Significant Adverse Events Research Articles

Impact of C-Reactive Protein and Liver Frailty Index on Sarcopenia and Poor Outcome in Liver Transplant Patients.

Sarcopenia is a complication that occurs after liver transplantation (LT), and it is a poor prognostic factor. A total of 23 healthy controls and 131 LT patients (18 - 76 weeks of age) were enrolled in the study. Pa-tients were grouped according to the North American Working Group on Sarcopenia in Liver Transplantation by performing pre- and post-transplant CT scans of the third lumbar (L3). The serum C-reactive protein (CRP) was analyzed and the liver frailty index (LFI) was assessed. Their associations with postoperative sarcopenia, skeletal muscle index (SMI), and poor outcomes were examined. Before LT, the serum CRP was increased in patients with LT, compared with the healthy subjects, and had the highest levels in patients with sarcopenia. There were seventy-nine patients with sarcopenia after LT, including 48 who had been diagnosed with sarcopenia preoperatively and 31 who had a new onset of sarcopenia after LT. There was a moderate-strength negative correlation between the preoperative and postoperative rates of change in CRP and L3 SMI. Patients assessed as frail preoperatively (LFI ≥ 4.5) were associated with postoperative sarcopenia, and 19 of the new postoperative sarcopenia cases occurred in patients assessed as frail preoperatively. The serum CRP levels and LFI were significantly higher in patients who experienced a prolonged hospitalization and early infections postoperatively than in patients without significant adverse events. CRP (post-LT) > 2.575 pg/mL (OR = 1.16, 95% CI: 1.06 - 2.39, p = 0.026) as well as frailty (OR = 1.36, 95% CI: 1.20 - 2.60, p = 0.001) were independent predictors of sarcopenia after LT in patients. Serum CRP levels and LFI may be effective for an early detection of sarcopenia in patients with LT.

Clinical outcomes after a biopsy diagnosis of antibody-mediated rejection in pediatric heart transplant recipients

BackgroundExtending graft survival after heart transplant (HT) is of paramount importance to achieve survival well into adulthood for childhood recipients. Acute rejection is a significant adverse event, and biopsy remains the most specific means for diagnosing acute cellular rejection (ACR) versus antibody-mediated rejection (AMR). MethodsAll children in the Pediatric Heart Transplant Society (PHTS) Registry who underwent HT between 1/2015 and 6/2022 and had ≥1 episode of treated rejection were included. Survival after rejection was compared between those with AMR and those with ACR-only. Secondary outcomes of infection, malignancy, and cardiac allograft vasculopathy (CAV) were assessed. Risk factors for graft loss after AMR were identified using Cox proportional hazard modeling. ResultsAmong 906 children treated for rejection during follow-up through 12/2022, 697 (77%) with complete biopsy information were included. AMR was present on biopsy in 261 (37%) patients; ACR-only was present in 436 (63%) patients. Time to treated rejection was earlier in those with AMR, median time from HT to rejection 0.11 versus 0.29 years, p=0.0006. When rejection occurred within the 1st year, survival after AMR was lower than survival after ACR-only. Predictors of graft loss after AMR were younger age at HT, diagnosis of congenital heart disease, and rejection with hemodynamic compromise. There was no difference in time to CAV, infection, or malignancy after treated rejection between groups. ConclusionsThe largest analysis of pediatric HT recipients treated for rejection with biopsy data to identify AMR underscores the continued importance of AMR on survival. AMR is associated with higher graft loss versus ACR when occurring in the first-year post HT. Predictors of graft loss after AMR identify patients who may benefit from increased surveillance, more aggressive rejection treatment, or augmented maintenance immunosuppression.

Prognostic Significance of Hemodynamics in Patients With Transposition of the Great Arteries and Systemic Right Ventricle.

Patients with transposition of the great arteries (TGA) and systemic right ventricle often confront significant adverse cardiac events. The prognostic significance of invasive hemodynamic parameters in this context remains uncertain. Our hypothesis is that the aortic pulsatility index and hemodynamic profiling utilizing invasive measures provide prognostic insights for patients with TGA and a systemic right ventricle. This retrospective multicenter cohort study encompasses adults with TGA and a systemic right ventricle who underwent cardiac catheterization. Data collection, spanning from 1994 to 2020, encompasses clinical and hemodynamic parameters, including measured and calculated values such as pulmonary capillary wedge pressure, aortic pulsatility index, and cardiac index. Pulmonary capillary wedge pressure and cardiac index values were used to establish 4 distinct hemodynamic profiles. A pulmonary capillary wedge pressure of ≥15 mm Hg indicated congestion, termed wet, while a cardiac index <2.2 L/min per m2 signified inadequate perfusion, labeled cold. The primary outcome comprised a composite of all-cause death, heart transplantation, or the requirement for mechanical circulatory support. Of 1721 patients with TGA, 242 individuals with available invasive hemodynamic data were included. The median follow-up duration after cardiac catheterization was 11.4 (interquartile range, 7.5-15.9) years, with a mean age of 38.5±10.8 years at the time of cardiac catheterization. Among hemodynamic parameters, an aortic pulsatility index <1.5 emerged as a robust predictor of the primary outcome, with adjusted hazard ratios of 5.90 (95% CI, 3.01-11.62; P<0.001). Among the identified 4 hemodynamic profiles, the cold/wet profile was associated with the highest risk for the primary outcome, with an adjusted hazard ratio of 3.83 (95% CI, 1.63-9.02; P<0.001). A low aortic pulsatility index (<1.5) and the cold/wet hemodynamic profile are linked with an elevated risk of adverse long-term cardiac outcomes in patients with TGA and systemic right ventricle.

Sorafenib safety evaluation: Real-world analysis of adverse events from the FAERS database

BackgroundSorafenib is approved for the targeted therapy of cancers such as liver cancer and renal cancer. Given its widespread use, drug-related adverse events have received attention, and the post-marketing regulatory link is crucial. ObjectiveBy using the FAERS database to mine the adverse events (AEs) related to sorafenib, comparing the association intensity of key AEs, and exploring potential drug-related AEs, it provides a reference for clinical medication. MethodsCollect ADE data related to sorafenib in the FAERS database from 2006 to 2023. Standardize the data, and map adverse events to system organ classes and preferred terms. Analyze using various signal quantification techniques such as ROR, PRR, BCPNN, and MGPS. ResultsAmong 18,520 adverse event reports (AERs) where sorafenib was the primary suspected drug, a total of 390 preferred terms (PTs) of adverse reactions were identified, covering 24 different system organ classes (SOCs). Specifically, the adverse events of sorafenib mainly involve the digestive system, skin and subcutaneous tissue, as well as non-specific physical discomfort including infection and injury. Among them, digestive system symptoms and skin toxicity are typical adverse reactions of sorafenib. We also observed uncommon but clearly strong AE signals, such as chloracne (n = 3, ROR 1756.39, PRR 1756.32, IC 8.78, EBGM 439.83), low-differentiated thyroid cancer (n = 4, ROR 585.47, PRR 585.44, IC 8.2, EBGM 293.22). It is worth noting that palmar-plantar erythrodysaesthesia syndrome (n = 2109, ROR 73.98, PRR 72.03, IC 6.01, EBGM 64.25) and hepatic encephalopathy (n = 457, ROR 37.44, PRR 37.23, IC 5.13, EBGM 35.07) have a higher incidence and signal intensity. In addition, we also observed some adverse events not mentioned in the official drug instructions, such as vitamin K deficiency or increased protein induced by antagonist II (PIVKA-II), abnormal alpha-fetoprotein, tumor metastasis, and splenic atrophy. ConclusionSorafenib carries the risk of various adverse reactions while providing therapeutic effects. In clinical applications, physicians should closely monitor the occurrence of digestive system reactions, skin lesions, endocrine system lesions, as well as injuries, infections, and other events.

A disproportionality analysis of sunitinib in the FDA adverse event reporting system (FAERS)

ObjectiveThis study aimed to analyze the FAERS database to identify adverse event associated with sunitinib to offer valuable insights for the judicious utilization of medication in clinical settings. MethodsVarious disproportionality analysis techniques, such as the reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network (BCPN), and multi-gamma Poisson shrinkage (MGPS), were employed to analyze adverse drug reaction (ADR) reports pertaining to sunitinib in the FAERS database from its market introduction up to the first quarter of 2023. Subsequently, a secondary screening process was conducted to identify reliable positive signals. ResultsThe analysis of sunitinib adverse event signals at the system-organ classification level encompassed 27 organ systems, with gastrointestinal and endocrine disorders emerging as the predominant SOCs. A total of 237 significant adverse events meeting all four algorithms were detected. Notably, this study revealed previously unreported adverse events, including pleural effusion and ascites, while potential adrenal toxicity-related adverse events, highlighted in the drug's specification, were not identified in this analysis. The study examined the relationship between the duration of sunitinib dosing and the onset of adverse events, revealing a median onset of 48 days (IQR, 15–160 days). The findings indicated that a majority of adverse events manifested early in the dosing period, with tumor progression, disease progression, and mortality becoming more prevalent after one year of treatment. ConclusionIn the clinical utilization of sunitinib, vigilant monitoring of potential adverse reactions is imperative during the initial phase of drug administration. In addition to the documented adverse reactions outlined in the drug specification, healthcare providers should remain attentive to potential adverse reactions such as pleural effusion, ascites, and tumor development.

780. NEOADJUVANT IMMUNOTHERAPY COMBINED WITH CHEMORADIOTHERAPY VS NEOADJUVANT CHEMORADIOTHERAPY FOR LOCALLY ADVANCED ESOPHAGEAL CARCINOMA (CSTAGEII-III): A MULTI-CENTER PROSPECTIVE RANDOMIZED CLINICAL TRIAL (ICROSS)

Abstract Background The role of neoadjuvant immunotherapy combined with chemoradiation in the treatment of esophageal cancer is not yet fully understood. This study aims to compare the efficacy and safety of neoadjuvant immunotherapy combined with chemoradiation versus traditional neoadjuvant chemoradiation in treating locally advanced esophageal squamous cell carcinoma (stages cII-III). Methods This prospective randomized controlled trial included histologically confirmed patients with potentially resectable esophageal squamous cell carcinoma (stages cII-cIII). Patients were randomly assigned to two groups: the treatment group (Arm A) received BGB-A317 (200mg IV) combined with the CROSS regimen of chemotherapy and radiation, while the control group (Arm B) received only the CROSS chemotherapy and radiation regimen. All patients underwent surgery followed by a five-year follow-up. The primary endpoints included pathological complete response rate (pCR), tumor regression grades, and lymph node clearance. Results The study enrolled 67 patients (52 males, 15 females) aged between 18-75 years. Tumor locations were as follows: upper segment in 16 cases, middle segment in 45 cases, and lower segment in 6 cases. A total of 64 patients were included in the analysis. There were no significant differences between the two groups in terms of pCR rates (Arm A 41.4% vs. Arm B 30.8%, p=0.414), tumor regression grades, Surgical time (221.09 ± 37.54 minutes vs. 227.05 ± 50.28 minutes, p=0.593), Estimated blood loss (182.73 ± 337.41 ml vs. 90.47 ± 66.36 ml, p=0.109), and postoperative hospital stay (9.31 ± 4.12 days vs. 8.42 ± 1.16 days, p=0.555). However, the treatment group had significantly more lymph nodes retrieved during surgery compared to the control group (26.86 ± 7.96 vs. 20.85 ± 9.68, p=0.020). The safety profiles were similar between the groups with no significant adverse events observed. Conclusion For patients with locally advanced esophageal squamous cell carcinoma, neoadjuvant immunotherapy combined with chemoradiation is comparable in efficacy and safety to neoadjuvant chemoradiation alone and may facilitate more effective lymph node clearance. Although these preliminary results are encouraging, further long-term follow-up and larger-scale studies are needed to validate these clinical findings once the study is complete.

Safety profile of levonorgestrel intrauterine system: Analysis of spontaneous reports submitted to FAERS

The levonorgestrel-releasing intrauterine system (LNG-IUS) is an established, long-acting contraceptive option. With the widespread use of the LNG-IUS, drug-reported adverse events (AEs) have also garnered significant attention. In this study, we conducted a real-world analysis using the FDA's Adverse Event Reporting System (FAERS) database to assess the incidence of AEs associated with LNG-IUS use. Data from FAERS spanning from 2004Q1 to 2024Q1 were reviewed, with a focus on reports in which LNG-IUS was the primary suspected and secondary suspect drug. Signal detection was carried out utilizing Standardized MedDRA Queries (SMQ) and Preferred Terms (PT), with reporting odds ratio (ROR), proportional reporting ratio (PRR), and information component (IC) employed to identify Signals of Disproportionate Reporting (SDR) for AEs. A positive SDR was defined when all three methods indicated significance. Analysis of 13 SMQs revealed notable SDRs in ear and eye disorders, cardiac arrhythmias, and lipodystrophy. Of the 61 suspected SDRs identified at the PT level, nearly half were not previously documented in labeling. Key potential signals of AEs associated with LNG-IUS use included increased heart rate, papilledema, idiopathic intracranial hypertension, cervical dysplasia, ruptured ovarian cyst, and uterine embedment and perforation. The findings underscore the importance of signal detection using FAERS data for identifying safety concerns related to LNG-IUS. Long-term observational studies are warranted to confirm and further elucidate these potential safety signals.

Neurokinin receptor antagonists as potential nonhormone treatments for vasomotor symptoms.

Managing menopause symptoms is challenging for women unable or unwilling to take hormone therapy. All nonhormone options thus far have shown less overall efficacy compared with hormone therapy and significant adverse events that limit their use. New science has identified the source of vasomotor symptoms, achieving relief of these bothersome symptoms by directly targeting the neurokinin 3 receptor and its related pathways. This Practice Pearl reviews the clinical data available on neurokinin receptor antagonists.

The Efficacy Of Continuous Non-Inhaled Intranasal Carbon Dioxide (CO2) In The Abortive Treatment Of Migraine: Results From Three Randomized, Double-Blinded, Placebo-Controlled Trials

Objective: Determining the efficacy, tolerability, and safety of continuous non-inhaled intranasal carbon dioxide (CO2) in the acute or abortive treatment of migraine. Background: Carbon dioxide gas infused in the nose and sinuses potentially blocks trigeminal nerve activation and subsequent neuropeptide release, probably through inhibition of voltage-gated channels. The pathogenesis of the migraine headache involves activation of the trigeminocervical system, which establishes the nociceptive innervation of the head through the trigeminal and occipital nerves. Methods: In three randomized, double-blinded, placebo-controlled trials, we randomized 350 subjects with migraine as defined by the International Headache Society (intent-to-treat population). We determined tolerability and safety in the 317 subjects who we exposed to treatment up to 24 hours post-dose (modified intent-to-treat population). We determined efficacy in the modified intent-to-treat and per-protocol populations at 15 minutes, half, one, two, and twenty-four hours post-dose in terms of pain freedom, freedom from headache-associated symptoms, and headache relief, treating migraine headaches of mild, moderate, or severe intensity. Results: We did not observe clinically significant systemic effects, either on blood carbon dioxide pressure or on the cardiovascular or respiratory system. No serious or clinically significant adverse events occurred and those reported were predominantly local, transient, and short-lived. Headache intensity strongly and in a negative way determined the efficacy of treatment with carbon dioxide but not with placebo, and even when placebo consisted of no gas, blinding seemed adequate. Conclusions: Continuous non-inhaled intranasal carbon dioxide seems safe, relatively well tolerated, and moderately effective for the acute or abortive treatment of migraine.

Comparative efficacy, safety, and tolerability of pharmacotherapies for acute mania in adults: a systematic review and network meta-analysis of randomized controlled trials.

The aim of this study was to provide evidence-based recommendations regarding the efficacy, safety, and tolerability of currently used pharmacological treatments for adults with acute bipolar mania. To achieve this, we conducted a systematic review and network meta-analysis (NMA) using R software and related packages. We searched primary clinical databases until February 2023 for reports of randomized controlled trials of drug treatments and adjunctive therapies for adults with acute bipolar mania, with outcomes including efficacy (mean change from baseline to endpoint in mania rating scores), safety (clinically significant adverse events from baseline to end of treatment), and tolerability (the proportion of patients who completed the whole trial to the planned endpoint). A total of 113 studies were included in our analysis, in which 23,491 participants (50.38% males; mean age = 38.6 years; mean study duration = 3.39 weeks; mean manic baseline score = 29.37) were randomly allocated to one of 51 monotherapies, adjunctive treatments, or placebo. Our results showed that tamoxifen (mean difference, -22.31 [-25.97, -18.63], N = 2, n1 = 43, n2 = 39) and tamoxifen+ lithium or valproate (LIT/VAL) (-16.37 [-22.55, -10.25], N = 1, n1 = 20, n2 = 20) had the best and second-best clinical efficacy in adults with acute bipolar mania over the placebo. Furthermore, olanzapine, paliperidone, quetiapine, ziprasidone, risperidone, divalproex, and haloperidol were significantly better tolerated than placebo. Combination therapies of antipsychotics and LIT/VAL appeared to be more effective than their corresponding monotherapies. While pharmacotherapies were associated with specific common adverse events, we found no evidence of increased incidence of headache or depression events compared to the placebo. Overall, our NMAs provided important insights into the effectiveness, safety, and tolerability of pharmacological treatments for acute bipolar mania and can help guide treatment decisions for clinicians.

Efficacy and safety of oral sodium bicarbonate in kidney-transplant recipients and non-transplant patients with chronic kidney disease: a systematic review and meta-analysis.

We investigated the efficacy and safety of oral sodium bicarbonate in kidney-transplant recipients and non-transplant patients with chronic kidney disease (CKD), which are currently unclear. PubMed, Cochrane Library, Embase, and Web of Science were searched for randomized controlled trials investigating the efficacy and safety of sodium bicarbonate versus placebo or standard treatment in kidney-transplant and non-transplant patients with CKD. Sixteen studies of kidney-transplant recipients (two studies, 280 patients) and non-transplant patients with CKD (14 studies, 1,380 patients) were included. With non-transplant patients, sodium bicarbonate slowed kidney-function declines (standardized mean difference [SMD]: 0.49, 95% confidence interval [CI]: 0.14-0.85, p = 0.006) within ≥12 months (SMD: 0.75 [95% CI: 0.12-1.38], p = 0.02), baseline-serum bicarbonate <22mmol/L (SMD: 0.41 [95% CI: 0.19-0.64], p = 0.0004) and increased serum-bicarbonate levels (mean difference [MD]: 2.35 [95% CI: 1.40-3.30], p < 0.00001). In kidney-transplant recipients, sodium bicarbonate did not preserve graft function (SMD: -0.07 [95% CI: -0.30-0.16], p = 0.56) but increased blood pH levels (MD: 0.02 [95% CI: 0.00-0.04], p = 0.02). No significant adverse events occurred in the kidney-transplant or non-transplant patients (risk ratio [RR]: 0.89, [95% CI: 0.47-1.67], p = 0.72; and RR 1.30 [95% CI: 0.84-2.00], p = 0.24, respectively). However, oral sodium bicarbonate correlated with increased diastolic pressure and worsened hypertension and edema (MD: 2.21 [95% CI: 0.67-3.75], p = 0.005; RR: 1.44 [95% CI: 1.11-1.88], p = 0.007; and RR: 1.28 [95% CI: 1.00-1.63], p = 0.05, respectively). Oral sodium bicarbonate may slow kidney-function decline in non-transplant patients with CKD taking sodium bicarbonate supplementation for ≥12 months or a baseline serum bicarbonate level of <22mmol/L, without preserving graft function in kidney-transplant recipients. Sodium bicarbonate may increase diastolic pressure, and elevate a higher incidence of worsening hypertension and edema. https://www.crd.york.ac.uk/prospero/, identifier CRD42023413929.

Safety and efficacy of bilateral superselective adrenal arterial embolization for treatment of idiopathic hyperaldosteronism: a prospective single-center study

ObjectiveThis study aimed to assess the efficacy and safety of bilateral superselective adrenal arterial embolization (SAAE) in patients with bilateral idiopathic hyperaldosteronism (IHA), a subtype of PA.MethodsNinety-eight patients with bilateral IHA underwent bilateral SAAE between August 2022 and August 2023. Sixty-eight patients were followed up for up to 12 months. The study outcomes were evaluated using the criteria provided by the Primary Aldosteronism Surgical Outcome (PASO) guidelines.ResultsThe mean reductions in systolic and diastolic blood pressure were 27.4 ± 21.3 mmHg and 23.1 ± 17.4 mmHg, respectively (p < 0.001). The rates of clinical success and biochemical success after adrenal artery ablation were 63.2% (43/68) and 39.7% (27/68), respectively. Overall, there were significant reductions in daily defined doses (DDD), aldosterone/renin ratio (ARR), and plasma aldosterone levels (p < 0.001). Plasma renin levels increased by a mean value of 10.4 ± 39.0 pg/mL (p = 0.049), and potassium levels increased by 0.40 ± 0.63 mmol/L (p < 0.001). No significant adverse events were reported during SAAE or the follow-up period of up to one year. Additionally, no abnormalities were detected by adrenal 68Ga-Pentixafor PET/CT scans before or after SAAE.ConclusionBilateral SAAE appears to lead to sustained improvements in blood pressure and biochemical parameters in patients with bilateral PA, with minimal adverse effects. This suggests that bilateral SAAE could serve as an effective alternative approach for treating bilateral IHA, potentially curing this condition.

Combination of High-Dose Daptomycin and Ceftriaxone for Cardiac Implantable Electronic Device Infections: A 10-Year Experience

PurposeCardiac implantable electronic device (CIED) infections are increasingly common. Gram-positive bacteria such as coagulase negative staphylococci and Staphylococcus aureus are the most commonly involved pathogens. The aim of this study was to describe the characteristics and outcome of patients with CIED infections who underwent device removal and were empirically treated with high dose (8–12 mg/kg daily) daptomycin (DAP) in combination with ceftriaxone (CRO). MethodsRetrospective, single center study including patients admitted at IRCCS San Raffaele Hospital (Milan, Italy), from June 2011 to June 2021, who underwent device removal for CIED infection and were empirically treated with DAP/CRO. FindingsOverall, 147 patients were included in this study. Median duration of therapy was 16 days (IQR 14–26). Empirical treatment with DAP/CRO was confirmed as definitive treatment in 140 patients (95.2%). In 7 (4.8%) patients DAP/CRO were discontinued according to the definite microbiological isolates: Corynebacterium spp. (4), Pseudomonas aeruginosa (2), Enterobacter cloacae (1). Ten patients (6.8%) underwent treatment simplification to narrow-spectrum antibiotics. One patient (0.6%) interrupted DAP-CRO due to pancytopenia.6-month follow-up was available for 123/147 patients (83.7%): 9 patients recurred with a CIED infection (7.3%), and 9 died (7.3%). ImplicationsIn our 10-year experience, high-dose DAP in combination with CRO represented a good option for empirical therapy of CIED infections. DAP-CRO combination was safe and effective, showing no significant drug-related adverse events and low rates of 6-month recurrence and mortality.

Adverse events of tissue plasminogen activators in acute myocardial infarction patients: a real-world and pharmacovigilance database analysis

BackgroundTissue plasminogen activator (tPA) is recommended as the preferred thrombolytic therapy for acute myocardial infarction (AMI). This study aimed to explore tPA-related adverse events (AEs) reported in the United States Food and Drug Administration Adverse Event Reporting System (FAERS), assess the potential safety of three preferred tPA therapies for treating AMI, and provide guidance for selecting tPA for prehospital thrombolysis.MethodFour algorithms, including ROR, PRR, BCPNN, and MGPS, were used to quantify the signals of Tenecteplase, Reteplase, and Alteplase related AEs and compare the differential degrees of the three tPA-associated AEs in the actual data.ResultWe detected 18 signals of Tenecteplase-induced AE, 29 signals of Reteplase-induced AE, and 22 signals of Alteplase-induced AE. Among the three drugs, Tenecteplase had the highest signal intensity for intracranial hemorrhage-related AE, followed by Alteplase. Besides, Reteplase had the highest signal intensity for procedure-related AE and Alteplase had the highest signal intensity for arrhythmia-related AE. The time-onset analysis indicates that we should be vigilant for AEs, especially within the first week and the first 1–2 days after medication.ConclusionThis study identified and compared the signals of AE related to Tenecteplase, Reteplase, and Alteplase in AMI patients.

The Abbreviated Methacholine Challenge Test is Safe for Children

To evaluate the safety of an abbreviated methacholine challenge test (MCT) protocol in children. This prospective, observational study enrolled children aged 6 through 18 years referred for the MCT. The abbreviated protocol was initiated with a methacholine dose of 0.03 mg/ml and escalated in fourfold increments, unless the forced expiratory volume at 1 second (FEV1) decline exceeded 10%, at which point the next dose was only doubled. The safety of this abbreviated approach was assessed by monitoring adverse events, and specifically, decreases in FEV1 over 40%, hypoxemia, or uncontrollable cough. The number of methacholine doses and test duration were recorded and compared with estimated outcomes derived from the full-length MCT protocol. One hundred and twelve participants, aged 13.7 years (±3.3), successfully completed the protocol. Fifty-seven (51%) presented a positive MCT response. No significant clinical adverse events were observed. Of all participants, 2.7% exhibited an exaggerated response, in line with previously reported findings for the full-length protocol. The abbreviated approach resulted in an estimated average time-savings of 18:19 minutes per participant, thus reducing test length by 22:47 minutes for a negative MCT and by 14:34 minutes for a positive outcome. This abbreviated MCT protocol is safe for children and effectively shortens the duration of the MCT.

Post-marketing safety of finerenone: a disproportionality analysis of the FDA adverse event reporting system

ABSTRACT Background Finerenone was approved for the treatment of type 2 diabetes patients with chronic kidney disease. However, the post-marketing safety of finerenone in the real world is unknown. Methods The quarterly reported data related to finerenone from the third quarter of 2021 to the second quarter of 2023 were collected by using the FAERS database. Two disproportionality analysis methods were estimated by using Reporting odds ratio (ROR) and Bayesian confidence propagation neural network (BCPNN). Results A total of 1067 adverse events (AEs) were included. Twenty-four kinds of system organ classes (SOCs) were classified for the organs and systems involved and 39 AEs with significant safety signals were identified using ROR and BCPNN at the preferred terms (PTs) level. Most AEs originated from the United States, and the median time to onset of AEs was 13 days. Three hundred and fifty-one (55.5%) reported serious outcome. The proportion of medication combinations was 29.0%. The most commonly reported AEs were the glomerular filtration rate decreased. Safety signals have also been observed in new and unexpected AEs. Conclusion The analysis of the AE signals may contribute to minimizing the risks associated with its use.

Safety of proteasome inhibitor drugs for the treatment of multiple myeloma post-marketing: a pharmacovigilance investigation based on the FDA adverse event reporting system

ABSTRACT Background The use of proteasome inhibitors (PIs), namely Bortezomib and Carfilzomib, revolutionized multiple myeloma (MM) treatment. Understanding their distinct adverse event (AE) profiles aids in tailored treatment plans. Research design and methods We analyzed FDA Adverse Event Reporting System (FAERS) data (Q1 2012-Q4 2023) for Bortezomib and Carfilzomib, utilizing reporting odds ratio (ROR), proportional reporting ratio (PRR), and Bayesian confidence propagation neural network (BCPNN). Results FAERS yielded 19,720 Bortezomib and 12,252 Carfilzomib AE reports. Males aged 45–65 exhibited higher AE susceptibility. Common AE systems included Infections, Nervous System Disorders, Blood Disorders, General Disorders, Cardiac Disorders, and Renal Disorders. New Bortezomib signals were sepsis and colitis. Carfilzomib exhibited elevated cardiac and renal toxicity but reduced peripheral neuropathy and thrombocytopenia. Conclusions FAERS analysis revealed new AE signals (sepsis, colitis) for Bortezomib and highlighted Carfilzomib’s heightened cardiac and renal risks compared to Bortezomib. Balancing PIs’ benefits and risks is crucial for clinical decision-making.

Ocular adverse events associated with antibody-drug conjugates in oncology: a pharmacovigilance study based on FDA adverse event reporting system (FAERS).

Antibody-drug conjugates (ADCs) have emerged as the focus and hotspots in the cancer field, yet the accompanying ocular toxicity has often been underestimated. We aimed to comprehensively and comparatively analyze the risk of ocular toxicity associated with various ADCs using the FDA Adverse Event Reporting System (FAERS) database. Data were extracted from the FAERS database from Q3 2011 to Q3 2023. We analyzed the clinical characteristics of ADCs-related ocular adverse events (AEs). These data were further mined by proportional analysis and Bayesian approach to detect signals of ADCs-induced ocular AEs. Moreover, the time to onset of ocular toxicity was also evaluated. A total of 1,246 cases of ocular AEs were attributed to ADCs. Ocular toxicity signals were observed in patients treated with belantamab mafodotin, brentuximab vedotin, enfortumab vedotin, mirvetuximab soravtansine, sacituzumab govitecan, trastuzumab deruxtecan, and trastuzumab emtansine. Of these, belantamab mafodotin, trastuzumab emtansine, and mirvetuximab soravtansine, whose payloads are microtubule polymerization inhibitors, were more susceptible to ocular toxicity. The ten most common ADCs-related ocular AEs signals are keratopathy [ROR = 1,273.52, 95% CI (1,129.26-1,436.21)], visual acuity reduced [ROR = 22.83, 95% CI (21.2-24.58)], dry eye [ROR = 9.69, 95% CI (8.81-10.66)], night blindness [ROR = 259.87, 95% CI (228.23-295.89)], vision blurred [ROR = 1.78, 95% CI (1.57-2.02)], photophobia [ROR = 10.45, 95% CI (9.07-12.05)], foreign body sensation in eyes [ROR = 23.35, 95% CI (19.88-27.42)], ocular toxicity [ROR = 144.62, 95% CI (117.3-178.32)], punctate keratitis [ROR = 126.21, 95% CI (101.66-156.69)], eye disorder [ROR = 2.71, 95% CI (2.21-3.32)]. In terms of onset time, sacituzumab govitecan displayed an earlier onset of 21days, while trastuzumab deruxtecan exhibited the latest onset of 223days. ADCs may increase the risk of ocular toxicity in cancer patients, leading to serious mortality. With the widespread application of newly launched ADCs, combining the FAERS data with other data sources is crucial for monitoring the ocular toxicity of ADCs. In addition, novel ocular toxicity signals not documented in product labeling were detected. Further research will be necessary to validate our findings in the future.

Functional cure induced by tenofovir alafenamide plus peginterferon-alpha-2b in young children with chronic hepatitis B: a case series study

Background and AimsData on the safety and effectiveness of tenofovir alafenamide (TAF) plus peginterferon-alpha (Peg-IFN-α) in children with chronic hepatitis B (CHB) are lacking. The current study aimed to present the characteristics of four pediatric CHB patients who obtained a functional cure by using TAF and Peg-IFN-α.MethodsIn this case series study initiated in May 2019, ten children who had no clinical symptoms or signs received response-guided (HBV DNA undetectable, hepatitis B e antigen [HBeAg] loss or seroconversion, and hepatitis B surface antigen [HBsAg] loss or seroconversion) and functional cure-targeted (HBsAg loss or seroconversion) TAF (25 mg/d, orally) plus Peg-IFN-α-2b (180 µg/1.73m2, subcutaneously, once weekly) in combination (9/10) or sequential (1/10) therapy. The safety and effectiveness of these treatments were monitored.ResultsAs of April 2024, four out of ten children obtained a functional cure after a mean of 31.5 months of treatment, and the other six children are still undergoing treatment. These four cured children, aged 2, 4, 8, and 6 years, were all HBeAg-positive and had alanine aminotransferase levels of 80, 47, 114, and 40 U/L; HBV DNA levels of 71200000, 93000000, 8220, and 96700000 IU/mL; and HBsAg levels of 39442.8, 15431.2, 22, and 33013.1 IU/mL, respectively. During treatment, all the children (10/10) experienced mild or moderate adverse events, including flu-like symptoms, anorexia, fatigue, and cytopenia. Notably, growth retardation (8/10) was the most significant adverse event; and it occurred in three cured children (3/4) treated with combination therapy and was present to a low degree in the other cured child (1/4) treated with sequential therapy. Fortunately, all three cured children recovered to or exceeded the normal growth levels at 9 months posttreatment.ConclusionsTAF plus Peg-IFN-α-2b therapy is potentially safe and effective for pediatric CHB patients, which may provide important insights for future clinical practice and study designs targeting functional cures for children with CHB.

How is political trust associated with economic and environmental policy prioritization? A longitudinal analysis between 2017 and 2022.

In this article, we examine the longitudinal development of economy-over-environment policy priorities in Finland during a period marked by several significant adverse societal events. In addition, we explore the influence of political trust on these priorities over time. We utilize a five-round panel dataset comprising 2155 observations (N = 431) to examine both within-individual and between-individual variations from late 2017 to early 2023. Our findings reveal a significant increase in the prioritization of the economy in each observation period following the COVID-19 outbreak. However, this trend is not observed among individuals with high levels of political trust. The within-individual analysis indicates that high political trust moderates, rather than causes, higher economy-over-environment prioritization. Our study highlights the significance of political trust as a preventing factor against the deprioritization of environmental policies, particularly when societies confront significant and intersecting adverse events.