Fibrosing colonopathy associated with cysteamine bitartrate delayed-release capsules in cystinosis patients.

BACKGROUND: The objective of this report is to identify and characterize cases of fibrosing colonopathy, a rare and underrecognized adverse event, associated with cysteamine delayed-release (DR) in patients with nephropathic cystinosis. METHODS: We searched the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS) and the medical literature for postmarketing reports of fibrosing colonopathy associated with cysteamine through August 2, 2023. RESULTS: We identified four cases of fibrosing colonopathy reported with the use of cysteamine DR. The time to onset ranged from 12 to 31 months. In one case, the patient required surgery to have a resection of a section of the strictured colon and a diverting ileostomy. Fibrosing colonopathy was diagnosed by histopathology in two of the cases. CONCLUSIONS: Our case series identified the risk of fibrosing colonopathy in patients taking cysteamine DR and prompted regulatory action by the FDA. As outlined in changes to the U.S. prescribing information for cysteamine DR, healthcare professionals should be aware of the potential risk of fibrosing colonopathy with cysteamine DR, especially as symptoms can be non-specific leading to misdiagnosis or delayed diagnosis. If the diagnosis of fibrosing colonopathy is confirmed, consideration should be given to permanently discontinuing cysteamine DR and switching to cysteamine immediate-release treatment.

Benchmarking a Molecular Flake Model on the Road to Programmable Graphene-Based Single-Atom Catalysts.

Single-atom catalysts (SACs) of embedding an active metal in nitrogen-doped graphene are emergent catalytic materials in various applications. The rational design of efficient SACs necessitates an electronic and mechanistic understanding of those materials with reliable quantum mechanical simulations. Conventional computational methods of modeling SACs involve using an infinite slab model with periodic boundary condition, limiting to the selection of generalized gradient approximations as the exchange correlation (XC) functional within density functional theory (DFT). However, these DFT approximations suffer from electron self-interaction error and delocalization error, leading to errors in predicted charge-transfer energetics. An alternative strategy is using a molecular flake model, which carved out the important catalytic center by cleaving C-C bonds and employing a hydrogen capping scheme to saturate the innocent dangling bonds at the molecular boundary. By doing so, we can afford more accurate hybrid XC functionals, or even high-level correlated wavefunction theory, to study those materials. In this work, we compared the structural, electronic, and catalytic properties of SACs simulated using molecular flake models and periodic slab models with first-row transition metals as the active sites. Molecular flake models successfully reproduced structural properties, including both global distortion and local metal-coordination environment, as well as electronic properties, including spin magnetic moments and metal partial charges, for all transition metals studied. In addition, we calculated CO binding strength as a descriptor for electrochemical CO2 reduction reactivity and noted qualitatively similar trends between two models. Using the computationally efficient molecular flake models, we investigated the effect of tuning Hartree-Fock exchange in a global hybrid functional on the CO binding strength and observed system-dependent sensitivities. Overall, our calculations provide valuable insights into the development of accurate and efficient computational tools to simulate SACs.

Characterization of Pediatric Reports in the US Food and Drug Administration Adverse Event Reporting System from 2010-2020: A Cross-Sectional Study.

INTRODUCTION: The Food and Drug Administration Adverse Event Reporting System (FAERS) is a database of adverse event (AE) and medication error reports for drugs and therapeutic biologics. Examining trends of reported individual case safety reports (ICSRs) provides context for evaluating safety concerns. OBJECTIVE: Characterize pediatric FAERS ICSRs and compare trends (1) to adult reports; (2) within pediatric subgroups. METHODS: This cross-sectional study examined FAERS ICSRs received between January 1, 2010, through December 31, 2020. Stratified age bands were neonates, infants, younger children, older children, adolescents, and adults. We characterized groups by patient demographic information, suspect products, AEs, and reporter type. RESULTS: From 2010 to 2020, there were 11,258,995 FAERS ICSRs; 3.1% described pediatric patients. Compared to adults, pediatric ICSRs had higher proportions of all serious outcomes except death. Within pediatric subgroups, neonates had the highest proportions of serious outcomes (96.2%) compared to infants, younger children, older children, and adolescents (79.8%, 67.9%, 59.5%, and 52.7%, respectively). Younger pediatric age groups were more likely to have weight information than older age groups but were less likely to include gender information. The most frequently reported AE was off label use for pediatrics and drug ineffective for adults. Products and AEs reported also differed among pediatric subgroups. Neonates, infants, and adolescents had entirely distinct sets of top five product-event combinations. CONCLUSION: Pediatric ICSRs represent a minority of FAERS reports but have distinctly different attributes relative to adult ICSRs. Reporting trends also vary within pediatric subgroups, which highlights the need for unique considerations for pediatric safety surveillance.

Assessment of the Impact of Mandated Postmarketing Pediatric-Focused Safety Reviews on Safety-Related Regulatory Actions 2013-2019.

The US Food and Drug Administration's (FDA's) routine postmarketing drug safety monitoring may lead to safety-related labeling changes for identified risks. Additionally, the Best Pharmaceuticals for Children Act (BPCA) and Pediatric Research Equity Act (PREA) require the FDA to conduct postmarket pediatric-focused safety reviews of adverse events. The purpose of these pediatric reviews is to identify risks associated with drug or biological products 18 months after the FDA approves a pediatric labeling change pursuant to studies conducted under the BPCA or PREA. These reviews are presented to the FDA Pediatric Advisory Committee (PAC) or publicly posted on FDA's website. The aim of this study was to evaluate the impact of pediatric reviews prompted by BPCA/PREA from October 1, 2013, to September 30, 2019. The impact was quantified by the number of new safety signals identified and the subsequent safety-related labeling changes resulting from pediatric reviews relative to safety-related labeling changes triggered by other data sources. Among 163 products with at least one pediatric review completed, a new safety signal that resulted in a safety-related labeling change was found for 5 of these products (representing 3 active ingredients); none described risks specific to the pediatric population. Between October 2013 and September 2021, there were 585 safety-related labeling changes implemented for products with at least one completed pediatric review. Less than 1% of 585 safety-related labeling changes were the result of a mandated pediatric review. Our study suggests that mandated pediatric reviews conducted 18 months after a pediatric labeling change provided minimal value over other postmarket safety surveillance activities.

Benzonatate Exposure Trends and Adverse Events.

BACKGROUND AND OBJECTIVES: Adverse events (AE), including death, occur in children with benzonatate use. This study aims to understand recent trends in benzonatate exposure and clinical consequences in pediatric patients. METHODS: This retrospective analysis of data from IQVIA pharmacy drug dispensing, National Poison Data System, National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance Project, FDA Adverse Event Reporting System, and the medical literature evaluated exposure trends and medication-related AEs with benzonatate. Trends for comparator narcotic and nonnarcotic antitussive medications were analyzed where possible for context. RESULTS: During the study period, pediatric benzonatate prescription utilization increased but remained low compared with pediatric utilization of dextromethorphan-containing prescription antitussive medications. Among the 4689 pediatric benzonatate exposure cases reported to US poison control centers from 2010 to 2018, 3727 cases (80%) were for single-substance exposures. Of these, 3590 cases (77%) were unintentional exposures and most involved children 0 to 5 years old (2718 cases, 83%). Cases involving intentional benzonatate exposure increased among children 10 to 16 years old with a more pronounced increase for multiple-substance exposures. Most benzonatate cases involving misuse or abuse were for children 10 to 16 years old (59 cases, 61%). The proportion of cases with serious adverse effects was low. There were few cases annually of serious AEs with benzonatate in children. CONCLUSIONS: There were rising patterns of unintentional ingestion of benzonatate in children 0 to 5 years old and intentional benzonatate ingestion in children 10 to 16 years old. Rational prescribing and improved provider and caregiver awareness of benzonatate toxic effects may reduce risks associated with benzonatate exposure.

Acute Hyperkinetic Movement Disorders as a Multifactorial Pharmacodynamic Drug Interaction Between Methylphenidate and Risperidone in Children and Adolescents.

PURPOSE/BACKGROUND: Acute hyperkinetic movement disorders have been reported with the concomitant use of attention-deficit/hyperactivity disorder (ADHD) stimulants and antipsychotics in children and adolescents. We analyzed postmarketing reports of suspected acute hyperkinetic movement disorder associated with concomitant use of ADHD stimulants and antipsychotics. METHODS/PROCEDURES: We searched for postmarketing reports of acute hyperkinetic movement disorders associated with concomitant use of ADHD stimulants-antipsychotics in the US Food and Drug Administration Adverse Event Reporting System through December 6, 2019. PubMed and EMBASE were also searched for acute hyperkinetic movement reports with the concomitant use of ADHD stimulants-antipsychotics through January 13, 2020. FINDINGS/RESULTS: We identified 36 cases resulting in acute hyperkinetic movement disorder associated with the concomitant use of ADHD stimulants-antipsychotics, 19 of which were also identified in the medical literature. From an ADHD stimulant perspective, methylphenidate products accounted for the largest number of cases (n = 23 [64%]), followed by amphetamine products (n = 9 [25%]) and atomoxetine (n = 4 [11%]). From an antipsychotic perspective, all 36 cases were reported with second-generation antipsychotics, particularly risperidone (n = 20 [56%]). Most of the cases were reported in boys (n = 31 [86%]) aged 6 to 12 years (n = 27 [75%]). Approximately 53% of the cases reported a time to onset within 24 hours of the drug change. Acute dystonic reactions (n = 27 [75%]) were the most frequently reported movement disorder. IMPLICATIONS/CONCLUSIONS: As outlined in changes to the US prescribing information for all methylphenidate and risperidone products, health care professionals should be aware that changes to this combination may be associated with a pharmacodynamic drug-drug interaction resulting in acute hyperkinetic movement disorder.

Leveraging Case Narratives to Enhance Patient Age Ascertainment from Adverse Event Reports.

INTRODUCTION: Missing age presents a significant challenge when evaluating individual case safety reports (ICSRs) in the FDA Adverse Event Reporting System (FAERS). When age is missing in an ICSR's structured field, it may be in the report's free-text narrative. OBJECTIVES: This study aimed to evaluate the performance and assess the potential impact of a rule-based natural language processing (NLP) tool that utilizes a text string search to identify patients' numerical age from unstructured narratives. METHODS: Using FAERS ICSRs from 2002 to 2018, we evaluated the annual proportion of ICSRs with age missing in the structured field before and after NLP application. Reviewers manually identified patients' age from ICSR narratives (gold standard) from a random sample of 1500 ICSRs. The gold standard was compared to the NLP-identified age. RESULTS: During the study period, the percentage of ICSRs missing age in the structured field increased from 21.9 to 43.8%. The NLP tool performed well among the random sample: sensitivity 98.5%, specificity 92.9%, positive predictive value (PPV) 94.9%, and F-measure 96.7%. It also performed well for the subset of ICSRs missing age in the structured field; when applied to these cases, NLP identified age for an additional one million ICSRs (10% of the total number of ICSRs from 2002 to 2018) and decreased the percentage of ICSRs missing age to 27% overall. CONCLUSIONS: NLP has potential utility to extract patients' age from ICSR narratives. Use of this tool would enhance pharmacovigilance and research using FAERS data.

The impact of a 'milking the COW' campaign in a regional hospital in Singapore.

BACKGROUND: Computerisation of various processes in hospitals and reliance on electronic devices raises the concern of contamination of these devices from the patient environment. We undertook this study to determine if an attached hand hygiene device that unlocks the screen of a computer on wheels (COW) on usage can be effective in decreasing the microbiological burden on computer keyboards. METHODS: An electronic hand sanitizer was integrated onto the COW. A prospective cohort study with a crossover design involving 2 control and 2 intervention wards was used. The study end point was the number of colony forming units found on the keyboards. Bacteria were classified into 4 main groups; pathogenic, skin flora, from the environment or those thought to be commensals in healthy individuals. We then used a mixed effects model for the statistical analysis to determine if there were any differences before and after the intervention. RESULTS: Thirty-nine keyboards were swabbed at baseline, day 7 and 14, with 234 keyboards cultured, colony forming units (CFUs) counted and organisms isolated. By mixed model analysis, the difference of mean bacteria count between intervention and control for week 1 was 32.74 (- 32.74, CI - 94.29 to 28.75, p = 0.29), for week 2 by 155.86 (- 155.86, CI - 227.45 to - 83.53, p < 0.0001), and after the 2-week period by 157.04 (- 157.04, CI - 231.53 to - 82.67, p < 0.0001). In the sub-analysis, there were significant differences of pathogenic bacteria counts for the Intervention as compared to the Control in contrast with commensal counts. CONCLUSION: A hand hygiene device attached to a COW may be effective in decreasing the microbiological burden on computer keyboards.

Association of Noninfectious Pneumonia With Ustekinumab Use.

Importance: The US Food and Drug Administration (FDA) conducts ongoing public health safety surveillance for drug and therapeutic biologic products. Identifying cases of acute and subacute noninfectious pneumonia supports the public health mission of the FDA. Objective: To identify and analyze postmarketing cases of noninfectious pneumonia associated with ustekinumab use. Design, Setting, and Participants: This retrospective analysis of postmarketing (spontaneous) case reports reviewed the FDA Adverse Event Reporting System (FAERS) and the PubMed databases from September 25, 2009, through November 20, 2017. Twelve cases of new-onset acute and subacute noninfectious pneumonia were identified after general marketing of ustekinumab. Cases were excluded if the time to symptom onset was more than 2 years from ustekinumab initiation and if an alternative origin for the noninfectious pneumonia (other than drug-induced) was reported. Main Outcomes and Measures: Cases of noninfectious pneumonia associated with ustekinumab use were analyzed for baseline and demographic information, reason for ustekinumab use, symptoms, time to onset, dose sequence, laboratory and diagnostic information, and clinical outcome. Results: Of the 12 cases, 8 were identified from the FAERS database and 4 from PubMed. The 12 cases (7 men [58%] and 5 women [42%], with a median [range] age of 63 [27-80] years) included 7 interstitial pneumonia (58%), 3 eosinophilic pneumonia (25%), 1 organizing pneumonia (8%), and 1 hypersensitivity pneumonitis (8%) diagnoses. All 12 cases reported a serious outcome, including 7 hospitalizations (58%) and 1 respiratory failure requiring mechanical ventilation (8%). No outcome of death was reported. All 12 cases were supportive of a temporal association; specifically, in 9 cases (75%), the pulmonary symptoms appeared after 1 to 3 doses of ustekinumab. In addition, 7 cases (58%) of positive dechallenge were reported, including 1 case of a positive rechallenge. Conclusions and Relevance: The postmarketing cases suggest an association between noninfectious pneumonia and use of ustekinumab; these findings have led to the addition of a new warning for ustekinumab users regarding the risk of developing noninfectious pneumonia.

Chemical Leukoderma Associated with Methylphenidate Transdermal System: Data From the US Food and Drug Administration Adverse Event Reporting System.

OBJECTIVE: To identify and characterize cases of chemical leukoderma, an underrecognized adverse event, associated with the methylphenidate transdermal system (MTS) reported to the US Food and Drug Administration Adverse Event Reporting System (FAERS). STUDY DESIGN: We searched the Food and Drug Administration Adverse Event Reporting System for reports of chemical leukoderma associated with MTS, received by the Food and Drug Administration from April 6, 2006 to December 23, 2014. RESULTS: We identified 51 cases of chemical leukoderma reported with the use of MTS. The median age was 11 years; 43 cases reported leukoderma at or near the application site only, and 7 reported leukoderma at other parts of the body in addition to the application site; 1 case did not provide enough information to confirm the affected site. The time to onset ranged from 2 months to 4 years after the initiation of MTS. MTS was discontinued in 31 cases. Thirteen patients were prescribed treatment for repigmentation. Three cases reported continued spread of leukoderma after MTS was discontinued. Nineteen cases were diagnosed as vitiligo, including 5 cases reporting histologic features consistent with vitiligo. Leukoderma was persistent in all cases. The median follow-up interval after the discontinuation of MTS in 23 cases was 14 months. CONCLUSIONS: As outlined in recent changes to the prescribing information for MTS, health care professionals need to be aware of the potential risk of chemical leukoderma caused by MTS, especially given that chemical leukoderma is often misdiagnosed as idiopathic vitiligo. MTS should be discontinued at the earliest sign of pigment loss and other treatment options considered.

Profilaxis antimicrobiana en cirugía ortopédica: cefazolina vs cefadroxilo IV / Antimicrobial prophylaxis in orthopedic surgery: cefazolina vs cefadroxilo IV

Toda intervención quirúrgica está expuesta a infectarse. La necesidad de profilaxis antimicrobiana en cirugía ortopédica para casos quirúrgicos agudos o electivas de cirugías limpias ha sido establecida como procedimiento de rutina. En Cirugía Ortopédica y Traumatología cuando se requiere el uso de implantes metálicos con el fin de realizar osteosíntesis o sustitución de las superficies articulares, aumenta el riesgo de infección, por tratarse de materiales extraños que son introducidos en el organismo. En estos casos la antibióticoterapia preventiva es de primordial importancia. Se realizó un estudio de profilaxis antimicrobiana, multicéntrico, aleatorizado, prospectivo, doble ciego, comparativo de grupos paralelos, con el fin de evaluar la eficacia de Cefadroxilo I.V. Vs. Cefazolina I.V. como antibióticos profilácticos mediante la determinación del número de pacientes infectados en cirugía de fracturas cerradas en la cuales se colocó material de síntesis. Se completaron 58 pacientes, 34 en el grupo de cefadroxilo y 24 en el grupo de cefazolina, al inicio los grupos fueron similares en cuanto a edad, sexo, tipo de fractura, tiempo de intervención, tiempo entre la fractura y la intervención.Más pacientes en el grupo de cefadroxilo tenían el tiempo máximo autorizado entre la fractura y la intervención (p: 0,07). Se presentó en el grupo de cefadroxilo una infección de la herida operatoria y un caso de eritema leve que cedió con tratamiento oral con cefadroxilo, sin diferencias entre los grupos.Hubo tres casos de eventos adversos, reacción anafiláctica a las 48 horas en el grupo de cefazolina que ameritó finalización de protocolo y hematoma en miembro inferior derecho y, en el grupo de cefadroxilo, una elevación discreta de enzimas hepáticas. La respuesta terapéutica de profilaxis antimicrobianano mostró diferencia entre los grupos. El cefadroxilo es tan eficaz como la cefazolina para la profilaxis antimicrobiana en pacientes con fracturas...

Any operation is exposed to infection. The need for antimicrobial prophylaxis in orthopedic surgery for acute or elective surgical cases of clean surgery is established as a routine procedure. Orthopedic Surgery when required the use of metallic implants in order to perform internal fixation or replacement of the articular surfaces, increases the risk of infection because they are foreign materials are introduced into the body. In these cases, preventive antibiotic therapy is very important. We performed a study of antimicrobialprophylaxis multicenter, randomized, prospective, double-blind, parallel group comparison in order to evaluate the effectiveness of Cefadroxil IV vs. Cefazolin I.V. as prophylactic antibiotics by determining the number of infected patients after fracture surgery in which synthetic material was placed. Fifty eigth patients were completed, 34 in the cefadroxil group and 24 in the cefazolin group, at the beginning the groups were similar in age, sex, fracture type, operative time, time between fracture and surgery. More patients in the cefadroxil group had the maximum allo-wable time between the fracture and surgery. (P: 0.07). In the cefadroxil group we found a wound infection and one case of mild erythema which resolved with oral treatment with cefadroxil, without differences between groups. There were three cases of adverse events, anaphylactic reaction to cefazolin at 48 h in the group that required finalization of protocol and hematoma in right leg and in the cefadroxil group, a moderate increase in liver enzymes. The therapeutic response of antimicrobial prophylaxis showed no difference between groups. Cefadroxil is as effective as cefazolin for antimicrobial prophylaxis in patients with fractures that warrant placement of synthetic material

Intestinal mucosa remodeling by recombinant human epidermal growth factor(1-48) in neonates with severe necrotizing enterocolitis.

BACKGROUND AND AIMS: Neonatal necrotizing enterocolitis (NEC) is a common and serious acquired gastrointestinal tract condition. This clinical study assessed the potential clinical efficacy and microscopic effects of recombinant human epidermal growth factor 1-48 (EGF(1-48)) in neonates with NEC. METHODS: This prospective, double-blind, randomized controlled study included 8 neonates with NEC. The study compared the effects of a 6-day continuous intravenous infusion of EGF(1-48) at 100 ng kg(-1) h(-1) against placebo. Clinical outcomes and morphological evaluation of serial rectal mucosal biopsies were assessed at baseline and 4, 7, and 14 days after starting EGF infusions. RESULTS: There was no difference between the clinical safety outcomes recorded for EGF(1-48) or placebo patients. Quantitative morphologic differences in the rectal mucosa biopsies were noted with EGF(1-48) treatment compared with baseline or placebo and included a statistically significant increase in the number of mitoses per mucosal crypt on study day 4, significantly increased thickness of rectal mucosa from baseline on study days 4 and 7, and increased crypt surface area of rectal mucosa in parallel with increased mucosa thickness on day 14. CONCLUSION: This study of EGF(1-48) in neonates with severe NEC showed that growth factor treatment was well tolerated and produced positive and measurable remodeling trophic effects on the gastrointestinal mucosa.