US Food Research Articles

Understanding the mechanisms of food effect on omaveloxolone pharmacokinetics through physiologically based biopharmaceutics modeling.

Omaveloxolone is a nuclear factor (erythroid-derived 2)-like 2 activator approved in the United States and the European Union for the treatment of patients with Friedreich ataxia aged ≥16 years, with a recommended dosage of 150 mg orally once daily on an empty stomach. The effect of the US Food and Drug Administration (FDA) high-fat breakfast on the pharmacokinetic profile of omaveloxolone observed in study 408-C-1703 (NCT03664453) deviated from the usual linear correlation between fed/fasted maximum plasma concentration (Cmax) and area under the concentration-time curve (AUC) ratios reported for various oral drugs across 323 food effect studies. Here, physiologically based biopharmaceutics modeling (PBBM) was implemented to predict and explain the effect of the FDA high-fat breakfast on a 150-mg dose of omaveloxolone. The model was developed and validated based on dissolution and pharmacokinetic data available across dose-ranging, food effect, and drug-drug interaction clinical studies. PBBM predictions support clinical observations of the unique effect of a high-fat meal on omaveloxolone pharmacokinetic profile, in which the Cmax increased by 350% with only a 15% increase in the AUC. Key parameters influencing omaveloxolone pharmacokinetics in the fasted state based on a parameter sensitivity analysis included bile salt solubilization, CYP3A4 activity, drug substance particle size distribution, and permeability. Mechanistically, invivo omaveloxolone absorption was solubility and dissolution rate limited. However, in the fed state, higher bile salt solubilization led to more rapid dissolution with predominant absorption in the upper gastrointestinal tract, resulting in increased susceptibility to first-pass gut extraction; this accounts for the lack of correlation between Cmax and AUC for omaveloxolone.

Nonalcoholic steatohepatitis/metabolic dysfunction-associated steatohepatitis emerging market: Preparing managed care for early intervention, equitable access, and integrating the patient perspective.

Nonalcoholic steatohepatitis (NASH)/metabolic dysfunction-associated steatohepatitis (MASH) is an advanced form of liver disease that can lead to significant morbidity and mortality primarily due to hepatic complications including fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure, as well as cardiovascular disease. As the development of NASH/MASH is closely linked to cardiometabolic risk factors such as obesity and type 2 diabetes mellitus, its prevalence is increasing along with the prevalence of those conditions. Identifying at-risk patients or those early in the disease process is essential to optimizing care and may prevent future complications. Current treatment options include disease-modifying interventions, off-label use of US Food and Drug Administration (FDA)-approved medications for comorbid conditions, and resmetirom, the recently first-ever FDA-approved medication specifically for use in NASH/MASH. There is also considerable continued activity in related drug development research with several other potential emerging treatments. With the increasing prevalence of NASH/MASH and emerging treatments, it is important for managed care organizations (MCOs) to be prepared to assist in patient care and implement equitable treatment management. Understanding patient perspectives and their experience with NASH/MASH provides insights for MCOs such as the need for education of both health care providers and patients to encourage early diagnosis and for enhancing access to individualized care including resources and support. Additionally, MCOs can consider potential management strategies for new and emerging treatments.

Screening Potential Cornea Donors for Signs of Sepsis

Purpose: This study sought to expand upon previous works to explore correlations between cornea donor characteristics and incidence of sepsis/donor ineligibility. Methods: The medical records of 837 potential cornea donors with signs of possible sepsis from 2 Eye Bank Association of America–accredited eye banks between 2009 and 2022 were reviewed by an infectious disease clinician consultant for US Food and Drug Administration-designated signs of sepsis. Data and machine learning analysis were performed to explore relationships between different donor features and donor eligibility. Results: A review of the potential cornea donor records revealed that the presence of a greater number of signs of sepsis was not associated with a higher probability of donor ineligibility (P = 0.45). The only single sign of sepsis that was associated with a higher likelihood of donor ineligibility determination was positive blood cultures (P < 0.001). Finally, if the patient's length of hospitalization was less than 24 hours, these potential donors were more likely to be deemed ineligible for cornea donation (P < 0.001). Machine learning analysis revealed length of hospitalization to be the most importantly weighted factor in determining donor eligibility. Conclusions: Based on our analysis of hundreds of medical records over more than a decade, the data suggest that potential cornea donors who 1) have a positive blood culture or 2) have a length of stay of less than 24 hours may be reasonably deemed likely not eligible for donation and not all forwarded to infectious disease consultants or their respective medical director. The results of this study call for further exploration with the collection of larger sample sizes and more representative populations of cornea donors to pursue potential protocols with respect to determining cornea donor eligibility.

Quintessence of currently approved and upcoming treatments for dry eye disease.

Dry eye disease (DED), also known as dry eye syndrome, is a multifactorial ocular surface disease. The aim of this review is to present the details of currently approved and upcoming treatment options for DED in a nutshell. We conducted a thorough literature search using PubMed and searched US FDA website, clinicaltrials.gov, and data available in public domain for currently approved and upcoming treatment options for DED. Currently, the US Food and Drug Administration (FDA)-approved medical treatments for treatment of DED include cyclosporine formulations (RESTASIS® [cyclosporine 0.05% ophthalmic emulsion], VEVYE® [cyclosporine 0.1% ophthalmic solution], and CEQUA™ [cyclosporine 0.09% ophthalmic solution]), XIIDRA® (lifitegrast), a leukocyte function-associated antigen-1 (LFA-1)/intracellular adhesion molecule-1(ICAM-1) inhibitor, EYSUVIS™ (loteprednol etabonate ophthalmic suspension 0.25%), a corticosteroid, and MIEBO™ (perfluorohexyloctane ophthalmic solution), a semifluorinated alkane. TYRVAYA™ (varenicline solution nasal spray), a cholinergic agonist, is another formulation approved for the treatment of the signs and symptoms of DED. The medical devices approved for treating DED due to meibomian glands dysfunction (MGD) include Lumenis OptiLight™ (intense pulsed light [IPL] device), TearCare® system, and TearScience™ LipiFlow™ thermal pulsation system. Punctal plugs are another treatment option approved for management of DED. There are hundreds of clinical studies evaluating newer treatments for managing the signs and symptoms. Cyclosporine formulations TJO-087 (cyclosporine A nanoemulsion 0.08%), SCAI-001 eye drops (cyclosporine 0.01%, 0.02%) are being evaluated against RESTASIS® and other approved treatments. The potential treatments being assessed include IC 265, OK-101, PL9643, SYL1001 (tivanisiran), SHJ002, OXERVATE® (cenegermin-bkbj ophthalmic solution 0.002%), HBM9036 (tanfanercept ophthalmic solution), OCS-02 (licaminlimab), MIM-D3 (tavilermide ophthalmic solution 5%), AR-15,512, BRM421, reproxalap, and AZR-MD-001 (selenium sulphide ointment 0.5%). The pathophysiology of DED is complex and multifactorial; there is a need to understand it even deeper. The new treatments and different delivery systems seem promising and provide a hope of effective treatment for DED.

Pasture-finishing of cattle in Western U.S. rangelands improves markers of animal metabolic health and nutritional compounds in beef.

As environmental and health concerns of beef production and consumption mount, there is growing interest in agroecological production methods, including finishing beef cattle on pastures with phytochemically diverse grasses, forbs, and/or shrubs. The goal of this metabolomics, lipidomics, and fatty acid methyl ester profiling study was to compare meat (pectoralis profundus) of Black Angus cattle from two commercial US beef finishing systems (pasture-finished on Western U.S. rangeland; n = 18 and grain-finished in a Midwest U.S. feedlot; n = 18). A total of 907 out of 1575 compounds differed in abundance between pasture-finished and grain-finished beef samples (all, false discovery rate adjusted P < 0.05). Pasture-finished beef contained higher levels of phenolic antioxidants (2.6-fold), alpha-tocopherol (3.1-fold), nicotinate/vitamin B3 (9.4-fold), choline (1.2-fold), myo-inositol (1.8-fold), and omega-3 fatty acids (4.1-fold). Grain-finished beef contained higher levels of gamma-tocopherol (14.6-fold), nicotinamide/vitamin B3 (1.5-fold), pantothenate/vitamin B5 (1.3-fold), and pyridoxine/vitamin B6 (1.3-fold); indicating that feeding some grain (by-products) could be beneficial to increase levels of certain B-vitamins. Pasture-finished beef samples also displayed lower levels of oxidative stress (homocysteine, 0.6-fold; and 4-hydroxy-nonenal-glutathione, 0.4-fold) and improved mitochondrial function (1.3-fold) compared to grain-finished animals. Two potential metabolites of fluoroquinolone antibiotics, 2,8-quinolinediol and 2,8-quinolinediol sulfate, were only observed in grain-finished beef, though the source remains unknown. While pasture-finished cattle displayed improved markers of metabolic health and concentrated additional, potentially health-promoting compounds in their meat, our findings should not be interpreted as that grain-finished beef is unhealthy to consume. Randomized controlled trials in humans are required to further assess whether observed differences between pasture-finished and feedlot-finished beef have an appreciable effect on human health.

Greenhouse gas emissions in US beef production can be reduced by up to 30% with the adoption of selected mitigation measures.

Greenhouse gas (GHG) emissions from beef production in the United States are unevenly distributed across the supply chain and production regions, complicating where and how to reduce emissions most effectively. Using spatially explicit life cycle assessment methods, we quantify the baseline GHG emissions and mitigation opportunities of 42 practices spanning the supply chain from crop and livestock production to processing. We find that the potential to reduce GHGs across the beef sector ranges up to 30% (20 million tonnes CO2e reduced and 58 million tonnes CO2 sequestered each year relative to the baseline) under ubiquitous adoption assumptions, largely driven by opportunities in the grazing stage. Opportunities to reduce GHGs in the feed, grazing and feedlot stages vary across regions, yet large-scale adoption across the entire beef supply chain is important. These findings reveal promising locations and practices to invest in to advance mitigation goals and an upper-end theoretical potential for mitigation in the beef industry.

Efficacy and Safety of Long-Acting Subcutaneous Lenacapavir in Heavily Treatment-Experienced People with Multi-Drug Resistant HIV-1: Week 104 Results of a Phase 2/3 Trial.

Lenacapavir is a long-acting HIV-1 capsid inhibitor for treatment of HIV-1 infection. We evaluated the efficacy and safety of lenacapavir in combination with an investigator-selected optimized background regimen (OBR) after 104 weeks in adults with multidrug-resistant HIV-1. This ongoing, international, Phase 2/3 trial at 42 sites included 72 adults living with multidrug-resistant HIV-1. Following a 2-week oral lenacapavir loading phase, participants received subcutaneous lenacapavir every 26 weeks with an OBR. HIV-1 RNA, CD4 cell counts, and adverse events were assessed over 104 weeks. One participant did not enter the extension phase. At Week 104, 44 of 71 participants (62%, 95% CI 50; 73) had HIV-1 RNA <50 copies/mL via US Food & Drug Administration (FDA) snapshot algorithm. When missing data (including discontinuations) were excluded, 44 of 54 participants (82%) had HIV-1 RNA <50 copies/mL at Week 104, mean CD4 cell count increased by 122 cells/µL (95% CI 80; 165), and the proportion of participants with CD4 cell count <200 cells/µL decreased from 64% (46 of 72) at Baseline to 29% (16 of 55). Fourteen participants had treatment-emergent lenacapavir resistance; seven resuppressed (HIV-1 RNA <50 copies/mL) while maintaining lenacapavir use. There were no Grade 4 or serious treatment-related adverse events. One participant discontinued study drug due to an injection site reaction. Treatment with subcutaneous lenacapavir in combination with an OBR was well tolerated and resulted in a high rate of virological suppression over 104 weeks. Lenacapavir represents an important treatment option in people with multidrug-resistant HIV-1.

Occurrence of Low Cardiac Index During Normotensive Periods in Cardiac Surgery: A Prospective Cohort Study Using Continuous Noninvasive Cardiac Output Monitoring.

Continuous cardiac output monitoring is not standard practice during cardiac surgery, even though patients are at substantial risk for systemic hypoperfusion. Thus, the frequency of low cardiac output during cardiac surgery is unknown. We conducted a prospective cohort study at a tertiary medical center from July 2021 to November 2023. Eligible patients were ≥18 undergoing isolated coronary bypass (CAB) surgery with the use of cardiopulmonary bypass (CPB). Cardiac output indexed to body surface area (CI) was continuously recorded at 5-second intervals throughout surgery using a US Food and Drug Administration (FDA)-approved noninvasive monitor from the arterial blood pressure waveform. Mean arterial blood pressure (MAP) and central venous pressure (CVP) were also analyzed. Low CI was defined as <2 L/min/m2 and low MAP as <65 mm Hg. We calculated time with low CI for each patient for the entire surgery, pre-CPB and post-CPB periods, and the proportion of time with low CI and normal MAP. We used Pearson correlation to evaluate the relationship between CI and MAP and paired Wilcoxon rank sum tests to assess the difference in correlations of CI with MAP before and after CPB. In total, 101 patients were analyzed (age [standard deviation, SD] 64.8 [9.8] years, 25% female). Total intraoperative time (mean [SD]) with low CI was 86.4 (62) minutes, with 61.2 (42) minutes of low CI pre-CPB and 25.2 (31) minutes post-CPB. Total intraoperative time with low CI and normal MAP was 66.5 (56) minutes, representing mean (SD) 69% (23%) of the total time with low CI; 45.8 (38) minutes occurred pre-CPB and 20.6 (27) minutes occurred post-CPB. Overall, the correlation (mean [SD]) between CI and MAP was 0.33 (0.31), and the correlation was significantly higher pre-CPB (0.53 [0.32]) than post-CPB (0.29 [0.28], 95% confidence interval [CI] for difference [0.18-0.34], P < .001); however, there was substantial heterogeneity among participants in correlations of CI with MAP before and after CPB. Secondary analyses that accounted for CVP did not alter the correlation between CI and MAP. Exploratory analyses suggested duration of low CI (C <2 L/min/m2) was associated with increased risk of postoperative acute kidney injury (odds ratios [ORs] = 1.09; 95% CI; 1.01-1.13; P = .018). In a prospective cohort of patients undergoing CAB surgery, low CI was common even when blood pressure was normal. CI and MAP were correlated modestly. Correlation was higher before than after CPB with substantial heterogeneity among individuals. Future studies are needed to examine the independent relation of low CI to postoperative kidney injury and other adverse outcomes related to hypoperfusion.

Effects of renal denervation on the incidence and severity of cardiovascular diseases.

Renal denervation (RDN) is a neuromodulation therapy performed in patients with hypertension using an intraarterial catheter. Recent randomized sham-controlled trials have shown that RDN has significant antihypertensive effects that last for more than 3 years. Based on this evidence, the US Food and Drug Administration has approved two devices, the ultrasound-based ReCor ParadiseTM RDN system and the radiofrequency-based Medtronic Symplicity SpyralTM RDN system, as adjunctive therapy for patients with refractory and uncontrolled hypertension. On the other hand, there have been no randomized sham-controlled prospective outcome trials on RDN, and the effects of RDN on cardiovascular events such as myocardial infarction, heart failure, and stroke have not been elucidated. This mini-review summarizes the latest findings focusing on the effects of RDN on organ protection and physiological function and symptoms in both preclinical and clinical studies. Furthermore, the feasibility of using blood pressure as surrogate marker for cardiovascular outcomes is discussed in the context of relevant clinical studies on RDN. A comprehensive understanding of the beneficial effects of RDN on the incidence and severity of cardiovascular diseases with their underlying mechanisms will enhance physicians' ability to incorporate RDN into clinical strategies to prevent cardiovascular events including myocardial infarction, heart failure, and stroke. This mini-review focuses on the effects of RDN on organ protection and physiological function and symptoms in preclinical and clinical studies. RDN is expected to reduce the onset and progression of cardiovascular diseases including myocardial infarction, heart failure, and stroke in clinical practice.LV left ventricular, LVEF left ventricular ejection fraction, VO2max maximal oxygen uptake, VT ventricular tachycardia, VF ventricular fibrillation, 6MWD 6-min walk distance, NT-proBNP N-terminal pro-B-type natriuretic peptide, NYHA New York Heart Association, BBB blood-brain barrier, BP blood pressure.

A real-world pharmacovigilance study of KRAS G12C mutation inhibitors based on the food and drug administration adverse event reporting system

IntroductionSotorasib and adagrasib have been widely used for the non-small cell lung cancer (NSCLC) patients harboring Kirsten rat sarcoma viral oncogene homolog (KRAS) G12C mutation. It's necessary to assess their safety profiles in the real-world population.MethodsA retrospective pharmacovigilance was conducted to examine adverse events (AEs) associated with sotorasib and adagrasib therapies using the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS). Disproportionality analysis was performed employing Venn analysis and four data-mining algorithms, including the reporting odds ratio (ROR), the proportional reporting ratio (PRR), the Bayesian confidence propagation neural network (BCPNN), and the multi-item gamma Poisson shrinker (MGPS).ResultsThe most commonly reported system organ classes (SOCs) for both adagrasib and sororasib were general, gastrointestinal, and investigations disorders. Notably, sotorasib exhibited significant signals for neoplasms and hepatobiliary disorders in four algorithms. Specifically, AEs related to neoplasms were predominantly associated with lung malignancies, all of which were consistent with the therapeutic indications of KRAS G12C mutation inhibitor. A total of 19 common AEs were identified in sotorasib and adagrasib, spanning gastrointestinal, general, hepatobiliary, investigations, metabolism, musculoskeletal, neoplasms, and respiratory disorders. 4 severe AEs (SAEs) were identified in sotorasib, with 3 SAEs displaying significant signals in four algorithms, including drug-induced liver injury, pancreatitis, and hepatic failure. In adagrasib, only 2 SAEs were detected, with renal failure showing significant signals in four algorithms.ConclusionThis study offers a comprehensive evaluation of the major safety signals associated with sotorasib and adagrasib, providing valuable information for clinicians regarding drug selection and safety considerations, thereby facilitating the design of future prospective safety studies.

Premarket Pivotal Trial End Points and Postmarketing Requirements for FDA Breakthrough Therapies

The US Food and Drug Administration (FDA) awards the breakthrough therapy designation to expedite development and review of therapeutics intended to treat serious conditions when preliminary clinical evidence demonstrates potential substantial improvement over existing therapies on clinically significant end points. Under the 21st Century Cures Act of 2016, the FDA is required to publish and routinely update a list of surrogate markers to provide industry sponsors with indication-specific information about end points that were or may be considered for approval. Therapeutics that are granted breakthrough therapy designation can receive accelerated or traditional approval; however, little is known about those approved through the latter pathway, where postmarketing confirmatory studies are typically not required, regardless of the end point used. To evaluate the primary end points used in premarket pivotal trials supporting FDA breakthrough therapy-designated approvals and to determine whether postmarketing studies confirming efficacy were required for approvals based on pivotal trials using surrogate markers as primary end points. This cross-sectional study used data from the Drugs@FDA database for all original breakthrough therapy-designated approvals from inception to December 31, 2023, in the US. The first designation was approved on November 1, 2013. Data analysis was performed in January 2024. Descriptive analyses were used to characterize the breakthrough therapy-designated indication approval pathways, the primary end points of pivotal efficacy trials, and their postmarketing requirements or commitments. From 2013 to 2023, the FDA approved 157 original indications with breakthrough therapy designation. Of these, 52 (33%) were granted accelerated approval and 105 (67%) were granted traditional approval. All accelerated approvals were based on pivotal trials using surrogate markers as primary end points and had FDA-required postmarketing studies to confirm efficacy. Of these 52 indications, 51 (98%) were approved based on surrogate end points listed in the FDA table of surrogate end points for the same indication. Among traditional approvals, 61 (58%) were based on pivotal trials using surrogate markers as primary end points, of which 4 (7%) had FDA-required postmarketing studies to confirm efficacy and 39 (64%) were approved based on surrogate end points listed in the FDA table for the same indication. In this cross-sectional study of original FDA breakthrough therapy-designated approvals from 2013 to 2023, trials supporting these approvals often used surrogate markers as primary end points (even when not approved via accelerated approval) and lacked FDA-required postmarketing studies to verify clinical benefit. These findings suggest that requiring postmarketing studies for breakthrough therapy-designated indications approved based on surrogate markers, regardless of approval pathway, may increase patient and clinician certainty of the expected clinical benefit.

Phosphodiesterase-5 inhibitors and hearing impairment: a disproportionality analysis using the US food and drug administration adverse event reporting system

ABSTRACT Background This study aimed to investigate the association between phosphodiesterase-5 inhibitors (PDE-5i) and hearing impairment adverse events (HIAEs) while providing an overview of the characteristics of drug-related HIAEs. Research design and methods We conducted a detailed pharmacovigilance analysis using data from the US Food and Drug Administration Adverse Event Reporting System (FAERS) database, covering 2004 to 2022. By calculating the reporting odds ratio (ROR) and the information component (IC), we identified signals that indicate the association between PDE-5i use and HIAEs. Results Among the 191,398 reports related to PDE-5i, we identified 2,608 cases of HIAEs. Signals were observed for both PDE-5i monotherapy and polytherapy, indicating combinations of drugs. Avanafil exhibited the strongest signal (ROR: 4.35, 95% CI: 2.56–7.41, IC: 2.09, 95% CI: 0.10–3.51), while vardenafil showed the weakest signal (ROR: 2.69, 95% CI: 2.21–3.28, IC: 1.14, 95% CI: 0.74–2.04). Sildenafil had the highest reported cases (ROR: 3.03, 95% CI: 2.82–3.24, IC: 1.57, 95% CI: 1.34–1.80). Conclusion These findings highlight a significant correlation between PDE-5i use and HIAEs, emphasizing the need for careful evaluation in clinical practice and providing appropriate guidance to patients before initiating treatment.

Systematic analysis of the adverse effects of commonly used clinical tetracycline drugs based on the FAERS database

ABSTRACT Background Tetracyclines are a class of antibacterial drugs commonly used in clinical practice, but there is no systematic analysis of the adverse effects (AEs) of these drugs. We performed such pharmacovigilance analyses using the US Food and Drug Administration Adverse Event Reporting System (FAERS) database to explore tetracycline-related AEs. Research design and methods We used the pharmacovigilance analysis tool Open Vigil 2.1 to access FAERS data and obtained AE reports from January 2004 to June 2023, including doxycycline, minocycline, tigecycline, omadacycline, sarecycline, and eravacycline as the top suspect drugs. The signal value of the AE of the analyzed drug was calculated by the reporting odds ratio (ROR). Results A total of 15,020 cases were identified by analyzing drugs. In terms of adverse signals, doxycycline caused gastrointestinal mucosal necrosis (ROR = 1699.652); minocycline was reported to cause bone hyperpigmentation (ROR = 30976.223); tigecycline is responsible for blood fibrinogen decreased (ROR = 1714.078). Conclusions AE reports of tetracycline drugs varied significantly. We found some AEs not mentioned in the instruction, such as the ototoxicity of tetracyclines. Doxycycline was associated with psychiatric side effects; minocycline presented in thyroid and skin tissue-associated tumors; abnormal signals were detected with eravacycline in the blood system.

Assessment of the potential nutritional value of cell-cultured chicken meat in light of European dietary recommendations

In 2023, the United States Department of Agriculture approved cell-cultured chicken meat (CCM) made with animal cell culture technology; similar applications may soon be submitted for assessment in Europe. This study employed data submitted to the US Food and Drug Administration to re-evaluate the nutritional and safety of CCM manufactured by one US-based company in the light of European Union recommendations. Compared to conventional chicken meat, serum-free CCM revealed lower content of protein, and the majority of indispensable amino acid contents, Mg, and vitamin B3, but higher levels of total fat, saturated fatty acids, cholesterol, vitamins B5, B6, and A, and minerals Ca, Cu, Fe, K, Mn, Na, P, Se, and Zn. Toxic elements (As, Cd, Pb, Hg) did not exceed allowance thresholds, though serum-free CCM had higher levels of Cd and Pb than conventional chicken meat. Although this first assessment of CCM generally falls within the European Union requirements, it is crucial to optimize the reproducibility of the production process due to observed variabilities in nutrient levels between tested lots. This study represents a re-evaluation of CCM offered by a single product, yet it should not be extrapolated to the entire field of cultured meat.

Cardiovascular adverse events associated with PARP inhibitors for ovarian cancer: a real world study (RWS) with Bayesian disproportional analysis based on the FDA adverse event reporting system (FAERS)

ABSTRACT Background To investigate the pharmacovigilance (PV) and make pairwise comparisons on reporting proportion, seriousness, and severity of outcomes of major adverse cardiovascular events (MACE) among poly(ADP-ribose) polymerase-inhibitors (PARPis) in treating ovarian cancer, fallopian tube carcinoma, and primary peritoneal cancer (collectively named EOC) from the US Food and Drug Administration Adverse Event Reporting System (FAERS). Research design and methods Data on adverse cardiovascular events reports related to EOC treatment submitted to FAERS from the first quarter of 2015 to the second quarter of 2023 were harvested. Three PARPis were identified: olaparib, niraparib, and rucaparib. Results Eventually, a total of 258,596 eligible records were enrolled with 12,331 reports including 5,292 reports of MACE and 7,039 reports of other cardiovascular events. For the primary composite endpoint, a PV signal associated with MACE was detected in niraparib (ROR = 1.12; IC025 = 0.03), whereas it was not detected in olaparib and rucaparib; For the secondary endpoint, PV signals associated with other cardiovascular events were detected in niraparib (ROR = 1.17;IC025 = 0.04), but not in olaparib and rucaparib. Conclusions For EOC patients, close monitoring of blood pressure, heart rate, and coagulation function should be conducted when selecting niraparib for treatment.

Pathways for the US food processing sector under economy-wide net zero in a multisector dynamic framework

The food processing sector is a large, energy-consuming and CO2-emitting industrial sector. The sector was estimated to account for 6 % of US industrial CO2 emissions in 2020. The sector uses significant amounts of fossil fuels, biomass, and electricity to perform a range of operations such as baking, drying, and refrigeration. Additionally, the sector is tightly linked to the agriculture and land use sectors. In this analysis, we use the Global Change Analysis Model (GCAM), a coupled, energy-economy-agriculture-land-use-water-climate systems model, to examine the role of the food processing sector in the EMF37 2050 US net-zero CO2 scenario. We explore the implications for technology and fuel choice and go beyond to examine US food consumption, food prices, and land-use change. To better understand the sensitivity of our results to alternative developments, we assess multiple sensitivity scenarios for the US and other world regions, with a focus on varied food processing energy intensity pathways.We find that along the EMF37 US net-zero path, the food processing sector electrifies the majority of its process heat. We also find that the industry phases-down natural gas use and completely phases-out coal. Additionally, we observe a marginal decrease in US food consumption per capita relative to our reference scenario. This primarily occurs due to the increase in consumer food prices resulting from increased demand for purpose-grown biomass crops, which compete with food crops for land resources. Finally, cumulative energy savings of 4.2 EJ are achieved from 2020 to 2050 in a scenario in which the US reduces its food processing intensity to EU-15 levels.

Potential roles for artificial intelligence in clinical microbiology from improved diagnostic accuracy to solving the staffing crisis.

This review summarizes the current and potential uses of artificial intelligence (AI) in the current state of clinical microbiology with a focus on replacement of labor-intensive tasks. A search was conducted on PubMed using the key terms clinical microbiology and artificial intelligence. Studies were reviewed for relevance to clinical microbiology, current diagnostic techniques, and potential advantages of AI in routine microbiology workflows. Numerous studies highlight potential labor, as well as diagnostic accuracy, benefits to the implementation of AI for slide-based and macroscopic digital image analyses. These range from Gram stain interpretation to categorization and quantitation of culture growth. Artificial intelligence applications in clinical microbiology significantly enhance diagnostic accuracy and efficiency, offering promising solutions to labor-intensive tasks and staffing shortages. More research efforts and US Food and Drug Administration clearance are still required to fully incorporate these AI applications into routine clinical laboratory practices.

The expanded French compassionate programme for elexacaftor–tezacaftor–ivacaftor use in people with cystic fibrosis without a F508del CFTR variant: a real-world study

Elexacaftor-tezacaftor-ivacaftor has been approved in Europe for people with cystic fibrosis with at least one F508del CFTR variant. Additionally, it is approved by the US Food and Drug Administration (FDA) for people with cystic fibrosis with at least one of 177 rare variants. The aims of this study were to describe the clinical response to elexacaftor-tezacaftor-ivacaftor for people with cystic fibrosis without a F508del CFTR variant in France and to determine CFTR variant responsiveness to elexacaftor-tezacaftor-ivacaftor based on the observed clinical response. The French compassionate programme expanded access to elexacaftor-tezacaftor-ivacaftor to people with cystic fibrosis, aged 6 years and older, without a F508del variant, excluding those with two variants previously characterised as non-responsive. Participants at France's 47 cystic fibrosis centres were given a 4-6 week trial of elexacaftor-tezacaftor-ivacaftor and response was determined by a centralised committee based on evolution of clinical data, lung function, and sweat chloride concentration. Responsiveness of individual CFTR variants was derived from observed clinical responses. The first compassionnate programme was launched on May 19, 2022; by March 8, 2024, 516 people with cystic fibrosis had been identified for inclusion in this real-word study: 37 were not included due to the presence of two variants previously characterised as non-responsive to elexacaftor-tezacaftor-ivacaftor, and 479 (229 females [48%] and 250 males [52%]) received elexacaftor-tezacaftor-ivacaftor for 4-6 weeks. Among 443 participants who received no CFTR modulator before elexacaftor-tezacaftor-ivacaftor, 83 had at least one FDA-approved variant, of whom 81 (98%) were responders and continued elexacaftor-tezacaftor-ivacaftor; in responders, mean absolute change in sweat chloride was -44·5 mmol/L (95% CI -39·1 to -49·8) and percentage of predicted FEV1 (ppFEV1) was 11·1 percentage points (95% CI 8·4 to 13·7; both comparisons p<0·0001). Among 360 participants with no FDA-approved variant and no previous CFTR modulator, 177 (49%) were responders; in responders, mean absolute change in sweat chloride was -20·5 mmol/L (-17·2 to -23·8) and ppFEV1 was 13·2 percentage points (11·4 to 15·0; both comparisons p<0·0001). Among 36 participants who were receiving ivacaftor before elexacaftor-tezacaftor-ivacaftor, 32 (89%) continued elexacaftor-tezacaftor-ivacaftor. Of 251 individual CFTR variants, 64 (28 FDA-approved) were classified as responsive or possibly responsive to elexacaftor-tezacaftor-ivacaftor, and 123 (two FDA-approved) as non-responsive or possibly non-responsive to elexacaftor-tezacaftor-ivacaftor. In France, over half of the population with cystic fibrosis without a F508del variant responded to elexacaftor-tezacaftor-ivacaftor, with most responders having no FDA-approved variant. The treatment period was relatively short and further research is warranted to describe the long-term safety and effectiveness of elexacaftor-tezacaftor-ivacaftor in this population. Association Vaincre la Mucoviscidose, Société Française de la Mucoviscidose, and Filière Maladies Rares MUCO-CFTR.

Advances in the application of robotic-assisted bronchoscopy

In recent years, advances in interventional bronchoscopy have led to safer and more effective solutions for the diagnosis and treatment of respiratory diseases. However, the techniques currently used to diagnose and treat peripheral pulmonary lesions (PPL) have certain limitations. Robotic-assisted bronchoscopy (RAB) offers a new solution to these limitations. Currently, three RABs have been approved by the US Food and Drug Administration (FDA) and are successfully marketed, while two domestic RABs are in the research and development stage. This article provided an overview of the advantages and disadvantages of various techniques and introduced five RABs in detail. It also discussed the advantages and disadvantages of RAB technology and future trends in its development.

Three Years On: The Role of Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria (PNH) since Its Initial Approval.

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare disease characterized by complement-mediated hemolysis and potentially life-threatening complications. Pegcetacoplan, an inhibitor of complement components C3 and C3b, was approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) in 2021. A recent expansion to its indication by the EMA has made pegcetacoplan available for the treatment of both complement inhibitor-naïve and -experienced patients with PNH who have hemolytic anemia, a similarly broad patient population as in the US. This approval was based on results from the Phase 3 PEGASUS study, where pegcetacoplan showed superiority over the C5 inhibitor eculizumab with regard to improving the hemoglobin level in patients with anemia despite eculizumab treatment, and the Phase 3 PRINCE study, where pegcetacoplan showed superiority over supportive care with regard to hemoglobin stabilization and improving the lactate dehydrogenase level in complement inhibitor-naïve patients. In light of this recent indication expansion by the EMA, this article describes how the strong efficacy of pegcetacoplan is linked to its mechanism of action, which provides broad hemolysis control over both intravascular and extravascular hemolysis to improve a range of disease markers and enhance patients' quality of life. Furthermore, additional data and learnings obtained from over 3 years of experience with pegcetacoplan are summarized, including long-term efficacy and safety results, real-world clinical experiences, pharmacokinetic characteristics, and extensive practical guidance for the first-to-market proximal complement inhibitor for PNH.