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Current Approaches in Postapproval Vaccine Safety Studies Using Real-World Data: A Systematic Review of Published Literature
No full textPurpose: Well-designed observational postmarketing studies using real-world data (RWD) are critical in supporting an evidence base and bolstering public confidence in vaccine safety. This systematic review presents current research methodologies in vaccine safety research in postapproval settings, technological advancements contributing to research resources and capabilities, and their major strengths and limitations. Methods: A comprehensive search was conducted using PubMed to identify relevant articles published from January 1, 2019, to December 31, 2022. Eligible studies were summarized overall by study design and other study characteristics (eg, country, vaccine studied, types of data source, and study population). An in-depth review of select studies representative of conventional or new designs, analytical approaches, or data collection methods was conducted to summarize current methods in vaccine safety research. Findings: Out of 977 articles screened for inclusion, 135 were reviewed. The review shows that recent advancements in scientific methods, digital technology, and analytic approaches have significantly contributed to postapproval vaccine safety studies using RWD. “Near real-time surveillance” using large datasets (via collaborative or distributed databases) has been used to facilitate rapid signal detection that complements passive surveillance. There was increasing appreciation for self-controlled case-only designs (self-controlled case series and self-controlled risk interval) to assess acute-onset safety outcomes, artificial intelligence, and natural language processing to improve outcome accuracy and study timeliness and emerging artificial intelligence–based analysis to capture adverse events from social media platforms. Implications: Continued development in the area of vaccine safety research methodologies using RWD is warranted. The future of successful vaccine safety research, especially evaluation of rare safety events, is likely to comprise digital technologies including linking RWD networks, machine learning, and advanced analytic methods to generate rapid and robust real-world safety information
In Pursuit of Optimal Outcomes: A Framework for Quality Standards in Immune Effector Cell Therapy
No full textImmune effector cell (IEC) therapy represents a transformative advancement in oncology, leveraging the immune system to combat various malignancies. This article outlines a comprehensive framework for establishing and maintaining quality standards in IEC therapy amidst rapid scientific and clinical advancements. We emphasize the integration of structured process measures, robust quality assurance, and meticulous outcome evaluation to ensure treatment efficacy and safety. Key components include multidisciplinary expertise, stringent accreditation protocols, and advanced data management systems, which facilitate standardized reporting and continual innovation. The collaborative effort among stakeholders—ranging from patients and healthcare providers to regulatory bodies—is crucial in delivering high-quality IEC therapies. This framework aims to enhance patient outcomes and cement the role of IEC therapy as a cornerstone of modern oncology, promoting continuous improvement and adherence to high standards across the therapeutic spectrum
FOXA2 Rewires AP-1 for Transcriptional Reprogramming and Lineage Plasticity in Prostate Cancer
No full textFOXA family proteins act as pioneer factors by remodeling compact chromatin structures. FOXA1 is crucial for the chromatin binding of the androgen receptor (AR) in both normal prostate epithelial cells and the luminal subtype of prostate cancer (PCa). Recent studies have highlighted the emergence of FOXA2 as an adaptive response to AR signaling inhibition treatments. However, the role of the FOXA1 to FOXA2 transition in regulating cancer lineage plasticity remains unclear. Our study demonstrates that FOXA2 binds to distinct classes of developmental enhancers in multiple AR-independent PCa subtypes, with its binding depending on LSD1. Moreover, we reveal that FOXA2 collaborates with JUN at chromatin and promotes transcriptional reprogramming of AP-1 in lineage-plastic cancer cells, thereby facilitating cell state transitions to multiple lineages. Overall, our findings underscore the pivotal role of FOXA2 as a pan-plasticity driver that rewires AP-1 to induce the differential transcriptional reprogramming necessary for cancer cell lineage plasticity
Morbidity and Neurodevelopmental Outcomes at 2 Years in Preterm Infants Undergoing Percutaneous Transcatheter Closure vs. Surgical Ligation of the PDA
No full textObjective: Review a cohort of preterm infants ≤29 weeks of gestation at birth and compare morbidities and neurodevelopmental outcomes based on PDA status and type of PDA closure. Study design: Single center observational retrospective-prospective case control study of premature infants who had no hsPDA, underwent surgical ligation or percutaneous transcatheter closure of the PDA. Neurodevelopmental testing was done using the Bayley Scales of Infant Development 3rd ed. Results: The percutaneous transcatheter closure group had an older post menstrual age and greater weight at the time of procedure, and started enteral feeds and achieved room air status at an earlier post procedure day. Infants in the surgical ligation group were more likely to experience vocal cord paralysis. There was no difference in neurodevelopmental outcomes between groups. Conclusion: Waiting for infants to achieve the appropriate size for percutaneous transcatheter closure of the PDA may lead to reduced short-term complications without increasing the risk of neurodevelopmental impairment
Growth Hormone Therapy Does Not Impact the Development of Intracranial Hypertension in Children With Chiari Malformation
No full textObjectives: Patients with Chiari malformation (CM) are prone to a variety of neurological sequelae, including benign intracranial hypertension (BIH). In these patients, BIH is attributed to impaired cerebrospinal fluid (CSF) flow due to anatomical abnormalities of the posterior fossa. Occasionally, patients with CM may require growth hormone therapy (GHT), which can increase the production of CSF. It is thought that patients with CM who undergo GHT are at high risk of BIH-Associated symptoms (BIHAS). We describe the incidence of neurological symptoms in 34 patients with CM before and during GHT. Methods: The database of a pediatric endocrinology center was queried for patients with CM who received GHT from 2010-22. Records were reviewed for adverse events. Demographic and radiological data were collected and analyzed. Patients with neoplastic disease, active inflammation, or acute trauma were excluded. CM diagnoses were independently assigned by a neuroradiology department. Patients were grouped based on the presence and nature of symptoms before and during GHT. Relationships between starting dose/BMI and occurrence of BIHAS/all GHT-Associated symptoms were evaluated. Results: GHT was not associated with new-onset or worsening of preexisting BIHAS in 33 out of 34 patients with CM. Five complex patients continued to have preexisting BIHAS, which did not worsen. Of the four patients who developed new-onset BIHAS during GHT, three patients\u27 symptoms were attributed to other medical conditions. No patient permanently discontinued GHT due to BIHAS. Conclusions: Growth hormone therapy is likely a safe treatment in patients with Chiari malformation and is unlikely to cause BIHAS
Effects of Cariprazine on Reducing Symptoms of Irritability, Hostility, and Agitation in Patients With Manic or Mixed Episodes of Bipolar I Disorder
No full textBackground: Hostility, irritability, and agitation are common in patients with bipolar I disorder. Post hoc analyses evaluated the effect of cariprazine on these symptoms in patients with bipolar I mania. Methods: Data were pooled from three randomized, double-blind, placebo-controlled phase 3 cariprazine trials in adults with bipolar I manic/mixed episodes (NCT00488618, NCT01058096, NCT01058668); pooled cariprazine doses (3–12 mg/d) were analyzed. Patients were categorized into hostility/irritability and agitation subgroups by baseline scores: Young Mania Rating Scale (YMRS) irritability and disruptive-aggressive behavior items score ≥ 2; Positive and Negative Syndrome Scale (PANSS) hostility item ≥ 2; PANSS–Excited Component (PANSS-EC) total score ≥ 14 and score ≥ 4 on ≥ 1 individual item. Changes from baseline to week 3 in hostility/irritability- and agitation-related outcomes were evaluated. Adjustments were made for the presence of other manic symptoms, sedation, and akathisia. Results: Most patients met subgroup inclusion criteria (YMRS hostility = 930; PANSS hostility = 841, PANSS-EC agitation = 486). In the YMRS subgroup, least squares mean differences in change from baseline were statistically significant for cariprazine versus placebo on YMRS hostility/irritability-related items (irritability [−0.93], disruptive-aggressive behavior [−0.79], combined [−1.75]; P ≤ 0.001 each), YMRS total score (−5.92, P ≤ 0.0001), and all individual YMRS items (−0.25 to −0.93, P ≤ 0.0001); differences remained significant after adjustment for other manic symptoms, sedation, and akathisia. Differences in PANSS hostility and PANSS-EC subgroups were significant for cariprazine versus placebo (P ≤ 0.001). Limitations: Post hoc analysis. Conclusion: Cariprazine demonstrated specific antihostility/irritability and anti-agitation effects in patients with manic/mixed episodes of bipolar I disorder and baseline hostility, irritability, or agitation
Dual Antiplatelet Therapy versus Intravenous Tissue Plasminogen Activator With Acute Minor Ischemic Stroke: A Systematic Review and Meta-Analysis of Safety and Efficacy
No full textObjectives: To compare the safety and efficacy of Dual Antiplatelet Therapy (DAPT) and Intravenous (IV) Tissue Plasminogen Activator (t-PA) in minor Acute Ischemic Stroke (AIS). Materials and Methods: Following Cochrane and PRISMA guidelines, we analyzed observational studies and clinical trials comparing DAPT and IV t-PA in patients with minor AIS. Databases included PubMed, Scopus, and Web of Science. Data extraction included study characteristics, patient demographics, and analyzed outcomes. RevMan 5.3 and OpenMetaAnalyst 2021 were used to analyze the data and assess heterogeneity, respectively. The risk of bias was determined using RoB 2.0 and the Newcastle-Ottawa scale. Results: This meta-analysis included five studies with 3,978 DAPT-treated patients and 2,224 IV t-PA-treated patients. We found no significant differences in achieving modified Rankin scale (mRS) scores of 0-1 (OR 1.11, 95 % CI: 0.79, 1.55, p = 0.56) and 0-2 (OR 0.90, 95 % CI: 0.61, 1.31, p = 0.57), as well as combined mRS scores (OR 1.05, 95 % CI: 0.82, 1.34, p = 0.72). Similarly, there were no significant disparities between the two treatment groups in NIHSS score change from baseline (MD 0.32, 95 % CI: -0.35, 0.98, p = 0.35) and in mortality rates (OR 0.87, 95 % CI: 0.26, 2.93, p = 0.83). Notably, in comparison to the IV t-PA group, the DAPT group exhibited a significantly lower incidence of bleeding (OR 0.31, 95 % CI: 0.14, 0.69, p = 0.004) and symptomatic intracranial hemorrhage (sICH) (OR 0.10, 95 % CI: 0.04, 0.26, p \u3c 0.00001). Conclusions: Our meta-analysis found no significant differences in efficacy between DAPT and IV t-PA. However, DAPT demonstrated a significantly lower risk of sICH and bleeding compared with IV t-PA
Lack of Genotoxicity Potential and Safety Assessment of 4-(2-Hydroxyethyl) Morpholine Present as an Impurity in Pharmaceuticals and Nutritional Supplements
No full text4-(2-Hydroxyethyl) morpholine (HEM) is widely used as a building block of macromolecules in the manufacture of pharmaceuticals and dietary supplements and could remain as an impurity in the finished products. An evaluation of HEM was conducted to identify endpoints that could be used to determine the point-of-departure (POD) for use in assessing the potential risk from exposure to HEM. No oral repeated dose toxicological studies of appropriate duration were found for HEM. Therefore, suitable analogue(s) were identified. Although oral repeated dose studies were available for the analogues, the studies were not of sufficient duration for use in the assignment of a POD for risk evaluation. Accordingly, the Threshold of Toxicological Concern (TTC) approach, which proposes that a de minimis value can be derived to qualitatively assess risk, was considered for HEM. To determine the appropriate TTC approach (genotoxic or non-genotoxic), the genotoxicity of HEM and its analogues were evaluated. The weight of the evidence indicated that HEM, and the appropriate analogues, are not genotoxic. Considering the chemical structure of HEM, the non-genotoxic Cramer class III TTC value of 1.5 μg/kg bw/day was determined to be appropriate for use in safety assessment of HEM as an impurity in products intended for human consumption