Occurrence Of Serious Adverse Events Research Articles

EXPRESS: Are All Generic Drugs Created Equal? An Empirical Analysis of Generic Drug Manufacturing Location and Serious Drug Adverse Events

Generic drugs provide lifesaving, affordable treatment to millions of people each day. Generic drug manufacturing has been steadily moving from advanced economies, such as the U.S., to emerging economies, such as India. Due to the opacity of drug supply chains, the quality risk implications of manufacturing in emerging economies has not been carefully empirically tested. This study addresses this gap. To do so, we identify a novel source of drug manufacturing location data which allows us to compare the occurrence of serious adverse events of generic drugs made in different locations. Using exact matching analyses based on the equivalency criteria established by the U.S. Food and Drug Administration (FDA), we find that generic drugs manufactured in India, where a majority of emerging economy generic drugs are made, are associated with significantly higher instances of serious adverse events than equivalent generic drugs made in the U.S., where a majority of advanced economy generic drugs are made. We further show that this key result is explained by mature generic drugs, which are particularly susceptible to operations and supply chain cost reduction efforts—efforts that unfortunately may compromise drug quality. Our study finding leads to implications for the FDA in their regulation of generic drugs.

P0586 Nationwide population-based cohort study on the use and persistence of infliximab (IV and SC) in France: the Riposte IBD study

Abstract Background Subcutaneous infliximab (IFX-SC) is available in France since 2021. Beyond the pivotal trials, real-life data is needed. The aim of the RIPOSTE study is to evaluate the real-life use of IFX-SC in France at a nationwide level. Methods Patients affiliated to the French national health insurance with at least one IFX-SC or intravenous (IV) delivery between February 1, 2021, and December 31, 2022, were included, regardless of therapeutic indication. Three patient groups were defined: patients treated solely with IFX-IV (control group); patients who had received less than 3 infusions of IFX-IV before initiating IFX-SC (initiation group); patients who had received at least 3 infusions of IFX-IV before initiating IFX-SC (switch group). Patients were followed from the first IFX infusion until IFX discontinuation, initiation of another advanced therapy, death, or December 31, 2022. Discontinuation of infliximab was defined by a period of at least 3 months after the last day of estimated exposure without any new treatment delivery. Persistence of IFX-SC was assessed by the Kaplan-Meier method. Concomitant exposure of immunosuppressant (IS) and the occurrence of serious adverse events were also assessed. Results A total of 45664 patients received at least one IFX delivery (fig.1), 30842 treated solely with IFX-IV and 12480 patients treated with IFX-SC. Overall, 7467 (59.8%) and 2982 (23.9%) were diagnosed with Crohn’s disease (CD) and ulcerative colitis (UC), including 1449 (19%) and 664 (22%) in the initiation group, respectively. In the initiation group, 129 (8.9%) and 59 patients (9.2%) with CD and UC had not received IFX-IV at induction. The mean age at cohort entry was 40 years (SD, 14.49) in CD and 43 years (SD, 15.73) in UC, with 49% and 53% of men respectively. At 6 months, an IS was associated with IFX-SC in 39% of CD and 34% of UC patients in the initiation group compared to 16% and 17% of CD and UC patients in the switch group. Median patient follow-up for both diseases was 0.92 years, (Q1-Q3; 0.50-1.25). At 6 months, 84% of CD patients (CI [0.82-0.86]) and 80% (CI [0.76-0.83]) of UC patients were still on IFX-SC in the initiation group. Among patients in the switch group, persistence was 90% (CI [0.9-0.91]) for both CD and UC (CI [0.89-0.91]). Switch-back to IFX-IV in patients exposed to IFX-SC during follow-up occurred in 33 CD (2.3%) and 13 UC patients (2.0%) in the initiation group compared to 203 CD (3.4%) and 77 UC patients (3.3%) in the switch group. No new safety signals were identified (Table 1). Conclusion Based on a nationwide population-based cohort, over 80% of patients initiating IFX-SC and over 90% in maintenance with IFX-SC remained on treatment at 6 months. These data are consistent with previously published data.

Hepatitis C Treatment With Generic Sofosbuvir-Based Regimens in Patients Undergoing Hemodialysis.

To assess the efficacy and safety of locally manufactured generic sofosbuvir-based direct-acting antivirals in the treatment of Hepatitis C virus (HCV) infected patients on maintenance hemodialysis. We have conducted a retrospective multicenter study including patients on maintenance hemodialysis, treated with sofosbuvir-based regimens between 01/01/2017 and 09/30/2021. Patients were treated for 12 or 24 weeks, with sofosbuvir 400 mg + ledipasvir 90 mg 3 times/week, or sofosbuvir 3 times/week + daclatasvir 60 mg/d, or sofosbuvir + daclatasvir in coformulation, 3 times/week. Sustained virological response was defined as a negative HCV RNA test 12 weeks after treatment. The occurrence of serious adverse events during treatment defines intolerance to treatment. Statistical analysis was performed using SPSS software (version 25). A total of 120 patients were treated; the mean age was 50 ± 14.17 years [18-78], 50% were men. Twenty-two patients (n = 22; 18.3%) were previously treated with pegylated Interferon. Genotype 1 was predominant (n = 68; 82%). Most of the patients (n = 53; 44.2%) had no significant fibrosis, and 24 (20%) had cirrhosis. The SVR rate was 93.3% (CI 95% [88.8; 97.8]) (n = 112), the serious adverse events rate was 10.8% (CI 95% [0.054-0.166]) (n = 13), including 2 deaths unrelated to direct-acting antivirals. Early treatment discontinuation occurred in 5.8% (n = 7), and a relapse in 0.8% (n = 1). On multivariate analysis, risk factors for serious adverse events included advanced liver fibrosis, thrombocytopenia, hypoalbuminemia, high bilirubin level, and pre-treatment status. Locally manufactured generic sofosbuvir-based regimens are safe and effective in maintenance hemodialysis patients. However, they should be closely monitored to manage comorbidities and complications during treatment.

The ADESTE trial: A phase 2 study of enibarcimab, a monoclonal antibody targeting adrenomedullin, in acute heart failure.

This study aimed to conduct a phase 2 proof-of-concept and safety study to evaluate the effect of ENIBARCIMAB (EN), a non-neutralizing humanized monoclonal antibody targeting the N-terminus of adrenomedullin (ADM), administered immediately after stabilization with standard of care (SoC) treatment, in patients hospitalized for acute heart failure (AHF). This prospective, open-label, controlled, interventional, multicenter, dose-escalation study was conducted at two cardiology sites in Indonesia. Patients were divided into two interventional groups sequentially receiving 0.5mg/kg (SoC+EN 0.5mg/kg, n=10; first cohort) and 2mg/kg (SoC+EN 2mg/kg, n=10; second cohort) of EN via 1-h intravenous (IV) infusion within 48h after admission for AHF. The control group (n=10) was treated with SoC therapy for AHF therapy. All patients were monitored continuously within 24h post-infusion and subsequent daily until discharge. Treatment-related serious adverse events (SAEs) were recorded during hospitalization and up to 90days after discharge. Both EN dosages were well-tolerated, and no significant safety issues were identified during hospitalization and up to 90days of follow up. SAEs occurred in 10% of patients in each EN group but were deemed not related to treatment. No significant differences in the occurrence of SAEs were found between the groups. Five deaths occurred: three (30%) in the control group as compared with two deaths (20%) in the SoC+EN 2mg/kg group. EN led to a significant increase in plasma bio-ADM levels within 24h post-infusion, with the SoC+2mg/kg group showing the highest increase. Within 1h from IV EN infusion, SoC+EN 2mg/kg compared with 0.5mg/kg, resulted in a significant percentage reduction in systolic, diastolic blood pressure, and mean arterial pressure. However, it did not result in severe hypotension and the need for drug discontinuation. In this pilot safety study of patients hospitalized for AHF, IV infusion of EN 0.5 and 2mg/kg increased circulating plasma bio-ADM levels and was well-tolerated without treatment-related SAEs occurring during hospitalization and up to 90days after discharge.

Safety of baricitinib in vaccinated patients with severe and critical COVID-19 sub study of the randomised Bari-SolidAct trial.

The Bari-SolidAct randomized controlled trial compared baricitinib with placebo in patients with severe COVID-19. A post hoc analysis revealed a higher incidence of serious adverse events (SAEs) among SARS-CoV-2-vaccinated participants who had received baricitinib. This sub-study aimed to investigate whether vaccination influences the safety profile of baricitinib in patients with severe COVID-19. Biobanked samples from 146 participants (55 vaccinated vs. 91 unvaccinated) were analysed longitudinally for inflammation markers, humoral responses, tissue viral loads, and plasma viral antigens on days 1, 3, and 8. High-dimensional analyses, including RNA sequencing and flow cytometry, were performed on available samples. Mediation analyses were used to assess relationships between SAEs, baseline-adjusted biomarkers, and treatment-vaccination status. Vaccinated participants were older, more frequently hospitalized, had more comorbidities, and exhibited higher nasopharyngeal viral loads. Baricitinib treatment did not affect antibody responses or viral clearance, but reduced markers of T-cell and monocyte activation compared to placebo (sCD25, sCD14, sCD163, sTIM-3). Age, baseline levels of plasma viral antigen, and several inflammatory markers, as well as IL-2, IL-6, Neopterin, CXCL16, sCD14, and suPAR on day 8 were associated with the occurrence of SAEs. However, mediation analyses of markers linked to SAEs, baricitinib treatment, or vaccination status did not reveal statistically significant interactions between vaccination status and SAEs. This sub-study did not identify any virus- or host-related biomarkers significantly associated with the interaction between SARS-CoV-2 vaccination status and the safety of baricitinib. However, caution should be exercised due to the moderate sample size. EU Horizon 2020 (grant number 101015736).

P38 Safety of biosimilars compared with originator adalimumab for psoriasis: a multinational cohort study

Abstract Adalimumab is a widely used biologic treatment for moderate-to-severe psoriasis. With the expiration of Humira®—the originator adalimumab—patent, adalimumab biosimilars have become available, offering the potential to reduce treatment costs. However, concerns about the safety of biosimilars in clinical practice remain a significant barrier to their widespread adoption for psoriasis treatment. This study aims to compare the safety of adalimumab biosimilars to Humira® for psoriasis in real-world practice. We conducted a prevalent-new user cohort study using data from the French National Health Data System (SNDS), the British Association of Dermatologists Biologics and Immunomodulators Register (BADBIR), and the Spanish Registry of Systemic Therapy in Psoriasis (BIOBADADERM). The study compared adalimumab-naive patients (new users) initiating biosimilars with those initiating Humira, and patients who switched from Humira to biosimilars (switchers) with those who continued on Humira. Patients were matched 1:1 based on previous adalimumab exposure time to create equal-sized cohorts of biosimilar and originator users. The primary outcome was serious adverse events (SAEs), defined as any medical events during the use of the study drugs resulting in death or hospitalization. In the result, a total of 7387 biosimilar new users and 3654 switchers were matched and compared respectively with Humira new users and continuous users. The incidence rates of SAEs per patient-year were similar between biosimilar and Humira new users [incidence rate ratio (IRR): 0.91, 95% confidence interval (CI): 0.80–1.05] and between switchers and continuous Humira® users (IRR: 0.92, 95% CI: 0.83–1.01). The time to the first SAE occurrence was significantly lower among biosimilar new users compared with Humira® new users [hazard ratio (HR), 0.83; 95% CI: 0.72–0.96]. However, this difference was observed only in registries where most Humira users were recruited before biosimilars were available, suggesting potential residual confounding from changes over time in practices and prescription trends. The time to the first SAE occurrence was similar between switchers and continuous Humira users (HR: 0.94, 95% CI: 0.85–1.05). In conclusion, adalimumab biosimilars demonstrated a comparable safety profile to Humira for both new users and patients who switched from Humira to biosimilars.

Age and clinical spectrum of COVID-19 are associated with safety of transarterial chemoembolization in hepatocellular carcinoma: a retrospective cohort study.

Hepatocellular carcinoma (HCC) patients with coronavirus disease 2019 (COVID-19) undergoing open surgery show increased adverse events (AEs) and mortality, while the safety of transarterial chemoembolization (TACE) in coinfected patients remains understudied, limiting available evidence. This study aims to investigate the safety of TACE in HCC patients coinfected with COVID-19, and to explore the potential risk factors affecting the occurrence of serious AEs (SAEs), thus providing evidence for clinical treatment strategies in such patients. This retrospective study involved HCC patients who underwent TACE with or without COVID-19 infection at our institution from November 2022 to February 2023. Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used for the diagnosis of COVID-19. Patients were divided into an infected group (diagnosed with COVID-19 within 2 weeks before or after the procedure) and an uninfected group (tested negative for COVID-19). SAEs were ascertained according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0. Logistic regression analysis of multiple clinical factors in preoperative baseline characteristics was performed to identify risk factors that might predict the occurrence of SAEs. A total of 118 patients (73 in the infected group, 45 in the uninfected group) were included, of whom 83.9% were male (86.3% in the infected group vs. 80.0% in the uninfected group) and the median age was 55.9±12.4 years (56.8±12.3 vs. 54.5±12.7 years). The clinical spectrum of COVID-19 in the infected group were 80.8% mild, 13.7% moderate, 1.4% severe and 4.1% critical. Sixteen of the 118 patients experienced SAEs (19.2% vs. 4.4%, P=0.046). The predominant SAEs were respiratory system diseases (9.6% vs. 0.0%) and liver damage (2.7% vs. 2.2%). In the univariate analysis, infection status [odds ratio (OR): 5.102, P=0.04, 95% confidence interval (CI): 1.102-23.627], gender (OR: 2.857, P=0.09, 95% CI: 0.862-9.468), age (OR: 1.061, P=0.03, 95% CI: 1.007-1.118) and clinical spectrum of COVID-19 (OR: 4.259, P<0.001, 1.943-9.336) were considered as the potential risk factors of grade ≥3 AEs. In multivariate analysis, younger age (OR: 1.064, P=0.044, 95% CI: 1.002-1.131) and a milder clinical spectrum of COVID-19 (OR: 5.736, P=0.004, 95% CI: 1.772-18.568) were independent factors associated with a lower occurrence of SAEs. TACE in HCC patients co-infected with COVID-19 was considered relatively safe. Age and clinical spectrum of COVID-19 were associated with SAEs in HCC patients treated with TACE.

Robotic minimally invasive inguinal hernia repair with the Dexter robotic system™: A prospective multicenter clinical investigation

BackgroundRobot-assisted transabdominal preperitoneal inguinal hernia repair (rTAPP) has been established with various robotic platforms. The Dexter robotic system is an open platform consisting of a sterile surgeon’s console, two robotic instrument arms, and one robotic endoscope arm. This study aimed to confirm the perioperative and early postoperative safety and clinical performance of the Dexter system in patients undergoing primary transperitoneal inguinal hernia repair.MethodsThe primary objectives of this multicenter study conducted at three centers in France, Germany, and Switzerland were to document the successful completion of rTAPP procedures and the occurrence of serious adverse events (Clavien–Dindo grades III–V), device-related events up to 30 days post-surgery. The procedures were performed by three surgeons with varying levels of experience in robotic systems.Results50 patients with a median age of 62.5 years (IQR 51.0–72.0) and BMI of 25.1 kg/cm2 (IQR 23.5–28.7), respectively, underwent inguinal hernia repair (33 unilateral, 17 bilateral). All surgeries were successfully completed using three standard laparoscopy trocars. There were no conversions to open surgery, intraoperative complications or device deficiencies. The median skin-to-skin operative time was 50 min (IQR 45–60) for unilateral hernias and 96 min (IQR 84–105) for bilateral hernias. The median console time was 30 min (IQR 26–41) for unilateral and 66 min (IQR 60–77) for bilateral hernias. Twenty-six patients were discharged on the day of surgery, and 22 on postoperative day 1.ConclusionThis study confirmed the use of the Dexter system in rTAPP was feasible and safe in multicenter cohorts, with operative times consistent with the literature on other robotic platforms. Our data demonstrated the accessibility of this new robotic approach, even when adopted by surgeons new to robotics. The Dexter system emerged as a valuable device in the hernia repair toolkit for both experienced robotic surgeons and those new to the field.

Long-Term Efficacy and Safety of Bimekizumab and Other Biologics in Moderate to Severe Plaque Psoriasis: Updated Systematic Literature Review and Network Meta-analysis.

Biologic treatments have made complete skin clearance in moderate to severe plaque psoriasis a real possibility. Although clinical trials demonstrated the superiority of bimekizumab over secukinumab, adalimumab, and ustekinumab, direct comparisons with other biologics are not available. This systematic literature review (SLR) and network meta-analysis (NMA) aimed to evaluate the 1-year efficacy and safety of bimekizumab versus other biologic systemic therapies for moderate to severe plaque psoriasis. We conducted an SLR to retrieve published randomised controlled trials (RCTs) in patients with moderate to severe plaque psoriasis. We searched MEDLINE, Embase, the Cochrane Central Register of Controlled Trials and Cochrane Database of Systematic Reviews and PsycINFO on 13 January 2022. Two NMA types were used to analyse the long-term achievement of 100% improvement from baseline in Psoriasis Area and Severity Index (PASI100): (1) NMA of cumulative clinical benefits, based on the area under the curve, from week0 to 52; (2) multinomial NMA at weeks44‒60. Binomial NMA was used to evaluate long-term serious adverse events (SAEs). The SLR identified 38 RCTs, of which 19 were included in the NMA. Bimekizumab 320mg administered every 4weeks to week16 then every 8weeks (Q4W/Q8W) showed a greater cumulative average number of days of PASI100 response compared with all other biologics. These differences were statistically significant versus all biologics, except risankizumab 150mg. The multinomial NMA demonstrated that interleukin (IL)-17 and IL-23 inhibitors were the most efficacious treatments. No significant differences were found in long-term occurrence of SAEs. Bimekizumab 320mg Q4W/Q8W was superior to most other treatments in maintaining complete skin clearance during the first year of treatment. It demonstrated a greater cumulative average number of days with completely clear skin while displaying a comparable safety profile compared with all other biologics.

Safety of left atrial appendage amputation during cardiothoracic surgery

Abstract Background Patients with atrial fibrillation (AF) are at risk for ischemic strokes, often originating from the left atrial appendage (LAA). Preventive LAA amputation (LAAA) during cardiac surgery has been shown to reduce ischemic stroke risk, both in patients with and without AF. However, the short-term safety and functional implication of LAAA in non-AF patients remain poorly understood. Besides possible surgical complications, there are suggestions that LAAA could lead to postoperative AF or influence neurohumoral changes resulting in fluid overload. Purpose To evaluate the safety of LAAA in patients without a history of AF undergoing routine cardiac surgery. Methods Patients underwent elective cardiac surgery between May 5 2015 and April 18 2018 in two high volume centers. Main inclusion criteria were a CHA2DS2-VASc≥ 2 and no history of AF. Patients without a history of AF, that participated in the PREDICT-AF study underwent concomitant LAAA and were compared with patients undergoing cardiothoracic surgery who were approached for participation in PREDICT-AF, but declined and subsequently did not undergo LAAA. Informed consent for the retrospective use of data was obtained through an opt-out procedure in these patients. The primary outcome of this analysis was the number of patients with any serious adverse event within 30 days postoperatively. Secondary outcomes were AF within 30 days postoperatively, death, rethoracotomy, time on extra corporal circulation(ECC) and heart failure related symptoms assessed through congestion on x-chest and weight trends. Adverse events were independently adjudicated by a cardiothoracic surgeon using pre-specified definitions. Results 150 patients in PREDICT-AF underwent LAAA. 284 Eligible patients declined participation and formed the control group. Patients in the LAAA group were more frequently male (87.3% vs 72.5%; p=0.001), were taller (176.0cm ± 8.2 vs 172.6cm ± 9.9; p&amp;lt;0.001) and weighed more (86.1kg CI[80.0, 92.2] vs 81.6kg CI[71.9, 91.1]; p=0.001) compared to controls. There were no significant differences in occurrences of serious adverse events (8% vs 12%; p=0.265), deaths (1.3% vs 1.8%; p=1) or rethoracotomies (3.3% vs 1.8%; p=0.483) between the LAAA and control group. Also, there was no difference in the incidence of postoperative AF (57, 38% vs 90, 31.7%; p=0.225), ECC time (104.5 minutes CI[81.0, 129.0] vs 98.0 CI[80.0, 124.5] p=0.371) or the presence of chest x-ray congestion (26.0% vs 27.8%; p=0.771) between the groups (Figure 1A). The spline plot of perioperative weight change from baseline, reveals no notable differences between the two groups (Figure 1B). Conclusion LAAA during routine cardiothoracic surgery is not associated with more surgical complications, postoperative atrial fibrillation or heart failure related symptoms. Given the generally high AF risk in patients undergoing cardiothoracic surgery, a strategy to preemptively resect the LAA may be feasible and safe.Figure 1 A &amp; B

The safety of corticosteroid therapy in IGA nephropathy: analysis of a real-life Italian cohort.

Systemic steroids are recommended for patients with IgA nephropathy (IgAN) and proteinuria. However, there are concerns about their safety due to an excess of serious adverse events (SAEs) in previous randomised trials. This study evaluates the incidence of SAEs in IgAN patients receiving different treatment regimens in clinical practice. Multicentre, retrospective, observational cohort study of 1209 patients (M/F: 864/345, mean age: 41.73 ± 14.92years) with biopsy-proven IgAN treated with renin angiotensin system (RAS) inhibitors (RASI) (n = 285), intravenous + oral steroids (n = 633), oral steroids (n = 99), steroids + immunosuppressants (n = 192). A total of 119 (9.8%) adverse events were reported, of which 67 (5.5%) were considered treatment-emergent, and 36 (2.9%) were SAEs (n = 23, 63.8% were infections). One patient died due to sepsis. A significant association was observed between AEs and immunosuppression [8 (2.8%) in RASI, 60 (9.4%) in steroids + immunosuppressants, 14 in oral steroids (14.1%) and 37 pts (19.2%) in steroids + immunosuppressants (p < 0.01)], age and estimated glomerular filtration rate (eGFR), but not with proteinuria and sex. On multivariate analysis, only older age was associated with the occurrence of SAEs. According to our findings, the incidence of SAEs during therapy with steroids alone or associated with immunosuppressors is lower in everyday clinical practice than in randomised clinical trials.

Association of Calf Circumference, Hand Grip Strength, and Physical Performance With Serious Adverse Events in Individuals With Subacute Stroke Hospitalized for Rehabilitation: An Observational Study

ObjectiveTo determine whether calf circumference, hand grip strength, and physical performance are linked to the incidence of serious adverse events (SAEs) in patients with subacute stroke. DesignRetrospective cohort study. SettingSingle rehabilitation hospital. ParticipantsPatients with stroke admitted for rehabilitation hospital. InterventionNot applicable. Main Outcome MeasuresThe incidence of SAEs, such as death, cardiovascular events including recurrent stroke, and conditions requiring transfer to another hospital for specialized care or immediate treatment for an acute illness during hospitalization. ResultsA total of 341 patients (median age: 74y) participated in this study, with 232 patients (68%) exhibiting low-physical performance. In the adjusted model, low-physical performance was significantly associated with SAEs (hazard ratio [HR], 3.01; 95% confidence interval [CI], 1.04-8.68; P=.042). However, low calf circumference (HR, 1.60; 95% CI, 0.76-3.38; P=.219) and low hand grip strength (HR, 0.98; 95% CI, 0.39-2.42; P=.960) did not show an independent association. ConclusionsLow-physical performance was independently associated with the occurrence of SAEs during hospitalization for rehabilitation in patients with subacute stroke.

A boost or a redundancy? on the value of combination of androgen receptor signal inhibitor and PARP inhibitor for advanced prostate cancer

AbstractPoly (ADP-ribose) polymerase (PARP) inhibitor (PARPi), as a novel endocrine therapy, has been investigated in patients with metastatic castration-resistant prostate cancer (mCRPC) in recent years. Multiple large-scale clinical trials have consistently demonstrated that various PARP inhibitors, including olaparib, rucaparib, niraparib, and talazoparib, confer longer radiographic progression-free survival (rPFS) compared to new hormonal agents (NHA) in mCRPC patients with homologous recombination deficiency (HRD). Moreover, the incidence of grade 3 and above adverse events did not significantly increase. Additionally, when combined with androgen receptor signaling inhibitors (ARSI), olaparib, niraparib, and talazoparib have shown significant extension of rPFS but also an increased occurrence of serious adverse events in HRD-positive patients. Only PROpel yielded positive results among the homologous recombination repair (HRR) mutation negative population. Therefore, it remains uncertain whether ARSI-PARPi combination therapy should be considered as first-line treatment for mCRPC patients without HRR mutations. In this review article, we aim to elucidate the necessity and feasibility of combination therapy versus monotherapy specifically within the HRR mutant population while exploring its potential applicability to other non-HRR mutant subtypes. Furthermore, we conducted a comprehensive search on registered clinical trials at present to summarize the research progress of PARP inhibitors in prostate cancer patients at different disease stages.

Adverse Events and Satisfaction Outcomes with Calcium Hydroxylapatite and Polycaprolactone Fillers in Facial Aesthetics: A Systematic Review

Objective: The aim of this study was to systematically review the safety and effectiveness of the injectable biostimulators dermal fillers calcium hydroxyapatite (CaHA) and polycaprolactone (PCL) in facial esthetic procedures. Materials and Methods: Comprehensive electronic searches were executed across six academic databases. The primary outcome focused on safety by examining studies that reported the incidence of adverse events (AEs). The secondary outcome gauged the satisfaction of the patients and injectors by validated esthetic scales. To evaluate biases, the Joanna Briggs Institute Checklist tools were employed. Results: We included a total of 79 studies. In the quantitative assessment of the CaHA, out of 5032 injected patients, 21.8% manifested early AEs, 0.85% experienced delayed reactions, and 0.27% had severe complications. Within the PCL group, consisting of 1119 patients, 83.3% exhibited early AEs, 5.6% had delayed reactions, and none had serious complications. Regarding esthetic satisfaction outcome, both products presented favorable results, but a limited number of studies assessed these data. In the studies evaluated qualitatively, a broad array of AEs were cataloged. Conclusions: The occurrence of serious AEs associated with CaHA and PCL fillers is relatively low. Both CaHA and PCL fillers exhibit favorable safety profiles, with most AEs being transient in nature.

Efficacy and safety of upadacitinib in the treatment of moderate-to-severe atopic dermatitis in adolescents: A systematic review and meta-analysis of randomized controlled trials.

To assess the efficacy and safety of upadacitinib in adolescents with moderate-to-severe atopic dermatitis (AD). A comprehensive search was conducted using PubMed, Medline, Embase, Web of Science, Clinical Trials Website, and Cochrane Library databases, spanning from their inception until February 18, 2024. The review incorporated all randomized controlled trials examining upadacitinib's efficacy in managing moderate to severe AD among adolescent patients. The methodological quality of the selected studies underwent thorough assessment utilizing the Cochrane systematic review methodology. Statistical analyses of the outcome measures were executed employing the Review Manager 5.3 software. The meta-analysis encompassed 4 studies in total. Compared to placebo, upadacitinib at doses of both 15 and 30 mg was associated with a significant enhancement in the eczema area and severity index-75% ([odds ratio, OR = 11.06, 95% confidence interval, CI (6.78-18.04), P < .00001]; [OR = 21.73, 95% CI (12.73-37.11), P < .00001]), a reduction in the numerical rating scale of ≥4 ([OR = 6.16, 95% CI (3.56-10.64), P < .00001]; [OR = 10.58, 95% CI (6.12-18.29), P < .00001]), and improvement in the investigator's global assessment to 0/1 ([OR = 8.85, 95% CI (4.86-16.10), P < .00001]; [OR = 21.43, 95% CI (11.64-39.46), P < .00001]). Regarding safety, upadacitinib at both 15 and 30 mg doses was linked to a statistically significant rise in the overall incidence of adverse events when juxtaposed with placebo ([OR = 1.57, 95% CI (1.01-2.44), P = .04]; [OR = 2.21, 95% CI (1.44-3.41), P = .0003]). Nevertheless, no statistically significant disparity was discovered in the occurrence of serious adverse events between upadacitinib and placebo ([OR = 1.02, 95% CI (0.27-3.84), P = .98]; [OR = 0.42, 95% CI (0.09-1.93), P = .26]). The findings from this meta-analysis indicate that upadacitinib demonstrates substantial effectiveness and tolerability in treating moderate to severe AD in adolescents. Moreover, upadacitinib provides a rapid reduction in pruritus and markedly ameliorates symptoms and signs, with the 30 mg dosage showing a more pronounced therapeutic effect relative to the 15 mg dosage.

Dose reduction and discontinuation due to the combination of CDK4/6 inhibitors and endocrine drugs: a systematic review and meta-analysis.

With the widespread use of CDK4/6 inhibitors, the number of discontinuations and reductions due to adverse events is increasing. Therefore, we examined the risk of dose reduction, discontinuation, and occurrence of serious adverse events and death due to adverse events when CDK4/6 inhibitors are combined with endocrine drugs. We searched English-language articles published up to February 10, 2024, using RR values (risk ratio) to indicate the risk of discontinuation, dose reduction, death, and the risk of serious adverse events. When CDK4/6 inhibitors were used in combination with endocrine drugs, abemaciclib resulted in the highest risk of discontinuation, dose reduction, and serious adverse events. Ribociclib caused the highest risk of death. When using CDK4/6 inhibitors in the clinical setting, a comprehensive evaluation should be performed to avoid dosage reductions and discontinuations and to choose the most appropriate treatment regimen.

Development and application of a serious adverse events risk model for concurrent chemoradiotherapy in patients with nasopharyngeal carcinoma.

The objective of this study was to construct a concise prediction model for serious adverse events (SAEs) in order to assess the likelihood of SAE occurrence among hospitalized patients undergoing concurrent chemoradiotherapy. An electronic database of a Cancer Centre was utilized to conduct a cross-sectional review survey. Our research involved the recruitment of 239 patients who were undergoing concurrent chemoradiotherapy in the Department of Nasopharynx and Radiotherapy. The clinical prediction rule was derived using logistic regression analysis, with SAE serving as the primary outcome. Internal verification was conducted. The occurrence rate of SAE in the derivation cohort was 59.4%. The ultimate model used had 3 variables, namely cystatin C, C-reactive protein, and serum amyloid A. The model exhibited an area under the curve of 0.626 (95% CI: 0.555-0.696; P < .001). The model accurately predicts the occurrence of SAE, and the variable data can be easily obtained, and the assessment technique is straightforward.

Methotrexate versus conventional disease-modifying antirheumatic drugs in the treatment of non-anterior sarcoidosis-associated uveitis

AimsTo compare the safety and efficacy of methotrexate (MTX), mycophenolate mofetil (MMF) and azathioprine (AZA) in non-anterior sarcoidosis-associated uveitis.MethodsRetrospective study including non-anterior sarcoidosis-associated uveitis according to the revised International Workshop...

Effects of Meditation and Breathing Therapy on Anxiety Improvement before and after Percutaneous Coronary Intervention in Patients with Coronary Artery Disease: A Prospective Cohort Study

Abstract Background: Coronary artery disease (CAD) is a leading cause of worldwide mortality, and percutaneous coronary intervention (PCI) has long been used to alleviate its symptoms. However, patient anxiety has been noted to exacerbate the negative symptoms of CAD, as well as reduce the effectiveness of PCI. Numerous techniques have been developed for alleviating patient stress, such as mindfulness and breathing exercises, though their efficacy with respect to improving PCI outcomes has still not been fully defined. In this study, we aimed to shed light by examining whether CAD patients who underwent such exercises demonstrated lowered anxiety and improved functional outcomes post-PCI compared to CAD patients who did not undergo these procedures. Methods: One hundred and sixty CAD patients were enrolled and randomly divided into two 80-member groups, one of which (intervention) was prescribed meditation therapies, in the form of 6-min mindfulness videos, breathing therapies carried out 12 times per cycle, for 3 times/day, as well as targeted psychological counseling. The other 80-patient group served as the untreated control (Con). Anxiety was monitored during that time period using the Zung’s Self-rating Anxiety Scale (SAS), while sleep quality was measured using the Pittsburgh Sleep Quality Index (PSQI); furthermore, various cardiac functioning parameters, such as heart rate, were measured. In addition, the occurrence of serious adverse events (SAEs) was monitored during the 3-month follow-up period post-PCI. Results: No significant differences were present between the intervention and Con groups for baseline patient characteristics, except for body mass index. However, the intervention group had lower stress levels, in the form of lower SAS, compared to baseline, while the opposite was true for the untreated Con group. Lower SAS also corresponded to lower PSQI pre-PCI in intervention, indicating that this group had improved sleep quality, while PSQI remained unchanged from baseline to PCI in Con. Along with lower stress levels, intervention had lower blood pressures, heart rate, and SAEs, compared to Con, both pre-PCI and during the 3-month follow-up period, illustrating that meditation and respiratory therapies are able to reduce stress pre-PCI, in turn improving PCI outcomes and reducing complications postprocedure. Conclusion: Meditation and respiratory therapies are able to effectively alleviate anxiety and improve sleep quality pre-PCI, in turn improving cardiac functional parameters and facilitating smooth PCI procedures. All of these improvements resulted in increased PCI success rates, lowered hospitalization time, and reduced postsurgical complications in the form of SAEs, enabling these strategies to be of great clinical utility for better preparing CAD patients for the procedure. Public Registration: ClinicalTrials.gov identifier is NCT05320848.

Real-world safety and discontinuation rates of fam-trastuzumab deruxtecan in advanced HER2-positive and HER2-low cancer.

e12518 Background: Fam-trastuzumab deruxtecan’s (Enhertu) 2022 approval for HER2-low breast cancer spurred widespread adoption of its utilization. DESTINY-Breast04 trial reported 9.9 months median progression-free survival (PFS); however, 16.2% experienced adverse events leading to treatment discontinuation. Our study evaluates real-world adverse event rates causing treatment discontinuation, to assess Enhertu's safety in patients with advanced metastatic cancer. Methods: A retrospective analysis was conducted at a community-based practice in Kansas, USA from 2020 to 2024. 99 patients with HER2-positive and HER2-low cancer, treated with Enhertu, with ECOG performance status of 0 and 1 were identified. Absolute values and proportions were used to represent categorical and nominal variables. Proportions between groups were analyzed using the likelihood ratio chi-square, Fisher's test, and the z-test. Statistical analyses were performed using SAS 9.4. The primary objective was to determine treatment discontinuation rates due to adverse events, while secondary objectives included assessing discontinuation rates due to disease progression, mortality rates, as well as progression-free survival, and dose interruption rates. Results: The average age of patients was 62 years, with 92% being females. The most common cancer types treated were Stage IV metastatic Breast Cancer (87%) and Gastric/Gastroesophageal Junction Cancer (9.1%). Of these cases, 44% were HER2-positive, while the rest were HER2-low. A total of 74% of patients discontinued treatment, with a mean duration of 5.4 months (95% Confidence Interval [CI] 4.2-6.7). Adverse events accounted for 9% of discontinuations, including interstitial lung disease/pneumonitis (33%), thrombocytopenia (11%), diarrhea (11%), nausea (22%), and dysgeusia (11%). 77% experienced grade 2 and 3 adverse events. Disease progression and death resulted in 49.4% and 11% of Enhertu discontinuation respectively. Among patients still on Enhertu (26%), the mean treatment duration was 13.5 months (95% CI 9.5-17.5). The mean PFS was 9.3 months (95% CI 6.2-9.4). Dose interruptions due to adverse events with subsequent resumption occurred in 18% of patients. Conclusions: In our community-based observational study on Enhertu discontinuation rates due to treatment-emergent adverse events (TEAEs), we found a 9% discontinuation rate—significantly lower than the 16.2% reported in the Breast04 trial, (P=0.045). The incidence of interstitial lung disease was 3%, considerably less than the 12% reported in Breast04. Importantly, no deaths related to TEAEs were observed, suggesting a lower occurrence of serious adverse events in clinical practice compared to clinical trials. These results underscore Enhertu's safety profile in advanced metastatic HER2-positive and low cancer.