–89 months), 56 patients (24.9%) died from cardiac disorders (16%, including acute myocardial infarction, heart failure, or sudden cardiac arrest), malignancy (14.3%), respiratory failure with pneumonia (12.5%), septic shock (12.5%), or another cause. Univariable and multivariable Cox regression analyses identified age (hazard ratio, HR, 1.057; 95% confidence interval, CI, 1019–1096; p = 0.0032), critical limb ischemia (CLI) (HR, 4135; 95% CI, 2171–7876; p < 0.0001), and the total dosage of paclitaxel (mg) (HR, 1.040; 95% CI, 1006–1074; p = 0.0210) as predictors of mortality during follow up. The subgroup analysis found that the total dosage of paclitaxel (mg) was also a predictor of mortality during follow up in the CLI group (HR, 1.046; 95% CI, 1007–1087, p = 0.0198). The estimated cut-off value of total cumulative paclitaxel dosage for predicting mortality was 12 mg as evaluated by minimum p value approach. This patient-level analysis identified the total cumulative dosage of paclitaxel as a predictor of mortality after the use of paclitaxel-coated balloons. Our results provide limited information about the potential dose–response relationship underlying paclitaxel-associated mortality concerns.

Association of metformin and development of dry age-related macular degeneration in a U.S. insurance claims database

Purpose: To assess whether metformin is associated with dry age-related macular degeneration (dAMD) development. Methods: In this retrospective cohort study, patients enrolled in a nationwide U.S. medical insurance claims database from 2002 to 2016 were included if they had diabetes mellitus, were ⩾55 years old, and were enrolled for ⩾2 years without a prior AMD diagnosis. The primary exposure was metformin use analyzed as either active or prior use or cumulative metformin dosage over the study period. A time updating Cox proportional hazard regression was used to estimate the hazard ratio of dAMD incidence with metformin exposure. Results: Among 1,007,226 diabetic enrollees, 53.3% were female and 66.4% were white with a mean hemoglobin A1c of 6.8%. Of eligible enrollees, 166,115 (16.5%) were taking metformin at the index date. Over the study period, 29,818 (3.0%) participants developed dAMD. In the active versus prior use of metformin model, active use conferred an increased hazard of developing dAMD (HR, 1.08; 95% CI, 1.04–1.12) while prior use had a decreased hazard (HR, 0.95; 95% CI 0.92–0.98). The cumulative metformin dosage model showed a significant trend toward increased hazard of dAMD incidence with increasing cumulative dosage ( p < 0.001), with the lowest dosage quartile having decreased hazard of dAMD incidence (HR, 0.95; 95% CI, 0.91–0.99) and the highest having increased hazard (HR, 1.07; 95% CI, 1.01–1.13). Conclusions: Small, conflicting associations between metformin exposure and development of dAMD were observed depending on cumulative dosage and whether drug use was active, suggesting metformin did not substantially affect the development of dAMD.

Association between genetic polymorphisms and osteonecrosis in steroid treatment populations: a detailed stratified and dose-response meta-analysis

Steroid treatment has become recognized as an important risk factor for avascular osteonecrosis of the femoral head. However, not all patients who receive long-term, high-dose steroids develop osteonecrosis, indicating that there are individual differences in occurrence. We explored the relationship between polymorphisms and steroid-induced osteonecrosis of the femoral head (SONFH) incidence with variables. We used a multilevel mixed-effects logistic regression model, which is an expansion of logistic regression, for each type of steroid, primary disease, drug dose, applied duration, and single-nucleotide polymorphism (SNP). We also conducted a dose-response meta-analysis to analyze the cumulative dosage and SONFH risk in mutation carriers. There were significant correlations between the ABCB1 rs1045642 mutant and SONFH in the prednisone-use and methylprednisolone/prednisone-use populations. The ABCB1 rs2032582 mutant homozygote had a protective effect in the methylprednisolone/prednisolone renal transplant population. For ApoB rs693, mutation increased the incidence of SONFH in prednisone-use and methylprednisolone/prednisolone-use populations and renal transplant patients. For ApoB rs1042031, mutation increased the risk of SONFH in the prednisone-use population. The PAI-1 rs1799768 mutation had a protective effect on the SONFH risk prednisone-use and renal transplant populations. ABCB1 rs1045642 mutations have a protective effect against SONFH, and ApoB rs693 and rs1042031 increase the SONFH risk. Cumulative dosage and treatment duration had little effect on the results. In addition, there was a dose-effect correlation in ABCB1 rs1045642 and rs2032582 mutation carriers.

Effects of multiple sclerosis and medications on menopausal age

Objectives We aimed to determine whether multiple sclerosis (MS) and methylprednisolone and disease-modifying drugs have an effect on menopausal age. Methods A total of 86 patients and 98 healthy subjects were included in this study. The natural menopausal age of the patients and healthy subjects were compared. The cumulative dosages of methylprednisolone, beta interferons (IFNβs), and glatiramer acetate were calculated. The effects of the Expanded Disability Status Scale (EDSS), duration of the disease, and cumulative dosage of medications on menopausal age were evaluated. Results The patients’ mean menopausal age was 45.3 ± 4.8 years and healthy subjects’ menopausal age was 46.8 ± 4.3 years, with no significant difference between the two groups. The cumulative dosage of methylprednisolone showed an effect on menopausal age. There was a significant inverse correlation between menopausal age and dosage of IFNβ-1b, while the disease duration and EDSS score showed no correlation with menopausal age. Conclusions We conclude that menopausal age is not affected by MS. However, long-term methylprednisolone and IFNβ-1b treatments may change menopausal age in a dose-dependent manner.

Osteonecrosis of the Jaw Associated with Chronic Bisphosphonates Therapy: An Italian Experience.

Background. Pamidronate (P) and Zoledronate (Z) are new generation bisphoshonates (BS) used for treatment of bone lesions in patients (pts) with multiple myeloma (MM), solid tumors and no oncologic diseases. They are monthly administered for prolonged periods of time and they are generally well tolerated. Recently, severe osteonecrosis (ON) of the jaw has been reported as an adverse effect of treatment. Avascular bone necrosis has been often observed after major dental procedure. In site of lesion, occasionally, Actinomyces spp were recovered from culture. The aetiology is not understood, although it has been postulated to be secondary to the antiangiogenic effect of BS. Patients. We performed a review of pts of the two hematologic departments treated in the last two years with monthly intravenous BS therapy (Pamidronate 90 mg and /or Zoledronate 4 mg). Overall, 118 patients were studied: 48 males, 70 females; 104 presented MM, 8 severe osteoporosis, 4 iperparathyroidism, 1 Paget disease and 1 breast carcinoma. All patients with a neoplastic disease had received at least one line of chemotherapy. Results. Fourteen pts presented ON (13 with MM and one with severe osteoporosis). The median doses of BS therapy were: 560 mg (range 0–6480 mg) for P, 80 mg (range 0–308 mg) for Z. Five pts had an important exposed jawbone and 11 pts developed ON after a previous tooth extraction. Mandible was involved in 9 pts and maxilla in 5. Diagnosis was made with oral inspection, X-ray, TC and histology. Actinomyces spp were recovered in only one patient. Statistical Analysis. All variables were analyzed for descriptive statistics and to check their distribution by Shapiro-Wilk test. The median values of cumulative dosage were used as cut-off points, and a score 0 was attributed to all dosages lower or equal to median dose, whereas a score 1 was attributed to all dosages grater than median doses. The presence and absence of the event were respectively coded as 1 and 0, and then logistic regression analysis was carried out. The significance for the whole univariate and multivariate models was set at p&lt; 0.05 for the regressors: the odds ratio (OR) was also calculated together with its CI 95%.. At univariate analysis, the significant contributor to oral lesions was only the dosage of pamidronate above or below median value (p=0.021). At multivariate analysis, significant regressors proved to be the female sex (p=0.032; OR 0.142)) and the score of cumulative dosage of drugs (p=0.005; OR 3.977; CI 95%.(OR) 1.517–10.424) Conclusions. Oncologists should pay attention to ON occurrence in long survivors in chronic therapy with BS. Major debridement surgeries are to be avoided if at all possible. Our preliminary data in these pts showed that the lesions are more probable in females than in males and that the administration of more than 560 mg of Pamidronate and of more than 80 mg of Zoledronate is significantly associated with ON lesions.

Radiation hardness of AlGaN/GaN based HEMTs

In this work we present steady-state characteristics and low-frequency noise spectra of AlGaN/GaN based high electron mobility transistors (HEMTs) exposed to gamma ray radiation. The devices with a variety of gate length (150-350 nm) and width (100-400 νm) were irradiated by 60Co gamma rays with doses in the range of 104-109 Rad and flux of 102 Rad/s. Dose dependencies of basic operating parameters of the transistors, such as saturation current (Isat), transconductance (gm), channel conductance (gc), and threshold voltage (VT) are analysed. Our study show that visible changes of above mentioned parameters are observed under relatively small doses (105 Rad) and strongly depend on the HEMT's topology. The transconductance decreases and threshold voltage becomes more negative for all devices while deviation of these parameters from its initial values does not exceed 20% at highest irradiation dose. At the same time variation of the channel conductance as well as saturation current depends to a high extent on the gate voltage (Vg). At |Vg| < |Vcr|, both Isat and gc show a reversal proportional to the cumulative dosage of radiation. However, at |Vg| > |Vcr|, drain saturation current and channel conductance increase with the cumulative dosage of radiation. The effect is more pronounced in short-length-gate devices.