Safety Data Research Articles

Safety of Empagliflozin: An Individual Participant-Level Data Meta-Analysis from Four Large Trials.

Empagliflozin is a sodium-glucose co-transporter-2 inhibitor used to treat type 2 diabetes (T2D) to improve glycemic control, reduce risk of cardiovascular death in patients with T2D, and treat patients with symptomatic chronic heart failure (HF) and chronic kidney disease (CKD). The safety profile of empagliflozin is well documented, although adverse events (AEs) remain of interest to clinicians. This study provides an up-to-date safety evaluation of empagliflozin. Data were pooled from four long-term trials which included: patients with T2D and established cardiovascular disease (EMPA-REG OUTCOME), patients with HF, with/without diabetes (EMPEROR-Reduced and EMPEROR-Preserved), and patients with CKD, with/without diabetes (EMPA-KIDNEY). Since three of the four trials evaluated empagliflozin 10mg, the meta-analysis was restricted to this dose. Total trial medication exposure was 19,727 patient-years for patients who received empagliflozin (n = 10,472) and 19,447 patient-years for placebo (n = 10,461). The percentages of patients with serious AEs, fatal AEs, and AEs leading to discontinuation were similar for both groups. The incidences of serious urinary tract infection and serious pyelonephritis or urosepsis were similar for both groups but higher for women taking empagliflozin versus placebo. Serious genital infections were not increased with empagliflozin versus placebo. There was a slight increase in ketoacidosis and serious volume depletion in patients who received empagliflozin versus placebo. The occurrence of serious acute kidney injury was lower with empagliflozin versus placebo. Empagliflozin was not associated with an increased incidence of severe hypoglycemia, bone fractures, or lower limb amputations. Empagliflozin is therefore considered safe in people without diabetes, the elderly, patients with very low estimated glomerular filtration rate, low body mass index, and HF. Safety is unaltered by blood pressure, concomitant medication for hypertension, HF, and immunosuppression. This meta-analysis of long-term safety data extends current knowledge and confirms the safety and tolerability of empagliflozin.

Real-world clinical outcome and safety of adjuvant human Interferon-alpha1b in resected stage IIIB or IIIC melanoma: results of a retrospective study

BackgroundHuman interferon-α1b (hIFN-α1b) is the first genetically engineered drug approved by the National Medical Product Administration for cancer therapy in China. hIFN-α1b is a relatively safe therapy and can improve survival in advanced melanoma and its long-term efficacy against resection of stage III melanoma is unknown.ObjectiveThe objective of this study is to assess the safety and efficacy of hIFN-α1b in patients with resected stage III melanoma.MethodsThe clinical data were collected from patients who underwent resection of stage IIIB or IIIC melanoma and received subcutaneous injection of hIFN-α1b every other day. The efficacy of hIFN-α1b was determined by rate of recurrence-free survival (RFS), distant metastasis-free survival (DMFS) and overall survival (OS). Safety data were acquired by review of adverse events at follow-ups.ResultsThe study included a total of 61 patients. The median follow-up duration was 45 months. The RFS at 12, 24, and 36 months were observed to be 75.4%, 47.4%, and 37.2% respectively, while the DMFS rates were found to be 83.6%, 65.5%, and 62.2%. Furthermore, the OS rates at these time points were recorded as being 100%, 81.9%, and 71.5%. The overall tolerability of hIFN-α1b was satisfactory, with only 8.2% of the patients experiencing grade 3/4 toxicity and no treatment-related deaths observed.ConclusionOur findings suggest that adjuvant hIFN-α1b treatment is relatively safe and may potentially enhance the rate of RFS, DMFS and OS in patients who have undergone resection for stage IIIB or IIIC melanoma.

A Phase I trial of Non-invasive Ventilation and seizure prophylaxis with levetiracetam In Children with Cerebral Malaria Trial (NOVICE-M Trial)

Background African children with cerebral malaria and seizures caused Plasmodium falciparum are at greater risk of poor outcomes including death and neurological sequelae. The agonal events are severe hypoventilation and respiratory arrest often triggered by seizures. We hypothesised that prophylactic anti-seizure medication (ASM) could avert ‘spikes’ of intracranial pressure during or following seizures and that adequate ventilation could be supported by biphasic Cuirass Ventilation (BCV) which requires no intubation. Methods A Phase I trial conducted in Kilifi, Kenya designed to provide data on safety, feasibility and preliminary data on seizure control using prophylactic ASM (levetiracetam) and BCV as non-invasive ventilatory support in children with cerebral malaria. Children aged 3 months to 12-years hospitalised with P falciparum malaria (positive rapid diagnostic test or a malaria slide), a Blantyre Coma Score ≤2 and a history of acute seizures in this illness are eligible for the trial. In a phased evaluation we will study i) BCV alone for respiratory support (n=10); ii) prophylactic LVT: 40mg/kg loading dose then 30mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10) and; iii) prophylactic LVT: 60mg/kg loading dose then 45mg/kg every 12 hours given via nasogastric tube for 72 hours (or until fully conscious) plus BCV support (n=10). Primary outcome measure: cumulative time with a clinically detected seizures or number of observed seizures over 36 hours. Secondary outcomes will be assessed by feasibility or ability to implement BCV, and recovery from coma within 36 hours. Safety endpoints include: aspiration during admission; death at 28 days and 180 days; and de-novo neurological impairments at 180 days. Conclusions This is a Phase I trial largely designed to test the feasibility, tolerability and safety of using non-invasive ventilatory support and LVT prophylaxis in cerebral malaria. Registration ISRCTN76942974 (5.02.2019); PACTR202112749708968 (20.12.2021).

Target trial emulation of carfilzomib safety among patients with relapsed/refractory multiple myeloma using a nationwide observational data in Korea

PurposeCarfilzomib, commonly used for relapsed/refractory multiple myeloma (RRMM), has been associated with various adverse events in randomized controlled trials (RCTs). However, real-world safety data for a more diverse population are needed, as carfilzomib received expedited approval. This study aimed to evaluate carfilzomib’s safety in Korea by comparing new users of KRd (carfilzomib, lenalidomide, and dexamethasone) to Rd (lenalidomide and dexamethasone) using a nationwide administrative claims database.MethodsThe retrospective cohort study utilized target trial emulation, focusing on adverse events in various organ systems similar to the ASPIRE trial.ResultsThis study included 4,580 RRMM patients between 2007 and 2020, and the KRd group showed significantly higher risks of hematologic adverse events (anemia, neutropenia, thrombocytopenia) and some non-hematologic adverse events (cough, hypokalemia, constipation, hypertension, heart failure) compared to the Rd group. Among non-hematologic adverse events, cardiovascular events (heart failure [HR 2.04; 95% CI 1.24–3.35], hypertension [HR 1.58; 95% CI 1.15–2.17]) had the highest risk in the KRd group.ConclusionThe safety profile of carfilzomib in Korean patients was similar to previous RCTs. Therefore, caution should be exercised when using carfilzomib in Asian individuals with RRMM due to the increased risk of cardiovascular adverse events.

A systematic literature review of clinical evidence and treatment burden in newly diagnosed high-risk pediatric patients with classical Hodgkin lymphoma.

This systematic literature review evaluated frontline treatment burden in pediatric and adolescent/young adult (AYA) patients with high-risk classical Hodgkin lymphoma (cHL) among studies originating from the United States. Data were extracted from 32 publications (screened: total, n=3115; full-text, n=98) representing 12 studies (randomized controlled trials [RCTs], n=2; non-comparative, non-randomized, n=7; observational, n=3). High-risk disease definitions varied across studies. Five-year event-free survival (EFS)/progression-free survival (PFS) was 86%-100% and 79%-94%, and complete response rates were 35%-100% and 5%-64% for brentuximab vedotin (BV)-containing and chemotherapy-alone regimens, respectively. In identified RCTs, BV-containing compared with chemotherapy-alone regimens demonstrated significantly longer 3-year EFS/5-year PFS. Hematological and peripheral neuropathy were the most commonly reported adverse events of interest, although safety data were inconsistently reported. Few studies evaluated humanistic and no studies evaluated economic burden. Results from studies with the highest quality of evidence indicate an EFS/PFS benefit for frontline BV-containing versus chemotherapy-alone regimens for pediatric/AYA patients with high-risk cHL.

The role of European chemical manufacturing companies in promoting effective communication of conditions of safe use by workers.

In 2006, the revised chemicals management legislation mandatedthat manufacturers of hazardous chemical substances conduct risk assessments for the entire substance life cycle. Additionally, they mustcommunicate use-specific safe handling advice (exposure scenarios) to their customer, asannex to the Safety Data Sheet (SDS). Despite significant efforts to develop workable solutions for chemical mixtures, this goal has not yet been fully achieved. Therefore, a Cefic research project (LRI B23) was commissioned on how to ensure meaningful health risk communication for workers across supply chains. The research project determined that risk-based safe use advice generated by manufacturers, often does not reach the intended end-user and was seen as not tailored to specific user needs. Recipients of the advice are also not prepared to act based on information developed by suppliers. From an industry perspective, the complexity of supply chains and substance life cycles are considered major barriers for effective safe use communication. Exposure scenarios for substance use in industrial work environments are often perceived as adding little value compared to existing safe use arrangements required by other health, safety, and environmental legislation applicable to employers and duty-holders. To attain meaningful use-specific safe handling advice for workers, including those at non-industrial premises who may benefit most from such advice, knowledge transfer and close collaboration between manufacturers and formulators remain key elements, supported by enhanced regulatory appreciation.

Trifluridine/tipiracil + oxaliplatin ± nivolumab vs FOLFOX ± nivolumab in HER2 negative advanced oesogastric adenocarcinoma: The PRODIGE73-UCGI40-LOGICAN trial.

Trifluridine/tipiracil (FTD/TPI) is approved in third-line treatment of patients with advanced/metastatic gastric and gastroesophageal junction adenocarcinomas (aGA/GEJA). The association of oxaliplatin with FTD/TPI is promising and the combination of FTD/TPI + oxaliplatin + nivolumab has shown a predictable and manageable safety profile. The aim is to evaluate the efficacy and safety of FTD/TPI plus oxaliplatin with or without nivolumab in patients, with HER2 negative aGA/GEJA, unfit for triplet chemotherapy (TFOX/mFLOT regimen), in the first-line metastatic setting in comparison with the standard of care FOLFOX with or without nivolumab. This study is a prospective randomised, open label, comparative, multicentre, phase II trial designed to include 118 patients. The primary objective is to evaluate the superiority of FTD/TPI plus oxaliplatin with or without nivolumab over FOLFOX regimen with or without nivolumab in terms of PFS in a population of patients non candidate for triplet chemotherapy. Nivolumab will be used for patients whose tumour express PD-L1 with a CPS score ≥5. PRODIGE73-UCGI40-LOGICAN study will provide efficacy and safety data on the association of FTD/TPI plus oxaliplatin with or without nivolumab versus FOLFOX regimen with or without nivolumab in first-line palliative setting, in patients with aGA/GEJA (NCT05476796).

Review on treatment of pleural metastasis and malignant pleural effusion with Pressurized IntraThoracic Aerosol Chemotherapy (PITAC)

Abstract Background Malignant pleural effusion (MPE) is a common and debilitating condition seen in advanced cancer disease, and life-expectancy is short. Symptoms include pain and severe shortness of breath. Current first-line treatment options include pleural drainage using catheters as well as pleurodesis. However, these treatment modalities are often inefficient and patients need repeated procedures. Pressurized IntraThoracic Aerosol Chemotherapy (PITAC) is a minimally invasive procedure, where antineoplastic agents are nebulized under pressure into the pleural space. Content We present the preliminary safety, feasibility, and response assessment data for PITAC based on a comprehensive literature review. Summary Five retrospective studies reported data on 38 PITACs in 21 patients. Data were heterogeneous and incomplete on several important aspects such as procedure, safety, local effect and long-term outcomes. PITAC seems technically feasible with a low risk of complications and may provide some reduction in MPE in selected cases. Outlook PITAC seems feasible, but prospective phase I and II studies are needed to define safety, indications, and efficacy.

Investigating and Improving Pedestrian Safety in an Urban Environment of a Low- or Middle-Income Country: A Case Study of Yaoundé, Cameroon

In Yaoundé, Cameroon, where walking dominates transport modes, pedestrian safety remains an issue as pedestrians account for a fair share of road traffic casualties, partly due to the lack of walking policies and pedestrian facilities safety data, hindering targeted intervention. This study used a pedestrian safety index (PSI) and the Global Walkability Index (GWI) to investigate 12 road segments frequented by diverse pedestrian groups. Indexes were graded from E—lowest to A—highest and analyzed using description and rank correlation. Main safety issues included lack of adequate and accessible sidewalks, bollards, pedestrian crossings, signage, shade, and street lighting. Only one segment (R7) achieved grade C, while the remainder scored D or E, indicating poor pedestrian safety conditions and an unpleasant walking experience. The correlation coefficient (0.69) between the PSI and GWI at a 99% significance level validated the safety assessment, providing confidence in the results. A seven-year (2024–2030) safety strategy is proposed to improve all roads to grade B. This strategy contains several interventions, including engineering improvement, which have been proven effective. This study offers evidence for city officials to improve pedestrian safety and informs walking policies and the implementation of upcoming projects. Future research should quantify the recommendations’ benefits and validate indexes with crash or conflict data.

Anatomical outcomes and complications of sacrocolpopexy using Surelift Uplift mesh: A multicentric observational study.

The study evaluated the anatomical and functional outcomes, as well as the safety data of laparoscopic sacrocolpopexy (LSC) for pelvic organ prolapse (POP) using a lightweight macroporous mesh. A multicentric observational study was developed including five expert centers between March 2011 and December 2019. Inclusion criteria were female patients with symptomatic ≥stage II POP (POP-Q classification), who underwent a LSC. A lightweight and macroporous mesh device (Surelift Uplift) was used. Baseline anatomical positions were evaluated using POP-Q stage. The anatomical outcomes and procedural complications were assessed during the postoperative period. Primary outcomes were anatomical success, defined as POP-Q stage ≤I, and subjective success, defined as no bothersome bulge symptoms, and no repeat surgery or pessary use for recurrent prolapse. A total of 325 LSCs were analyzed with a median patient age of 66 (interquartile range [IQR] 61-73). After a median follow-up of 68 months (IQR 46.5-89), anatomical success was found in 88.9%, whereas subjective success was seen in 98.5% of the patients. Recurrent prolapse presented as cystocele (1.5%). Reported complications were bladder (4.6%) or rectum lesions (0.6%), de novo urinary incontinence (12.9%), and mesh extrusion (1.2%). LSC provides significant clinical improvement and excellent anatomical results, with a low risk of serious complications for women with ≥2 grade POP in a real clinical practice setting.

Azithromycin for Pediatric Critical Asthma: A Multicenter Retrospective Cohort Study.

To characterize the prescribing trends and clinical outcomes related to azithromycin (AZI) among children hospitalized for critical asthma (CA). We performed a multicenter, retrospective cohort study using the Pediatric Health Information Systems registry of children 3 to 17 years of age hospitalized in a PICU for CA from January 2011 to December 2022. We excluded for alternative indications for AZI (eg, atypical pneumonia, B. pertussis infection, acute otitis media, acute sinusitis, pharyngitis/tonsillitis, and urethritis). The primary outcome was AZI prescribing rate by hospital and calendar year (trends assessed by Joinpoint regression). Cohorts with and without AZI exposure were further characterized by demographics, CA treatments, and inpatient outcomes using descriptive and comparative (ie, χ2 and Wilcoxon rank tests) statistics. Of the 47 797 children studied, 9901 (20.7%) were prescribed AZI with a downward annual trend noted from 34.7% in 2011% to 12.4% in 2022 (-1.7% per year, R2 = 0.91). Median institutional AZI prescribing rate was 19.2% (interquartile range [IQR] 11.7%-28%; total range 5.6%-60%). Compared with children not prescribed AZI, those prescribed AZI were older (median 8.3 [IQR 5.7-11.6] vs 7.3 [4.9-10.8] years, P < .001) and experienced a more severe clinical trajectory with greater rates of bilevel positive airway pressure ventilation (19.7% vs 12.6%, P < .001), invasive ventilation (22.1% vs 13.5%, P < .001), extracorporeal life support (0.8% vs 0.1%, P < .001), and median length of stay (4 [IQR 3-6] vs 3 [IQR 2-4] days, P < .001). Between 2011 and 2022, 20.7% of children hospitalized for CA were prescribed AZI notwithstanding the absence of trial-derived efficacy or safety data for this indication and population.

Intravesical oxybutynin treatment for neurogenic detrusor overactivity : Efficacy and safety data from clinical practice with the first intravesical oxybutynin treatment authorized in Germany

Existing therapies for neurogenic detrusor overactivity (NDO), i.e. oral anticholinergics and botulinum toxin injections, can be associated with serious adverse effects or are not always sufficiently effective. Therefore, there is aneed for alternative safe and effective treatment options for NDO. Intravesical oxybutynin has been successfully used for several years as a prescription drug in adults and children with spinal cord injury and spina bifida. In 2019, VESOXX® (FARCO-PHARMA, Cologne, Germany) became the first registered intravesical oxybutynin product in Germany, which is indicated for the suppression of neurogenic detrusor overactivity (NDO) in children from 6years of age and adults, who are managing bladder emptying by clean intermittent catheterisation (CIC), if they cannot be adequately managed by oral anticholinergic treatment due to lack of efficacy and/or intolerable side effects. Overall, there are limited data regarding therapy with intravesical oxybutynin, with the majority of publications being retrospective case series. To date, there are limited data on the efficacy and safety of the newly approved intravesical oxybutynin therapy (VESOXX®) in NDO patients. This noninterventional case series from daily routine treatment which evaluated the physician reports of 38patients suggests that intravesical oxybutynin effectively improves maximum detrusor pressure (Pdet max) by decreasing it by 59% from 51.94 cmH2O ± 26.12 standard deviation (SD) to 21.07 cmH2O ± 17.32 SD (P < 0.001, n = 34). Maximum bladder pressure (MBC) increased by 34% from 260.45 ml ± 200.26 SD to 348.45 ml ± 175.90 SD. Positive or similar effects compared to previous therapies were seen in bladder morphology, number of incontinence episodes, urinary tract infections and adverse drug effects. This case series demonstrates that intravesical oxybutynin is an important addition to current therapies for the treatment of NDO and it is also efficacious in the rare setting of other underlying diseases beyond spinal cord injury or spina bifida. The approved intravesical oxybutynin preparation VESOXX® may be auseful alternative for patients who do not respond to other therapies or suffered side effects.

Efficacy and safety of abatacept for systemic juvenile idiopathic arthritis: a systematic review.

This systematic review assessed the efficacy and safety of abatacept in patients with systemic juvenile idiopathic arthritis (JIA). Studies published between 2000 and 2021 were searched using PubMed, Embase, Cochrane, Ichushi-Web and clinical trial registries. The risk of bias was assessed according to the manual for development clinical practice guidelines by Minds, a project to promote evidence-based medicine in Japan. Seven observational studies were included. American College of Rheumatology pediatric 30/50/70 responses at 3, 6 and 12 months were 64.8%/50.3%/27.9%, 85.7%/71.4%/42.9% and 80.0%/50.0%/40.0%, respectively. Outcomes on systemic symptoms, joint symptoms and activities of daily living were not obtained. No macrophage activation syndrome or infusion reaction occurred. Serious infection occurred in 2.6% of cases. Abatacept improved the disease activity index. In addition, abatacept was as safe as interleukin-6 (IL -6) and IL-1 inhibitors. However, both the efficacy and safety data in this systematic review should be reviewed with caution because their quality of evidence is low or very low. Further studies are needed to confirm the efficacy and safety of abatacept for systemic JIA, especially its efficacy on joint symptoms.

Ketamine for mood disorders, anxiety, and suicidality in children and adolescents: a systematic review.

Mood disorders, anxiety, and suicidality in youth are increasing and rapid-acting treatments are urgently needed. One potential is ketamine or its enantiomer esketamine, which was FDA approved in 2019 to treat major depressive disorder with suicidality in adults. This systematic review evaluated the evidence for the clinical use of ketamine to treat mood disorders, anxiety, and suicidality in youth. The PRISMA guidelines were used, and a protocol registered prospectively ( https://osf.io/9ucsg/ ). The literature search included Pubmed/MEDLINE, Ovid/MEDLINE, Scopus, CINAHL, PsychInfo, and Google Scholar. Trial registries and preprint servers were searched, and authors contacted for clarification. Studies reported on the clinical use of ketamine to treat anxiety, depression, bipolar disorder, or suicidality in youth ≤19years old and assessed symptoms before and after ketamine use. Study screening and data extraction were conducted independently by 2-4 authors. Safety, tolerability, and efficacy data were collected. The Cochrane Risk of Bias guidelines assessed the quality of the evidence. Twenty-two published reports based on 16 studies were identified: 7 case studies, 6 observational studies, 3 randomized trials, and 6 secondary data analyses. Studies reported immediate improvements in depression, anxiety, and suicidality. Improvements were maintained for weeks-months following treatment. Ketamine was well-tolerated with the most common side effects being dizziness, nausea, and mild dissociation. Transient hemodynamic changes were reported, all of which resolved quickly and did not require medical intervention. Initial evidence suggests ketamine is safe and may be effective for mood disorders, anxiety, and suicidality in youth. Further randomized trials are warranted.

Prostate Risk and Monitoring During Testosterone Replacement Therapy.

Men with hypogonadism have reduced risk of prostate cancer mortality; whether testosterone treatment increases the risk of prostate safety events in men with hypogonadism remains controversial. Several studies including four larger randomized trials-the Testosterone Trials, TEstosterone and Atherosclerosis Progression in Aging Men (TEAAM) Trial, Testosterone for Diabetes Mellitus Trial, and Testosterone Replacement therapy for Assessment of long-term Vascular Events and efficacy ResponSE in hypogonadal men (TRAVERSE) Trial-treated men with testosterone or placebo for one year or longer and reported prospectively-ascertained prostate safety data. The TRAVERSE Trial, because of its large size, longer duration, and adjudication of prostate events, has provided comprehensive data on the risk of adverse prostate events during TRT. Among men with hypogonadism, carefully screened to exclude those at high risk of prostate cancer, the incidences of high-grade or any prostate cancer, acute urinary retention, surgical procedure for benign prostatic hyperplasia, prostate biopsy, or new pharmacologic therapy for lower urinary tract symptoms were low and did not differ between the testosterone and placebo groups. Testosterone did not worsen lower urinary tract symptoms. TRT was associated with a greater increase in PSA than placebo in the first year of treatment. Conclusions: Testosterone treatment of men with hypogonadism, screened to exclude those at high risk of prostate cancer, is associated with low risk of adverse prostate events. Baseline evaluation of prostate cancer risk and a standardized monitoring plan can minimize the risk of unnecessary prostate biopsy while enabling the detection of high-grade prostate cancers in men receiving TRT.

Challenges and pitfalls of youth-onset type 2 diabetes.

The incidence and prevalence of youth-onset type 2 diabetes mellitus (T2DM) are increasing. The rise in frequency and severity of childhood obesity, inclination to sedentary lifestyle, and epigenetic risks related to prenatal hyperglycemia exposure are important drivers of the youth-onset T2DM epidemic and might as well be responsible for the early onset of diabetes complications. Indeed, youth-onset T2DM has a more extreme metabolic phenotype than adult-onset T2DM, with greater insulin resistance and more rapid deterioration of beta cell function. Therefore, intermediate complications such as microalbuminuria develop in late childhood or early adulthood, while end-stage complications develop in mid-life. Due to the lack of efficacy and safety data, several drugs available for the treatment of adults with T2DM have not been approved in youth, reducing the pharmacological treatment options. In this mini review, we will try to address the present challenges and pitfalls related to youth-onset T2DM and summarize the available interventions to mitigate the risk of microvascular and macrovascular complications.

Dupilumab Safety and Efficacy up to 1 Year in Children Aged 6 Months to 5 Years with Atopic Dermatitis: Results from a Phase 3 Open-Label Extension Study.

Pediatric patients with moderate-to-severe atopic dermatitis (AD) often experience a high disease burden and have a high risk of persistent disease. Standard-of-care immunosuppressive systemic treatments have been used off-label for AD in pediatric patients despite concerns for suboptimal safety with continuous use and risk of relapse upon discontinuation. The biologic agent dupilumab is the first systemic treatment approved for moderate-to-severe AD in children as young as 6 months. Long-term safety and efficacy data in this patient population are needed to inform continuous AD management. The purpose of this work was to determine the long-term safety and efficacy of dupilumab treatment up to 1 year in an open-label extension (OLE) study [LIBERTY AD PED-OLE (NCT02612454)] in children aged 6 months to 5 years with moderate-to-severe AD who previously participated in the 16-week, double-blind, phase 3 LIBERTY AD PRESCHOOL trial (NCT03346434 part B; parent study) and were subsequently enrolled in PED-OLE. In PED-OLE, patients received dupilumab every 4 weeks according to a weight-tiered regimen (body weight ≥ 5 kg to < 15 kg: 200 mg; ≥ 15 kg to < 30 kg: 300 mg). Data for 142 patients were analyzed, 60 of whom had completed the 52-week visit at time of database lock. Mean age at baseline was 4.1 y [SD, 1.13; range, 1.0-5.9 years]. A majority (78.2%) of patients reported ≥ 1 treatment-emergent adverse event (TEAE), most of which were mild or moderate and transient. The most frequently reported TEAEs were nasopharyngitis (19.7%), cough (15.5%), and pyrexia (14.1%). One TEAE led to treatment discontinuation (severe urticaria, which resolved in 1 day). By week 52, 36.2% of patients had achieved an Investigator's Global Assessment score of 0/1 (clear/almost clear skin), and 96.6%, 79.3%, and 58.6% had at least 50%, 75%, or 90% improvement, respectively, in Eczema Area and Severity Index scores. Consistent with results seen in adults, adolescents, and older children (aged 6-11 years), treatment with dupilumab for up to 1 year in children aged 6 months to 5 years with inadequately controlled moderate-to-severe AD demonstrated an acceptable long-term safety profile and sustained efficacy. These results support the long-term continuous use of dupilumab in this patient population. ClinicalTrials.gov Identifiers: NCT02612454 and NCT03346434 (part B).

Optimizing pediatric periprocedural pain management part I-Evolving ethics and topical anesthetics.

Pediatric procedure-related pain management is often incompletely understood, inadequately addressed, and critical in influencing a child's lifelong relationship with the larger health care community. We highlight the evolution of ethics and expectations around optimizing periprocedural pain management as a fundamental human right. We investigate the state-of-the-art of topical anesthetics, reviewing their mechanisms of action and providing comparisons of their relative safety and efficacy data to help guide clinical selection. In total, this two-part review offers a combination of conventional approaches and innovative techniques that should be used multimodally-in series and in parallel-to help optimize pain management and provide alternatives to sedation medication and general anesthesia.

Sensitivity of Daphnia spinulata Birabén, 1917 to glyphosate at different salinity levels.

Daphnia spinulata Birabén, 1917 is an endemic cladoceran species, frequent in the zooplankton communities of the shallow lakes of the Pampean region of Argentina. These lakes have varying salinity levels and, being located in agricultural areas, are frequently subject to pesticide pollution. This study aimed to determine the effects of the herbicide glyphosate (Panzer Gold®) in combination with different salinity levels on the biological parameters of D. spinulata and its recovery ability after a short exposure. Three types of assays were performed: an acute toxicity test, a chronic assessment to determine survival, growth and reproduction, and recovery assays under optimal salinity conditions (1g L-1). The LC50-48h of glyphosate was 7.5mg L-1 (CL 3.15 to 11.72). Longevity and the number of offspring and clutches were significantly reduced due to the combined exposure of glyphosate and increased salinity. The timing of the first offspring did not recover after glyphosate exposure. Our results reveal that D. spinulata is sensitive to the herbicide Panzer Gold® at concentrations well below those indicated in the safety data sheet of this commercial formulation, which causes stronger negative effects in conditions of higher salinity. Further research is needed to shed light on the sensitivity of this cladoceran to glyphosate and its variability under other interactive stress factors.

Real-world insights and outcomes related to ciclosporin A 0.1% cationic emulsion for the long-term treatment of dry eye disease in Germany: Country-level sub-analysis of the PERSPECTIVE study

Abstract Purpose The PERSPECTIVE study was a real-world European, non-interventional, multicenter, observational study that evaluated the effectiveness, tolerability, and safety of ciclosporin A (CsA) 0.1% cationic emulsion (CE) in routine clinical practice as a treatment for adults with severe keratitis and dry eye disease (DED) that remained insufficiently controlled with artificial tears. This sub-analysis examined data from ophthalmology clinics in Germany to provide more precise insights into treatment patterns, outcomes, and clinical decision-making related to CsA 0.1% CE. Methods Study data were collected from adults starting CsA 0.1% CE (one drop in both eyes at bedtime) and followed up at Week 4, 12, and 24, and Month 12. The primary endpoint was mean change from baseline in corneal fluorescein staining (CFS) score (Oxford Grade Scale) at Month 12. Secondary endpoints examined the severity of ocular signs and symptoms, and adverse events (AEs). Results A total of 236 patients from 20 ophthalmology clinics in Germany participated in the PERSPECTIVE study (69.9% female; mean age 60.8 years). Following treatment with CsA 0.1% CE, patients experienced significant reductions in CFS score from Week 4, which were maintained through to Month 12 (P &lt; 0.0001). From baseline, 81.6% of patients experienced an improvement in CFS score at Month 12. CsA 0.1% CE provided significant reductions in the severity of eyelid and conjunctival erythema at Month 12 compared with baseline (P &lt; 0.001), as well as significant reductions in the severity of subjective ocular symptoms (all P ≤ 0.015). Safety data were consistent with the known safety profile of CsA 0.1% CE. Tolerability was rated as “satisfactory,” “good,” or “very good” by 97.2% of physicians and 95.7% of patients. Conclusion Outcomes in Germany were similar to those reported for the overall European study population and are indicative of the treatment results that ophthalmologists may expect to see with CsA 0.1% CE treatment in real-life clinical practice. Treatment with CsA 0.1% CE provided long-term improvements over 12 months and was generally well tolerated.