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The recent introduction of the innovative therapy, onasemnogene abeparvovec (Zolgensma®), has revolutionized the spinal muscular atrophy (SMA) therapeutic landscape. Although Zolgensma® therapy has proven to lead to functional improvements in SMA children, some gaps in its safety profile still need to be investigated. To better characterize the Zolgensma® safety profile, we conducted a retrospective observational study, analyzing all the Individual Case Safety Reports (ICSRs) referred to it and collected in the European pharmacovigilance database between 1 January 2019 and 22 September 2023. We found 661 ICSRs related to Zolgensma®, with a growing trend in the annual reporting. The majority of the reports were sent by healthcare professionals and referred to infant females. In more than 90% of the cases, Zolgensma® was the only reported suspected drug. Out of a total of 2744 reported ADRs, increased hepatic enzymes, pyrexia, vomiting, and thrombocytopenia were the most commonly reported adverse reactions. Of these adverse reactions (ADRs), 56.9% were serious, causing or prolonging the patient's hospitalization. A total of 39 ICSRs related to cases with a fatal outcome. Alterations in the heart rhythm, acute hepatic failure, and hepatic cytolysis emerged among the cardiac and hepatic disorders, respectively. [ABSTRACT FROM AUTHOR]

Background: Periprocedural prophylaxis in medicine encompasses the set of measures (physical, chemical, and pharmacological) used to reduce the risk of infection. Antibiotic prophylaxis (AP) refers to the administration of a short-term regimen of antibiotics shortly before a medical procedure to reduce the risk of infectious complications that can result from diagnostic and therapeutic interventions. The outspreading growth of multidrug-resistant bacterial species and changes in the bacterial local ecosystem have impeded the development of a unique scheme of AP in urology. Objectives: To review the literature and current guidelines regarding AP for urological diagnostic and therapeutic procedures, and to define agents, timing, and occasions when administering pharmacological prophylaxis. Secondly, according to current literature, to open new scenarios where AP can be useful or useless. Results: Major gaps in evidence still exist in this field. AP appears useful in many invasive procedures and some sub-populations at risk of infectious complications. AP is not routinely recommended for urodynamic exams, diagnostic cystoscopy, and extracorporeal shock-wave lithotripsy. The available data regarding the use of AP during the transperineal prostate biopsy are still unclear; conversely, in the case of the transrectal approach AP is mandatory. AP is still considered the gold standard for the prevention of postoperative infective complications in the case of ureteroscopy, percutaneous nephrolithotomy, endoscopic resection of bladder tumor, endoscopic resection of the prostate, and prosthetic or major surgery. Conclusion: The review highlights the complexity of determining the appropriate candidates for AP, emphasizing the importance of considering patient-specific factors such as comorbidities, immunocompetence, and the nature of the urologic intervention. The evidence suggests that a one-size-fits-all approach may not be suitable, and a tailored strategy based on the specific procedure and patient characteristics is essential. [ABSTRACT FROM AUTHOR]

Simple Summary: One of the oldest anticancer drugs in use is doxorubicin. It associates with cardiotoxicity that until now remains unresolved. Diastolic cardiac dysfunction can be the first sign, and develops at the very low doses. We asked whether short-term changes were preceded by even earlier effects. We tested functional and molecular changes in cardiac fibroblasts after very brief exposure to doxorubicin. Cardiac fibroblasts increased energy metabolism and differentiated into myofibroblast, expressing markers of cell activation and phenotype change. These results demonstrate that cardiac fibroblasts are effector cells that swiftly react to systemically administered drug. From the very first contact with doxorubicin, they can actively contribute to the initial phase of pathological myocardial remodeling. Thus, it is conceivable to foresee these cells as a target to counteract the cardiotoxicity of doxorubicin at the very early stage. The application of doxorubicin (DOX) is hampered by cardiotoxicity, with diastolic dysfunction as the earliest manifestation. Fibrosis leads to impaired relaxation, but the mechanisms that operate shortly after DOX exposure are not clear. We asked whether the activation of cardiac fibroblasts (CFs) anticipates myocardial dysfunction and evaluated the effects of DOX on CF metabolism. CFs were isolated from the hearts of rats after the first injection of DOX. In another experiment, CFs were exposed to DOX in vitro. Cell phenotype and metabolism were determined. Early effects of DOX consisted of diastolic dysfunction and unchanged ejection fraction. Markers of pro-fibrotic remodeling and evidence of CF transformation were present immediately after treatment completion. Oxygen consumption rate and extracellular acidification revealed an increased metabolic activity of CFs and a switch to glycolytic energy production. These effects were consistent in CFs isolated from the hearts of DOX-treated animals and in naïve CFs exposed to DOX in vitro. The metabolic switch was paralleled with the phenotype change of CFs that upregulated markers of myofibroblast differentiation and the activation of pro-fibrotic signaling. In conclusion, the metabolic switch and activation of CFs anticipate DOX-induced damage and represent a novel target in the early phase of anthracycline cardiomyopathy. [ABSTRACT FROM AUTHOR]

Background: Amyloid A (AA) amyloidosis is a protein misfolding disease arising from serum amyloid A (SAA). Systemic AA amyloidosis recently was shown to have a high prevalence in shelter cats in Italy and was associated with azotemia and proteinuria. Objectives: Investigate urine protein profiles and diagnostic biomarkers in cats with renal AA amyloidosis. Animals: Twenty‐nine shelter cats. Methods: Case‐control study. Cats with renal proteinuria that died or were euthanized between 2018 and 2021 with available necropsy kidney, liver and spleen samples, and with surplus urine collected within 30 days before death, were included. Histology was used to characterize renal damage and amyloid amount and distribution; immunohistochemistry was used to confirm AA amyloidosis. Urine protein‐to‐creatinine (UPC) and urine amyloid A‐to‐creatinine (UAAC) ratios were calculated, and sodium dodecyl sulfate‐agarose gel electrophoresis (SDS‐AGE) and liquid chromatography‐mass spectrometry (LC‐MS) of proteins were performed. Results: Twenty‐nine cats were included. Nineteen had AA amyloidosis with renal involvement. Cats with AA amyloidosis had a higher UPC (median, 3.9; range, 0.6‐12.7 vs 1.5; 0.6‐3.1; P =.03) and UAAC ratios (median, 7.18 × 10−3; range, 23 × 10−3‐21.29 × 10−3 vs 1.26 × 10−3; 0.21 × 10−3‐6.33 × 10−3; P =.04) than unaffected cats. The SDS‐AGE identified mixed‐type proteinuria in 89.4% of cats with AA amyloidosis and in 55.6% without AA amyloidosis (P =.57). The LC‐MS identified 63 potential biomarkers associated with AA amyloidosis (P <.05). Among these, urine apolipoprotein C‐III was higher in cats with AA amyloidosis (median, 1.38 × 107; range, 1.85 × 105‐5.29 × 107 vs 1.76 × 106; 0.0 × 100‐1.38 × 107; P =.01). In the kidney, AA‐amyloidosis was associated with glomerulosclerosis (P =.02) and interstitial fibrosis (P =.05). Conclusions and Clinical Importance: Renal AA amyloidosis is associated with kidney lesions, increased proteinuria and increased urine excretion of SAA in shelter cats. Additional studies are needed to characterize the role of lipid transport proteins in the urine of affected cats. [ABSTRACT FROM AUTHOR]

Tangential flow filtration (TFF) through a 30 kDa nominal molecular weight cut‐off (MWCO) ultrafiltration membrane is widely employed to concentrate purified monoclonal antibodies (mAbs) to levels required for their formulation into injectable biologics. While TFF has been used to remove casein from milk for cheese production for over 35 years, and in pharmaceutical manufacture of biotherapeutic proteins for 20 years, the rapid decline in filtration rate (i.e., flux) at high protein concentrations is a limitation that still needs to be addressed. This is particularly important for mAbs, many of which are 140–160 kDa immunoglobulin G (IgG) type proteins recovered at concentrations of 200 mg/mL or higher. This work reports the direct measurement of local transmembrane pressure drops and off‐line confocal imaging of protein accumulation in stagnant regions on the surface of a 30 kDa regenerated cellulose membrane in a flat‐sheet configuration widely used in manufacture of biotherapeutic proteins. These first‐of‐a‐kind measurements using 150 kDa bovine IgG show that while axial pressure decreases by 58 psi across a process membrane cassette, the decrease in transmembrane pressure drop is constant at about 1.2 psi/cm along the 20.7 cm length of the membrane. Confocal laser scanning microscopy of the membrane surface at the completion of runs where retentate protein concentration exceeds 200 mg/mL, shows a 50 μm thick protein layer is uniformly deposited. The localized measurements made possible by the modified membrane system confirm the role of protein deposition on limiting ultrafiltration rate and indicate possible targets for improving membrane performance. [ABSTRACT FROM AUTHOR]