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This study investigated the effect of oral and topical sodium bicarbonate (SB) on soccer-specific performance during simulated soccer exercise. In a block randomized, double-blind, crossover design, 10 collegiate male soccer players (stature: 181.7 ± 3.2 cm, body mass: 81.7 ± 10.5 kg) performed soccer-specific performance tests (countermovement jumps, Illinois agility, 8 × 25 m repeated sprints) throughout a 90-min soccer-specific aerobic field test (SAFT90) following 0.3 g/kg body mass SB in capsules (SB-ORAL), 0.9036 g/kg body mass PR Lotion (SB-LOTION), or placebo capsules and lotion (PLA). Soccer-specific performance tests were conducted pre-SAFT90, during half-time and post-SAFT90. Blood samples were analyzed for acid–base balance (pH; bicarbonate, HCO 3 − ) and strong ions (sodium, Na+; potassium, K+). Average sprint times were quicker for SB-ORAL than PLA during half-time (3.7%; p =.049; g =.57) and post-SAFT90 (4.9%; p =.041; g =.66). SB-ORAL increased pH and HCO 3 − prewarm-up and during half-time (p <.05), and lowered K+ during half-time (p =.035) compared with PLA. SB-LOTION increased pH (p =.019) and lowered K+ (p =.012) during half-time compared with PLA. SB-LOTION increased Na+ postexercise compared with PLA (p =.008). Repeated sprint times during simulated soccer exercise improved for SB-ORAL, which might have been mechanistically underpinned by elevated blood buffering capacity and greater regulation of strong ion concentration. Consuming SB in capsules is a more effective strategy than topical SB application for improving blood buffering capacity and repeated sprint performance throughout competitive soccer matches. [ABSTRACT FROM AUTHOR]

Individualized genetic therapies-medicines that precisely target a genetic variant that may only be found in a small number of individuals, as few as only one-offer promise for addressing unmet needs in genetic disease, but present unique challenges for trial design. By nature these new individualized medicines require testing in individualized N-of-1 trials. Here, we provide a framework for maintaining scientific rigor in N-of-1 trials. Building upon best practices from traditional clinical trial design, recent guidance from the United States Food and Drug Administration, and our own clinical research experience, we suggest key considerations including comprehensive baseline natural history, selection of appropriate clinical outcome assessments (COAs) individualized to the patient genotype-phenotype for safety and efficacy assessment over time, and specific statistical considerations. Standardization of N-of-1 trial designs in this fashion will maximize efficient learning from this next generation of targeted individualized therapeutics.

BackgroundProject Orbis is a global initiative that aims to streamline regulatory review processes across international regulators in the USA, Canada, Australia, UK, Israel, Brazil, Singapore, and Switzerland to bring promising cancer drugs to patients earlier. We explored the clinical benefit, time to regulatory approval and health technology assessment recommendations, reimbursement outcomes, and monthly treatment prices of cancer drugs reviewed through this initiative.MethodsFor this retrospective, comparative analysis, we identified cancer drug approvals reviewed through Project Orbis in the USA, Canada, and the UK between May 1, 2019, and Nov 1, 2023. Approvals of cancer drugs reviewed Project Orbis were extracted from the Food and Drug Administration (FDA) Oncology Centre of Excellence and all other FDA approvals from the Drugs@FDA database. The co-primary outcomes were time of regulatory review, time from regulatory approval to health technology assessment recommendation (England, Scotland, and Canada), reimbursement outcomes, clinical benefit (defined as median gains in progression-free survival and overall survival) between cancer drug approvals reviewed by Project Orbis and other FDA approval processes, and monthly treatment prices. The Wilcoxon rank-sum and Fisher's Exact tests were used to examine statistical significance between approvals reviewed through Project Orbis and other FDA approvals during the same period.FindingsBetween May 1, 2019 and Nov 1, 2023, 81 (33%) of 244 cancer drugs approved by the FDA were reviewed through Project Orbis. The median overall survival gains were 4·1 months (IQR 3·3-5·1) compared with 2·7 months (2·1-3·9) for other FDA approvals. Similarly, progression-free survival gains were 2·6 months (IQR 1·7-4·9) for Project Orbis compared with 2·6 months (0·6-5·1) for other FDA approvals. Neither overall survival (p=0·11) nor progression-free survival (p=0·44) gains were significantly different between the two cohorts of approvals. Of the 14 UK Medicines and Healthcare products Regulatory Agency (MHRA) approvals reviewed by the Scottish Medicines Consortium (SMC), the agency gave positive recommendations for all 14 (100%). Of the 15 MHRA approvals reviewed by the National Institute for Health and Care Excellence (NICE), the agency gave positive recommendations for six (40%). Of the 49 approvals reviewed by the Canadian Agency for Drugs and Technologies in Health (CADTH), the agency conditionally recommended 44 (90%). The time between regulatory approval to NICE recommendation increased from a median of 137 days (IQR 102-172) in 2021 to 302 days (184-483) in 2023, SMC recommendation increased from 185 days (in 2021 for one drug only) to 368 days (IQR 313-476) in 2023, and CADTH decision increased from 97 days (in 2020 for one drug only) to 202 days (IQR 153-304) in 2023. The median monthly price of approvals reviewed through Project Orbis was US$20 000 per month (IQR 13 000-37 000).InterpretationClinical outcomes of Project Orbis were no different than other FDA approvals during the same time, and access, after a successful health technology assessment, was considerably delayed or absent, raising questions about whether Project Orbis participation translates into faster patient access to medicines with high clinical benefit and sustainable costs. Although future challenges might benefit from regulatory harmonisation, the advantages are currently unclear.FundingNone.

ImportanceIn oncology randomized clinical trials, suboptimal access to best available care at recurrence (or relapse) may affect overall survival results.ObjectiveTo assess the proportion and the quality of postrecurrence treatment received by patients enrolled in US Food and Drug Administration (FDA) registration trials of systemic therapy in the adjuvant or neoadjuvant setting.Evidence reviewFor this systematic review, all trials leading to an FDA approval from January 2018 through May 2023 were obtained from the FDA website and drug announcements. Randomized clinical trials of an anticancer drug in the neoadjuvant or the adjuvant setting were included. Trials of supportive care treatment and treatments given in combination with radiotherapy were excluded. Information abstracted for each trial included tumor type, setting, phase, type of sponsor, reporting and assessment of postrecurrence, and overall survival data.FindingsA total of 14 FDA trials met the inclusion criteria. Postrecurrence data were not available in 6 of 14 registration trials (43%). Of the 8 remaining trials, postrecurrence treatment was assessed as suboptimal in 6 (75%). Overall, only 2 of 14 trials (14%) had data assessed as appropriate.Conclusions and relevanceThis systematic review found that 43% of randomized clinical trials of anticancer treatment in the adjuvant or neoadjuvant context failed to present any assessable postrecurrence treatment data. In instances in which these data were shared, postrecurrence treatment was suboptimal 75% of the time. The findings suggest that regulatory bodies should enforce rules stipulating that patients have access to the best standard of care at recurrence.

Caffeine is an ergogenic substance that is consumed globally in many forms. The use of buccally absorbable formulations instead of gastrointestinal uptake has become increasingly popular over the years, especially when accelerated absorption with minimal gastrointestinal stress is desired. This study investigated the impact of five different formulations and administration routes of caffeine on the whole blood concentrations of caffeine, paraxanthine, and theobromine: caffeinated capsules, tablets, shots, pouches, and chewing gums. A uniform dose of caffeine (200 mg) was administered to 16 healthy recreational athletes (26.0 ± 2.1 years) using a randomized crossover design. Samples were taken in the form of dried blood spots at 16 different time points in a 2-hr timeframe after drug administration. The samples were analyzed using a validated liquid chromatography–tandem mass spectrometry method. The results for caffeine showed no significant differences in the overall bioavailability (area under the concentration–time curve), maximal concentration, and time to maximum concentration. However, when analyzing the bioavailability of caffeine in the first 5, 10, and 15 min, the liquid caffeine formulation was superior to other administered forms (p <.05). This indicates that caffeine solubility has a major influence on its absorption rate. In sports, the rate of caffeine absorption must be considered, not only when ingesting anhydrous caffeine, but also when choosing buccal absorption. These findings imply that general guidelines for ergogenic caffeine use should consider the formulation used and, accordingly, the corresponding route of absorption. [ABSTRACT FROM AUTHOR]

Objectives: Sedation is commonly utilized for individuals otherwise unable to receive dental treatment, such as those with disabilities, medically complex conditions, and dentophobics. The aim was to characterize the profiles of patients receiving various types of sedation and assess the corresponding success rates. Method and materials: This was a 5-year records-based retrospective study. Data regarding the indication for sedation, medical history, sedation type, and treatments performed were recorded. Results: In total, 103 patients underwent 389 treatment sessions under sedation; 42.7% of the patients were disabled. The most commonly administered sedation was moderate sedation, (49.4%), followed by deep (36.8%) and inhaled sedation (13.9%). Successful treatment results were achieved in 96.1% of sessions, with no adverse effects noted during recovery. The high success rates were independent of patient age, sex, and sedation type. There was a positive association between the indication for sedation and the type of sedation. The medically complex patients and the dentophobic patients received mainly moderate sedation (85.3% and 58.2%, respectively), whereas the disabled patients received deep sedation (51.2%). In total, 94% of patients were returning (revisiting) patients. A statistically significant association was found between the type of sedation administered and the success rate during the first and last sessions (P< .001). The success rate at the first session may be predictive of the success in subsequent sessions. Conclusion: A significant positive correlation was found between patient characteristics and the chosen sedation type leading to a high success rate across the various sedation modalities. [ABSTRACT FROM AUTHOR]

Purpose: To examine the clinical efficacy of a chlorhexidine gargle combined with recombinant bovine basic fibroblast growth factor (rb-bFGF) gel in the treatment of recurrent oral ulcers and its effects on inflammatory factors, immune function, and recurrence rate. Materials and Methods: Ninety-six patients with recurrent oral ulcers were randomly assigned to two groups: experimental (treatment with chlorhexidine gargle plus rb-bFGF gel) and control (treatment with chlorhexidine gargle alone) (n = 48 cases). The therapeutic efficacy, clinical improvement of symptoms, and recurrence rate within 3 months were compared between the two groups. Serum inflammatory factor and immune factor levels of patients in the two groups were measured before and after treatment. Results: A statistically significantly higher total effective rate was found in patients of the experimental group (95.83%) versus the control group (81.25%) (p < 0.05). The time to onset of pain relief was shortened, the duration of pain relief was prolonged, and VAS scores for pain level were lower in the experimental than the control group (p < 0.05). Among patients in the experimental group, the number of oral ulcers and ulcer area decreased, and faster onset of pain relief and time until normal eating improved in comparison to the control group (p < 0.05). Reduced levels of IL-2, IL-6, IL-8, and TNF-α were observed in the experimental vs the control group (p < 0.05). Elevated levels of CD3+, CD4+, and NKT and reduced levels of CD8+ were found in the experimental group compared to the control group (p < 0.05). The ulcer recurrence rate of patients in the experimental group (8.33%) was notably lower in comparison to the control group (29.17%). Conclusion: Chlorhexidine gargle plus rb-bFGF gel can improve the clinical outcome of patients with recurrent oral ulcers. It can reduce the levels of inflammatory factors, improve immune function, and reduce the recurrence rate. [ABSTRACT FROM AUTHOR]

BACKGROUND: Artemisinin resistance in Plasmodium falciparum threatens global malaria elimination efforts. To contain and then eliminate artemisinin resistance in Eastern Myanmar a network of community-based malaria posts was instituted and targeted mass drug administration (MDA) with dihydroartemisinin-piperaquine (three rounds at monthly intervals) was conducted. The prevalence of artemisinin resistance during the elimination campaign (2013-2019) was characterized. METHODS: Throughout the six-year campaign Plasmodium falciparum positive blood samples from symptomatic patients and from cross-sectional surveys were genotyped for mutations in kelch-13-a molecular marker of artemisinin resistance. RESULT: The program resulted in near elimination of falciparum malaria. Of 5162 P. falciparum positive blood samples genotyped, 3281 (63.6%) had K13 mutations. The prevalence of K13 mutations was 73.9% in 2013 and 64.4% in 2019. Overall, there was a small but significant decline in the proportion of K13 mutants (p

We report our initial real-world experience with 177Lu-PSMA-617 radioligand therapy. Methods: We performed a retrospective review of patients treated with 177Lu-PSMA-617. Pretreatment PSMA PET, laboratory findings, overall survival, a fall in prostate-specific antigen by 50% (PSA50), and toxicities were evaluated. Results: Ninety-nine patients were included. Sixty patients achieved a PSA50. Seven of 18 (39%) patients who did not meet the TheraP PSMA imaging criteria achieved a PSA50. Nineteen of 31 (61%) patients who did not meet the VISION laboratory criteria achieved a PSA50. Sixty-three patients had a delay or stoppage in therapy, which was due to a good response in 19 patients and progressive disease in 14 patients. Of 10 patients with a good response who restarted treatment, 9 subsequently achieved a PSA50 on retreatment. The most common toxicities were anemia (33%) and thrombocytopenia (21%). Conclusion: At our center, patients who did not meet the TheraP PSMA imaging criteria or the VISION laboratory criteria benefited from 177Lu-PSMA-617 radioligand therapy.

BACKGROUND: Randomized controlled trials found that twice-yearly mass azithromycin administration (MDA) reduces childhood mortality, presumably by reducing infection burden. World Health Organization (WHO) issued conditional guidelines for mass azithromycin administration in high-mortality settings in sub-Saharan Africa given concerns for antibiotic resistance. While prolonged twice-yearly MDA has been shown to increase antibiotic resistance in small randomized controlled trials, the objective of this study was to determine if macrolide and non-macrolide resistance in the gut increases with the duration of azithromycin MDA in a larger setting. METHODS AND FINDINGS: The Macrolide Oraux pour Réduire les Décès avec un Oeil sur la Résistance (MORDOR) study was conducted in Niger from December 2014 to June 2020. It was a cluster-randomized trial of azithromycin (A) versus placebo (P) aimed at evaluating childhood mortality. This is a sub-study in the MORDOR trial to track changes in antibiotic resistance after prolonged azithromycin MDA. A total of 594 communities were eligible. Children 1 to 59 months in 163 randomly chosen communities were eligible to receive treatment and included in resistance monitoring. Participants, staff, and investigators were masked to treatment allocation. At the conclusion of MORDOR Phase I, by design, all communities received an additional year of twice-yearly azithromycin treatments (Phase II). Thus, at the conclusion of Phase II, the treatment history (1 letter per 6-month period) for the participating communities was either (PP-PP-AA) or (AA-AA-AA). In Phase III, participating communities were then re-randomized to receive either another 3 rounds of azithromycin or placebo, thus resulting in 4 treatment histories: Group 1 (AA-AA-AA-AA-A, N = 51), Group 2 (PP-PP-AA-AA-A, N = 40), Group 3 (AA-AA-AA-PP-P, N = 27), and Group 4 (PP-PP-AA-PP-P, N = 32). Rectal swabs from each child (N = 5,340) were obtained 6 months after the last treatment. Each child contributed 1 rectal swab and these were pooled at the community level, processed for DNA-seq, and analyzed for genetic resistance determinants. The primary prespecified outcome was macrolide resistance determinants in the gut. Secondary outcomes were resistance to beta-lactams and other antibiotic classes. Communities recently randomized to azithromycin (groups 1 and 2) had significantly more macrolide resistance determinants than those recently randomized to placebo (groups 3 and 4) (fold change 2.18, 95% CI 1.5 to 3.51, Punadj < 0.001). However, there was no significant increase in macrolide resistance in communities treated 4.5 years (group 1) compared to just the most recent 2.5 years (group 2) (fold change 0.80, 95% CI 0.50 to 1.00, Padj = 0.010), or between communities that had been treated for 3 years in the past (group 3) versus just 1 year in the past (group 4) (fold change 1.00, 95% CI 0.78 to 2.35, Padj = 0.52). We also found no significant differences for beta-lactams or other antibiotic classes. The main limitations of our study were the absence of phenotypic characterization of resistance, no complete placebo arm, and no monitoring outside of Niger limiting generalizability. CONCLUSIONS: In this study, we observed that mass azithromycin distribution for childhood mortality among preschool children in Niger increased macrolide resistance determinants in the gut but that resistance may plateau after 2 to 3 years of treatment. Co-selection to other classes needs to be monitored. TRIAL REGISTRATION: NCT02047981 https://classic.clinicaltrials.gov/ct2/show/NCT02047981.

Assessing the feasibility of 2030 as a target date for global elimination of trachoma, and identification of districts that may require enhanced treatment to meet World Health Organization (WHO) elimination criteria by this date are key challenges in operational planning for trachoma programmes. Here we address these challenges by prospectively evaluating forecasting models of trachomatous inflammation-follicular (TF) prevalence, leveraging ensemble-based approaches. Seven candidate probabilistic models were developed to forecast district-wise TF prevalence in 11 760 districts, trained using district-level data on the population prevalence of TF in children aged 1-9 years from 2004 to 2022. Geographical location, history of mass drug administration treatment, and previously measured prevalence data were included in these models as key predictors. The best-performing models were included in an ensemble, using weights derived from their relative likelihood scores. To incorporate the inherent stochasticity of disease transmission and challenges of population-level surveillance, we forecasted probability distributions for the TF prevalence in each geographic district, rather than predicting a single value. Based on our probabilistic forecasts, 1.46% (95% confidence interval [CI]: 1.43-1.48%) of all districts in trachoma-endemic countries, equivalent to 172 districts, will exceed the 5% TF control threshold in 2030 with the current interventions. Global elimination of trachoma as a public health problem by 2030 may require enhanced intervention and/or surveillance of high-risk districts.

BACKGROUND: The US Food and Drug Administration (FDA) has expanded the use of surrogate markers in drugs approved for oncology/hematology indications. This has likely resulted in a greater number of approvals and possibly drugs coming to market faster, but it is unknown whether these drugs also improve overall survival (OS) for patients taking them. METHODS: We sought to estimate the percentage of oncology drugs that have shown to improve OS in a cross-sectional analysis of US FDA oncology drug approvals (2006-2023). We searched for OS data in registration trials and the peer-reviewed literature. RESULTS: We found 392 oncology drug approvals. Eighty-seven (22%) drug approvals were based on OS, 147 drug approvals were later tested for OS benefit (38% of all approvals and 48% of drugs approved on a surrogate), and 130 (33%) have yet to be tested for OS benefit. Of the 147 drug approvals later tested for OS, 109 (28% of all approvals and 74% of drugs later tested for OS) have yet to show OS benefit, whereas 38 (10% of all approvals and 26% of drugs later tested for OS benefit) were later shown to have OS benefit. In total, 125 out of 392 (32%) drugs approved for any indication have been shown to improve OS benefit at some point, and 267 (68%) have yet to show approval. CONCLUSION: About 32% of all oncology drug approvals have evidence for an improvement in OS. Higher standards are needed in drug regulation to ensure that approved drugs are delivering better patient outcomes, specifically in regards to survival.

With the widespread adoption of intranasal radiofrequency (RF) devices, our objective was to report national adverse events (AEs) associated with their use. The Food and Drug Administration's Manufacturer and User Facility Device Experience was queried. A total of 24 device-related AEs were reported, 11 (45.8%) for Celon® (Olympus), 3 (12.5%) for Vivaer® (Aerin), 2 (8.3%) for Neuromark® (Neurent), and 8 (33.3%) for Rhinaer® (Aerin). Seven (63.6%) of the Celon®-related complications were related to tissue necrosis (largely user error-related), but 1 (9.1%) episode of pediatric ocular palsy was also reported. Vivaer® complications included synechiae formation, a mucosal perforation, and a case of empty nose syndrome. Of the posterior nasal nerve ablating devices, 9 of 10 AEs were epistaxes, of which 7 (77.8%) required operative intervention. Surgeons should exercise vigilance and tissue-appropriate device settings when utilizing RF devices. Epistaxis and tissue necrosis may occur, as well as more rare, but devastating, complications.

Policy Points Current medical device regulatory frameworks date back half a century and are ill suited for the next generation of medical devices that involve a significant software component. Existing Food and Drug Administration efforts are insufficient because of a lack of statutory authority, whereas international examples offer lessons for improving and harmonizing domestic medical device regulatory policy. A voluntary alternative pathway built upon two-stage review with individual component review followed by holistic review for integrated devices would provide regulators with new tools to address a changing medical device marketplace.

ObjectiveTo characterize adverse events related to use of the perirectal spacing agent SpaceOAR, we examined the Manufacturer and User Facility Device Experience (MAUDE) database.MethodsThe MAUDE database was queried for "SpaceOAR" and "Augmenix" from June 2015 (when SpaceOAR was approved by the Food and Drug Administration) to October 2022. Reports were reviewed for adverse events (AEs), operative procedures performed because of the AE, and changes to the radiation plan. AEs were categorized using Common Terminology Criteria for Adverse Events (CTCAE), version 5.0.ResultsSix hundred fifty-four reports were reviewed. Eighty-four were excluded and 4 reports reviewed 2 separate cases of SpaceOAR administration. Five hundred seventy-four cases were ultimately included. Three deaths were reported (0.5% of all AEs). One point six percent of cases represented CTCAE grade 4 injuries (life-threatening consequences; urgent intervention indicated), 15.9% grade 3 (severe but not immediately life-threatening; hospitalization), 24.2% grade 2 (moderate; local/noninvasive intervention), and 57% of events were CTCAE grade 1 (mild; asymptomatic or mild symptoms). Bowel diversion occurred in 29 cases (9%).ConclusionBoth asymptomatic (n = 311) and debilitating (n = 12) complications of SpaceOAR hydrogel use were identified. Death, gel embolization, anaphylaxis, rectal ulcerations, and infections requiring bowel or urinary diversions were among the complications reviewed. Providers should consider these potential complications before perirectal spacer administration and during patient counseling.

Vaccines are one component to the public health strategies to alleviate the COVID-19 pandemic. Hesitancy regarding COVID-19 vaccines in the United States has been problematic, which is not surprising given increasing overall vaccine hesitancy in recent decades. Most vaccines are administered during childhood years. Consequently, understanding hesitancy toward administration of vaccines in this age group may provide insight into possible interventions to reduce vaccine hesitancy. The present study analyzed a subset of over 130,000 public comments posted in response to a notice of meeting of the vaccine advisory group to the Food and Drug Administration. The meeting addressed whether to recommend Emergency Use Authorization (EUA) of the COVID-19 vaccine for children ages 5-11. The results of the study demonstrate that most comments opposed EUA and these comments were associated with statements that indicated misperceptions of risk. Findings provide interesting insights regarding the role of public comments generally but also suggest that the public participation process in notice and comment can be modified to serve as an intervention to align individual perceptions of risk more closely with evidence-based assessment of risk. In addition, the findings provide opportunities to consider strategies for public health messaging.

Plant-derived polyphenols are naturally occurring compounds widely distributed in plants. They have received greater attention in the food and pharmaceutical industries due to their potential health benefits, reducing the risk of some chronic diseases due to their antioxidant, anti-inflammatory, anticancer, cardioprotective, and neuro-action properties. Polyphenolic compounds orally administered can be used as adjuvants in several treatments but with restricted uses due to chemical instability. The review discusses the different structural compositions of polyphenols and their influence on chemical stability. Despite the potential and wide applications, there is a need to improve the delivery of polyphenolics to target the human intestine without massive chemical modifications. Oral administration of polyphenols is unfeasible due to instability, low bioaccessibility, and limited bioavailability. Nano-delivery systems based on polysaccharides (starch, pectin, chitosan, and cellulose) have been identified as a viable option for oral ingestion, potentiate biological effects, and direct-controlled delivery in specific tissues. The time and dose can be individualized for specific diseases, such as intestinal cancer. This review will address the mechanisms by which polysaccharides-based nanostructured systems can protect against degradation and enhance intestinal permeation, oral bioavailability, and the potential application of polysaccharides as nanocarriers for the controlled and targeted delivery of polyphenolic compounds. [ABSTRACT FROM AUTHOR]

Extracellular vesicles (EVs) are naturally occurring non-replicating particles released from cells, known for their health-promoting effects and potential as carriers for drug delivery. Extensive research has been conducted on delivery systems based on culture-cell-derived EVs. Nevertheless, they have several limitations including low production yield, high expenses, unsuitability for oral administration, and safety concerns in applications. Conversely, food-derived EVs (FDEVs) offer unique advantages that cannot be easily substituted. This review provides a comprehensive analysis of the biogenesis pathways, composition, and health benefits of FDEVs, as well as the techniques required for constructing oral delivery systems. Furthermore, it explores the advantages and challenges associated with FDEVs as oral nanocarriers, and discusses the current research advancements in delivering active phytoconstituents. FDEVs, functioning as a nanocarrier platform for the oral delivery of active molecules, present numerous benefits such as convenient administration, high biocompatibility, low toxicity, and inherent targeting. Nevertheless, numerous unresolved issues persist in the isolation, characterization, drug loading, and application of FDEVs. Technical innovation and standardization of quality control are the key points to promote the development of FDEVs. The review aimed to provide frontier ideas and basic quality control guidelines for developing new functional food based on FDEVs oral drug delivery system. HIGHLIGHTS: Extracellular vesicles (EVs) are excellent nano-carriers for active molecules. Food-derived EVs (FDEVs) are better sources of EVs in delivery applications. Active phytoconstituents could be protected by loading them into FDEVs. The development of FDEVs-based delivery system is promising in new functional food. [ABSTRACT FROM AUTHOR]

Rationale: Phosphodiesterase 4 (PDE4) inhibitors are a newer class of drugs that induce bronchodilation and have anti‐inflammatory effects, making them susceptible to misuse as performance enhancers in competitive sports. Methods: This study explores the metabolic conversion of PDE4 inhibitor ibudilast in thoroughbred horses after oral administration and in vitro using equine liver microsomes and Cunninghamella elegans. A liquid chromatography‐high resolution mass spectrometry method was used to postulate the plausible structures of the detected metabolites. Results: A total of 20 in vivo metabolites were identified under experimental conditions, including 12 Phase I and 8 Phase II conjugated metabolites. Phase I metabolites were predominantly formed through hydroxylation (mono‐, di‐, and tri‐hydroxylation). Demethylated metabolites were also identified during this investigation. Additionally, the research detected Phase II metabolites conjugated with glucuronic and sulfonic acids. Conclusions: The data presented here can assist in detecting the PDE4 inhibitor ibudilast and uncover its illicit use in competitive sports. [ABSTRACT FROM AUTHOR]

Cucurbitacin B (CuB) is a natural triterpenoid with diverse pharmacological effects including potent anticancer activity. However, its oral bioavailability is hampered by limited metabolism in vivo. We characterized CuB's in vivo metabolism in rats to uncover bioactive metabolites retaining therapeutic potential, using a robust UHPLC-Q-TOF–MS/MS workflow. This workflow combined molecular networking, fragmentation filtering, and mass defect filtering to identify CuB metabolites in rat urine, plasma, and feces following oral administration. Thirteen metabolites were identified and seven were confirmed. Major phase I transformations involved hydrolysis, reduction, epoxidation, and amination. Phase II conjugation included cysteine, glutathione, glucuronide, and gluconic acid conjugates. Notably, one of the main metabolites formed was the cysteine conjugate CuB-Cys. CuB-Cys maintained similar in vitro antiproliferative activity to CuB on HepG2, MCF-7, and PANC-1 cancer cell lines. However, it demonstrated lower cytotoxicity towards non-cancerous L02 cells, highlighting improved therapeutic selectivity. Mechanistically, CuB-Cys induced greater apoptotic signaling in HepG2 cells than CuB via enhanced caspase activation and disrupted BAX-Bcl-2 balance. This represents the first systematic characterization of CuB's in vivo metabolic pathway. The identification and confirmation of CuB-Cys provide insight for drug development efforts aiming to maintain therapeutic efficacy while reducing toxicity, via metabolite-based approaches. Our findings shed light on strategies for improving CuB's clinical potential. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) antiviral administration and adherence are essential to reach the World Health Organization's 2030 hepatitis elimination goals. As HBV treatment guidelines are now simplified and expanded, adherence to treatment will be critical, but challenges to adherence are poorly studied. After introducing tenofovir disoproxil fumarate (TDF) monotherapy to expectant mothers with high-risk HBV in Kinshasa, DRC, we conducted semi-structured interviews to understand medication adherence behaviors, to complement pill counts and measurement of TDF metabolite levels. Key facilitators of adherence identified included trust in healthcare workers, a better understanding of HBV, and family support. Identified barriers included fear of stigma and low health literacy. Knowledge about HBV disease remains low, underscoring the importance of ongoing education of clinic staff and patients alike. [ABSTRACT FROM AUTHOR]

BACKGROUND: Postinflammatory hyperpigmentation (PIH) is a skin disorder characterized by hyperpigmentation resulting from heightened inflammation and/or damage to the basement membrane, melanocytes, and keratinocytes, leading to abnormal and excessive pigment deposition. Oral tranexamic acid (TXA), originally used as an antifibrinolytic for managing excessive bleeding, has garnered attention for its demonstrated safety and efficacy in treating melasma. There is a growing body of evidence regarding the use of TXA in the treatment of PIH. OBJECTIVE: To review the mechanism of action of oral TXA in treating PIH and examine the use of oral TXA in preventing and/or treating PIH associated with laser-based and light-based treatments in individuals with skin color. METHODS: Review of relevant articles from 2000 to present found in the Cochrane Library, PubMed, Embase, and Google Scholar, regarding the use of oral TXA in the treatment of PIH. RESULTS: Studies reviewed investigated the efficacy of oral tranexamic acid (TXA) in treating postinflammatory hyperpigmentation (PIH) and use in preventing PIH when used in conjunction with other treatments. All studies demonstrated significant improvement in PIH without significant adverse effects and side effects. CONCLUSION: Oral tranexamic acid is emerging as a safe and effective treatment in the prevention and treatment of postinflammatory hyperpigmentation. [ABSTRACT FROM AUTHOR]

The results from the POET (Partial Oral Treatment of left-sided Endocarditis) trial were published in August 2018 and established noninferiority of oral step-down antibiotic treatment in stabilized patients with infective endocarditis (IE). Data on length of hospital stay (LOS) and safety following the POET trial are warranted. The goal of this study was to examine changes in LOS and safety (mortality and relapse of bacteremia) before and after POET publication. Using Danish nationwide registries, patients with first-time IE caused by Streptococcus spp., Enterococcus faecalis , Staphylococcus aureus , or coagulase-negative staphylococci from 2012 to 2021 were identified. Median LOS was examined according to publication date (before and after September 2018). Mortality and relapse of bacteremia at 180 days of follow-up were examined. We identified 3,008 patients before POET publication (median age 72.8 years) and 1,740 after publication (median age 75.2 years) (P < 0.0001). The median LOS decreased by 8 days: 41 days (Q1-Q3: 29-49 days) before POET publication and 33 days (Q1-Q3: 21-44 days) after POET publication (P < 0.0001). Similar reductions in LOS were seen across microbiological etiologies and age groups. Reduction in LOS was most pronounced in nonsurgically treated patients. Mortality from IE admission to a maximum of 180 days' follow-up was 27.5% before POET publication and 28.3% after publication (P = 0.41). The bacteremia relapse rate within 180 days was 3.5% before POET publication and 1.6% after publication (P = 0.0002). Following the POET trial, we found a reduction in median LOS of 8 days with no change in mortality and an associated lower rate of relapse of bacteremia. [Display omitted] [ABSTRACT FROM AUTHOR]

Objectives: Scabies is a neglected skin disease that disproportionately affects people from resource poor and overcrowded countries. Global data on prevalence and risk factors are limited. This article aims to estimate the global burden of scabies and identifies the risks associated with it. Methods: Databases (PubMed, Scopus and Cochrane Reviews) were accessed to identify studies of scabies prevalence published between 2000 and 2024. Results were pooled to estimate prevalence and identify factors, which explained between‐study heterogeneity. Odds ratios (ORs), risk of bias, subgroup analyses and meta‐regression were used to describe variation in effect size and heterogeneity based on country‐level demographic and economic variables. Results: Seventy studies yielded a pooled prevalence of 11.9% (95% confidence interval [CI]: 9.60–14.7) with substantial heterogeneity I2=100%τ2=1.04. Prevalence was highest in Oceania (17.9%; 95% CI: 13.9–22.8) compared to other regions. Pooled risk factors for scabies showed significant associations for demographic and behavioural factors including contact history with household members with itch (OR 11.3; 95% CI 4.82–26.51; I2=96%; n = 7), lack of soap use (OR 3.41; 95% CI: 2.56–4.54; I2=44%; n = 7), bed‐sharing (OR 2.64; 95% CI: 1.50–4.63; I2=76%; n = 7), sharing of clothes (OR 2.52; 95% CI: 1.58–4.03; I2=85%; n = 7), infrequent bathing (OR 2.13; 95% CI: 1.41–3.22; I2=77%; n = 6), presence of pets (OR 1.76; 95% CI: 1.08–2.87; I2=84%; n = 4) and being a male (OR = 1.19; 95% CI: 1.04–1.37; I2=83%; n = 22). Socioeconomic factors were not convincingly associated with scabies prevalence. Conclusion: Prevalence of scabies is associated with geographic location and behavioural factors, but not between‐country socioeconomic status. In addition to mass drug administration, risk factors are identified which may be included in health promotion programmes to reduce scabies prevalence and its sequelae in the long term. [ABSTRACT FROM AUTHOR]

Rural environments in the United States present challenges to wellness, but there is a lack of tools with which to categorize rurality at the subcounty level. The most common tool, the Food and Drug Administration's 2010 Rural–Urban Commuting Area (RUCA) codes, uses data that are over a decade old and cannot accommodate regional differences in rurality. The purpose of this study was to develop a census-tract classification system of rurality and demonstrate its use in describing HIV outcomes. We transformed census-tract measures (population density, natural resource workforce, walkability index, household type, and air quality) into local scales of rurality using factor analysis. We surveyed public health practitioners to determine cutpoints and compared the resulting categorization with RUCA codes. We characterized the incidence of HIV in Washington State according to rurality category. Our classification system categorized 25% of census tracts as rural, 19% as periurban, and 56% as urban. Our survey yielded cutoffs that were more conservative in categorizing urban areas than RUCA codes. The rate of HIV diagnosis was substantially higher in urban areas. Our rural–urban classification system offers an alternative to RUCA codes that is more responsive to regional differences. [ABSTRACT FROM AUTHOR]

BACKGROUND AND OBJECTIVES: Respiratory syncytial virus (RSV) commonly causes hospitalization among US infants. A maternal vaccine preventing RSV in infants, RSV bivalent prefusion F maternal vaccine (RSVpreF), was approved by the US Food and Drug Administration and recommended by the Advisory Committee on Immunization Practices. Our objective was to evaluate the health benefits and cost-effectiveness of vaccinating pregnant persons in the United States using RSVpreF. METHODS: We simulated RSV infection and disease with and without seasonal RSVpreF vaccination in half of the pregnant persons in the annual US birth cohort during weeks 32 through 36 of gestation. Model inputs came from peer-reviewed literature, Food and Drug Administration records, and epidemiological surveillance databases. The results are reported using a societal perspective in 2022 US dollars for a 1-year time frame, discounting future health outcomes and costs at 3%. Sensitivity and scenario analyses were performed. RESULTS: Year-round maternal vaccination with RSVpreF would prevent 45 693 outpatient visits, 15 866 ED visits, and 7571 hospitalizations among infants each year. Vaccination had a societal incremental cost of $396 280 per quality-adjusted life-year (QALY) saved. Vaccination from September through January cost $163 513 per QALY saved. The most influential inputs were QALYs lost from RSV disease, the cost of the vaccine, and RSV-associated hospitalization costs; changes in these inputs yielded outcomes ranging from cost-saving to $800 000 per QALY saved. CONCLUSIONS: Seasonal maternal RSV vaccination designed to prevent RSV lower respiratory tract infection in infants may be cost-effective, particularly if administered to pregnant persons immediately before or at the beginning of the RSV season. [ABSTRACT FROM AUTHOR]

Between December 2014 and May 2020, the United States Food and Drug Administration approved 9 indications for poly (ADP-ribose) polymerase (PARP) inhibitor use in ovarian cancer. Between June 2022 and September 2022, all 3 indications for PARP inhibitor treatment of recurrent ovarian cancer were withdrawn. Between November 2022 and September 2023, all 3 indications for PARP inhibitor maintenance therapy in recurrent ovarian cancer were restricted. The 3 indications for PARP inhibitor maintenance therapy in newly diagnosed advanced ovarian cancer are unchanged. This article reviews the timelines and data leading to regulatory changes for PARP inhibitor use in ovarian cancer in the United States. [ABSTRACT FROM AUTHOR]

Purpose: To report a case of presumed fungal infection in a patient with JIA following prolong immunosuppression, and after initiation of adalimumab therapy. Method: Retrospective Chart Review. Result: A 20-year-old female, previously diagnosed with JIA, presented with a three-week history of blurred vision in her left eye. She had a long history of treatment with oral corticosteroids, sulfasalazine, and methotrexate, followed by tocilizumab injections and later etanercept. Recently, she was started on adalimumab injections. Fundus examination of the left eye demonstrated multifocal retinitis scattered throughout the fundus. Optical coherence tomography of the lesions showed hyperreflectivity in the inner retina with posterior shadowing and vitreous aggregates extending into the vitreous cavity. After her second adalimumab dose, she experienced blurred vision. Examination of the fundus revealed multifocal retinitis in the left eye, sparing the macula. After stopping immunomodulators and starting empirical antifungal therapy with oral fluconazole, her retinal lesions began to improve. A vitreous biopsy was performed, and intravitreal voriconazole was administered, but microbiological tests were negative. Nevertheless, her retinal lesions resolved almost completely with continued antifungal treatment. By the 6-week follow-up, her retinitis had fully resolved, maintaining excellent visual acuity. Conclusion: This case underscores the need for a high index of suspicion for infection in patients with long-term immunosuppression, highlighting the importance of early therapeutic intervention. [ABSTRACT FROM AUTHOR]

Objective: Both periodontal disease and obesity are risk factors for dementia, but their links to 1brain function remain unclear. In this study, we examined the effects of oral infection with a periodontal pathogen on cognitive function in a mouse model of obesity, focusing on the roles of microglia. Methods: To create a mouse model of diet-induced obesity and periodontitis, male C57BL/6 J mice were first fed a high-fat diet containing 60% lipid calories for 18 weeks, beginning at 12 weeks of age, to achieve diet-induced obesity. Then, Porphyromonas gingivalis administration in the oral cavity twice weekly for 6 weeks was performed to induce periodontitis in obese mice. Results: Obese mice orally exposed to P. gingivalis showed cognitive impairment in the novel object recognition test. Increased expression levels of inflammatory cytokines (e.g. interleukin-1β and tumor necrosis factor-α) were observed in the hippocampus of P. gingivalis-treated obese mice. Immunohistochemical analysis revealed that microglia cell body size was increased in the hippocampus and prefrontal cortex of P. gingivalis-treated obese mice, indicating microglial activation. Furthermore, depletion of microglia by PLX3397, a colony-stimulating factor 1 receptor inhibitor, ameliorated cognitive dysfunction. Conclusion: These results suggest that microglia mediate periodontal infection-induced cognitive dysfunction in obesity. [ABSTRACT FROM AUTHOR]

Objective: To examine the effects of a university's health vaccination initiative in increasing vaccination rates among international students/scholars in the United States. Methods: The vaccination initiative included: increasing vaccination opportunities by holding a pre-registration event, providing vaccine recommendations from healthcare professionals including a bilingual health interpreter, implementing campus-based marketing strategies, sending reminders using social media, and offering free and affordable vaccines. Results: Total 575 international students/scholars attended from 2016 to 2019 (N = 118, 163, 193, and 101, respectively), showing an increase compared to 2015. The most common vaccines administered were for influenza, human papillomavirus (HPV), tetanus, diphtheria, and acellular pertussis (Tdap), and Hepatitis A. Slightly less than one-quarter of participants received three or more vaccines. More women than men received HPV vaccine. Participants shared they would not have been vaccinated without this initiative and wished for more vaccination events. Conclusions: Future efforts are needed to implement this initiative across universities to further evaluate its effectiveness. [ABSTRACT FROM AUTHOR]

This study assesses the use of population pharmacokinetics (PopPK) in supporting pediatric dosing of novel biological drug products. The labeling for biologic drug products approved by the US Food and Drug Administration (FDA) from 2002 until 2021 was reviewed to identify those with a pediatric indication. For the drugs with a pediatric indication, the dosing regimen(s) based on age groups, dosing strategy, the use of PopPK to support the dose, and the types of pediatric clinical trials were reviewed. Data were collected from FDA's review documents and product labels on the Drugs@FDA website, and as needed, more clinical trial details were collected from PubMed and clinicaltrials.gov. The role of PopPK analyses in dosing was captured when mentioned in the label or review as playing a role in selecting the approved pediatric dose and/or in verifying the adequacy of the studied dose to support labeling. Between 2002 and 2021, FDA approved 169 biological products, and 78 of 169 (46%) products have an approved indication for which the label contains dosing recommendations for pediatric use. For the 78 products approved in pediatrics, there was a total of 180 clinical trials that included pediatric patients. Phase 3 pediatric trials commonly supported pediatric approval and dosing for the reviewed products (64%, 50/78 products; 56.1%, 101/180 trials). PopPK analyses were reported to play a critical role in dose selection, prediction, and verification for 40 of the 78 products (51%), including informing pediatric dosing in the absence of pediatric data (e.g., drugs approved under animal rule), comparing exposures to the exposure range observed in adults, and informing alternative dosing strategies in certain age or body weight groups. PopPK analyses have been applied in a variety of ways to inform pediatric dosing and support extrapolation from adult data or other pediatric age groups for biologics. Understanding and learning from these past cases on the use of pharmacometrics tools to support pediatric dosing of biological products can inform future pediatric development programs. [ABSTRACT FROM AUTHOR]

Introduced by the Hatch‐Waxman Amendments of 1984, 505(b)(2) applications permit the US Food and Drug Administration to rely, for approval of a new drug application, on information from studies not conducted by or for the applicant and for which the applicant has not obtained a right of reference. This pathway is designed to circumvent the unnecessary duplication of studies already conducted on a previously approved drug. It can lead to a considerably more efficient and expedited route to approval compared to a traditional development path. Model‐informed drug development refers to the utilization of a diverse array of quantitative models in drug development to streamline the decision‐making process. In this approach, diverse quantitative models that integrate knowledge of physiology, disease processes, and drug pharmacology are employed to address drug development challenges and guide regulatory decisions. Integration of these model‐informed approaches into 505(b)(2) regulatory submissions and decision‐making can further expedite the approval of new drugs. This article discusses some applications of model‐informed approaches that were used to support 505(b)(2) drug development and regulatory actions. Specifically, various quantitative models such as population pharmacokinetic and exposure‐response models have been employed to provide evidence of effectiveness, guide dosing in subgroups such as subjects with hepatic or renal impairment, and inform policies. These case study examples collectively underscore the significance of model‐informed approaches in drug development and regulatory decisions associated with 505(b)(2) submissions. [ABSTRACT FROM AUTHOR]

Cenerimod is a sphingosine‐1‐phosphate receptor 1 modulator that reduces tissue availability of circulating lymphocytes. The compound is in Phase 3 development for the treatment of systemic lupus erythematosus. Its pharmacokinetic properties are characterized by slow absorption and multiphasic elimination with a long terminal half‐life (t½), potentially caused by enterohepatic circulation (EHC). In this trial in healthy participants, oral cenerimod 0.5 and 4 mg once daily was administered for 50 days, followed by oral administration of activated charcoal (ie, 50 mg every 12 h for 11 days, starting 24 h after the last cenerimod dose), to investigate the potential EHC of cenerimod and assess whether elimination of cenerimod can be accelerated. The multiple‐dose pharmacokinetics, pharmacodynamics, safety, and tolerability of cenerimod were also evaluated. For both doses, peak plasma concentrations were reached 6 and 7 h after dosing. Cenerimod accumulated approximately eightfold and (near) steady‐state conditions were reached after 50 doses, resembling clinically meaningful exposure to cenerimod. The t½ following 0.5 and 4 mg of cenerimod was 767 and 799 h (ie, 32 and 33 days) and 720 and 780 h (ie, 30 and 33 days) with or without administration of charcoal, respectively, indicating no statistically significant difference. Therefore, charcoal did not accelerate cenerimod elimination suggesting that there is no EHC of cenerimod. A reversible, dose‐dependent decrease in total lymphocyte count was observed. No safety concerns were identified; administration of charcoal was well tolerated. [ABSTRACT FROM AUTHOR]

Introduction: Uncertainty surrounds the optimal routine laboratory monitoring in acne patients treated with isotretinoin. Objective: Our aim was to evaluate the risk of mild and severe laboratory abnormalities in patients with acne starting isotretinoin versus oral antibiotic treatment. Methods: A global population‐based retrospective cohort study assigned two groups of patients with acne‐prescribed isotretinoin (n = 79,012) and oral antibiotics (n = 79,012). Comprehensive propensity‐score matching was conducted. Results: Compared to acne patients treated with oral antibiotics, those under isotretinoin demonstrated an increased risk of grade ≥3 hypertriglyceridemia (hazard ratio [HR], 7.85; 95% confidence interval [CI], 5.58–11.05; P < 0.001) and grade ≥3 elevated aspartate transaminase (AST) levels (HR, 1.45; 95% CI, 1.13–1.85; P = 0.003) within the initial 3 months of treatment. The absolute risk of these abnormalities among isotretinoin initiators was 0.4% and 0.2%, respectively. The risk difference of these findings was clinically marginal: 3 and 1 additional cases per 1,000 patients starting isotretinoin, respectively. There was no significant risk of grade ≥3 impairment in cholesterol, alanine transaminase, gamma‐glutamyl transferase, or creatinine levels under isotretinoin. Most laboratory abnormalities were documented 1–3 months after drug initiation in time‐stratified analysis. Conclusion: Isotretinoin is associated with a clinically marginal increased risk of severe hypertriglyceridemia and hypertransaminasemia. Routine blood testing should be performed 1–3 months after commencing therapy. [ABSTRACT FROM AUTHOR]

• Norepinephrine reduces maternal bradycardia versus phenylephrine. • Both vasopressors equally maintain blood pressure and neonatal outcomes. • No significant difference in umbilical blood gas between both vasopressors. • Larger trials are needed to confirm and guide clinical practice. We conducted a systematic review and meta -analysis to evaluate the fetomaternal outcomes after the administration of norepinephrine or phenylephrine for the treatment of post spinal hypotension in preeclamptic women undergoing a cesarean section. We searched on PubMed, Embase, Scopus, Cochrane CENTRAL, and clinicaltrials.gov from inception till June 2024. Randomized controlled trials of preeclamptic women receiving norepinephrine or phenylephrine for post spinal hypotension were included. Two reviewers extracted data onto an Excel spreadsheet. R version 4.4 was used for statistical analysis. Risk ratios (RR) and their 95% confidence intervals (CIs) were calculated and pooled using the random effects model. Cochrane's risk of bias (RoB 2) tool was used for quality assessment. This review has been registered with PROSPERO (CRD42024532740). A total of 4 trials, comprising 413 participants, were included in this review. 206 patients received norepinephrine, while 207 received phenylephrine. The incidence of maternal bradycardia was significantly lower in the norepinephrine group compared with the phenylephrine group (RR = 0.25, 95 % CI = 0.16 to 0.39, p < 0.01). There were no statistical differences in other maternal outcomes or in the umbilical artery and umbilical vein blood gas analysis values. We also analyzed adverse events such as nausea (RR = 1.00, 95 % CI: 0.62 to 1.60, p = 1.00) and vomiting (RR = 0.99, 95 % CI: 0.89 to 1.11, p = 0.61), but they did not show a significant association with any group. All the trials had a moderate or low risk of bias. Bolus doses of NE and PE for the treatment of post-spinal hypotension in preeclamptic women undergoing cesarean sections were found to exhibit comparable neonatal outcomes. However, NE provided superior maternal safety due to a lower incidence of bradycardia compared to PE. [ABSTRACT FROM AUTHOR]

Background: With the recent Food & Drug Administration (FDA) approval of cellular therapy that requires product manipulation prior to administration in combination with a short stability window, the need was identified for local dose preparation within the pharmacy rather than the off-site stem cell processing laboratory. This approval gave rise to assessment of regulatory standards surrounding cellular therapy, evaluation and revision of current standard operating procedures and policies with formal process validation, assessment of occupational exposure mitigation and safety considerations, and development of staff training and education. Objective: To describe and provide insight into the stepwise process of FACT validation and onboarding of commercially available cellular therapy products that require sterile compounding manipulation within a pharmacy prior to administration. Discussion: A multidisciplinary effort is required to attain FACT certification and implement pharmacist compounding of cellular therapy products. 1 Local preparation within a pharmacy facilitates a sound operational workflow and provides a pathway to perform aseptic manipulations of cellular therapy products safely and efficiently. Conclusion: Safe and successful administration of cellular therapies handled and compounded by pharmacy department staff along with program validation requires a preemptive review utilizing a multidisciplinary approach for process development. This manuscript will provide a foundation based on consistency and transparency in effective cellular therapy sterile compounding and aseptic manipulation, proper handling and disposal procedures, increased communication through creation and optimization of treatment plans and order-sets, standardized medical center staff education, and development of policies and standard operating procedures for the entire health care team. [ABSTRACT FROM AUTHOR]

Introduction: In recent years, most molecular target drugs have been administered orally, as prescribed at ambulatory services in hospitals and at patients' homes. Telephone follow-up is increasingly being used in clinical practice for patients needing additional support post-discharge and for the prevention of hospital readmissions. The purpose of this study was to clarify the clinical benefits of telephone follow-up while administering oral anticancer drugs. Methods: This was a single-center, observational, retrospective study. We evaluated hepatocellular carcinoma patients who received sorafenib or lenvatinib between March 2010 and February 2018. The primary endpoint was the incidence of adverse events. Results: From the total of 130 patients, 83 patients received telephone follow-up and 47 did not. The incidence of hand–foot skin reactions significantly reduced in patients with telephone follow-up (odds ratio (OR) 3.69, 95% confidence interval (CI) 1.16–11.8, p = 0.020). The median durations (ranges) of adherence to oral chemotherapy were 259 days (15−1730) for the telephone follow-up group and 121 days (14−1105) for the no-telephone follow-up group (p < 0.001). Moreover, the disease control rate was significantly higher in the telephone follow-up group (OR 2.52, 95% CI 1.15–5.53, p = 0.020). Conclusions: Remote interventions, such as telephone follow-up, are useful means of managing adverse events in patients receiving oral anticancer drugs and can lead to improved treatment results. [ABSTRACT FROM AUTHOR]

Introduction: To date, there is no adherence estimator to identify risk of nonadherence prior to initiating oral oncolytics. Methods: A workgroup was assembled through the National Community Oncology Dispensing Association and tasked with creating a tool to meet this need. Tool constructs were defined after a review of the literature identifying top barriers to adherence. A second literature search was conducted to identify questions targeting specific barriers from validated adherence questionnaires. Once a finalized draft was complete, the risk assessment tool was built into an electronic survey where a risk category can be automatically calculated for the patient. Results: The six most impactful factors affecting compliance to oral oncolytics were identified as patient's confidence, health literacy, perception of treatment, quality of life, social support, and complexity of chemotherapy regimen. A six-item questionnaire was created with five patient-directed questions and one clinician-directed question. Examples and descriptions were provided for clinicians to consider when categorizing complexity of a regimen. The tool was designed for responses to each question to be indexed into categories through a 10-point system. Results will be stratified into low, moderate, or high risk for nonadherence. Conclusion: The creation of a tool to predict nonadherence prior to starting therapy is an unmet need for patients initiating oral oncolytics. The aim of this tool is to meet those needs and better guide clinicians to provide patients with strategies to better manage nonadherence. Next steps include tool validation and piloting in clinical practice. [ABSTRACT FROM AUTHOR]

Introduction: Imatinib is an orally administered tyrosine kinase inhibitor with wide clinical use in different indications from solid tumors to hematologic malignancies. Inclusion body myositis (IBM) is an acquired myopathy of both inflammatory and degenerative nature. Case report: We present an 81 years old male with a history of gastrointestinal stromal tumor (GIST) operated 8 years ago and was evaluated for the progressive loss of weight and muscle strength leading to total immobilization in 6 months. He was under imatinib for 8 years despite the remission of GIST. Physical examination disclosed diffuse loss of muscle strength, most prominently involvement of distal upper and proximal lower extremity in an asymmetrical pattern with normal serum creatinine kinase level (CK). Further investigations including bilateral thigh MRI, electromyography (EMG), and PET/CT suggested myositis and degenerative myopathy and ruled out any malignancy. Quadriceps femoris biopsy proved the diagnosis of IBM and no trigger except for imatinib was displayed. Management and outcome: Clinical improvement in terms of weight loss and muscle weakness was achieved after the discontinuation of imatinib. Discussion: This is the first case of IBM associated with prolonged use of imatinib not reported in the literature so far. Since imatinib is widely used in different conditions, it is important to be aware of even its rare adverse effects. Poor response of IBM to conventional immunosuppressive agents enhances the value of etiology identification to relieve symptoms in addition to supportive care. [ABSTRACT FROM AUTHOR]

Objective: This study aims to compare the safety and efficacy of misoprostol administered orally and vaginally in obese pregnant women at term with either gestational hypertension or diabetes. Methods: A total of 264 pregnant women were enrolled and categorized into two groups based on their primary condition: hypertension (134 cases) or diabetes mellitus (130 cases) and were further divided into subgroups for misoprostol administration: orally (Oral group) or vaginally (Vaginal group). The primary outcomes measured were changes in the Bishop score following treatment, induction of labor (IOL) success rates, requirement for oxytocin augmentation, duration of labor, mode of delivery, and cesarean section rates. Results: Significant enhancements in Bishop scores, decreased cesarean section rates and increased success rates of IOL were noted in both administration groups. The incidence of vaginal delivery within 24 h was significantly higher in the Vaginal group compared to the Oral group. Adverse effects, including nausea, uterine overcontraction, hyperfrequency of uterine contraction and uterine hyperstimulation without fetal heart rate deceleration, were significantly more prevalent in the Vaginal group than in the Oral group. Conclusion: Misoprostol administration, both orally and vaginally, proves effective for labor induction in obese pregnant women with hypertension or diabetes. However, the oral route presents a lower risk of adverse maternal and neonatal outcomes, suggesting its preference for safer labor induction in this demographic. [ABSTRACT FROM AUTHOR]

Objectives: To compare the efficacy and adverse events of different oral corticosteroids (OCSs) withdrawal methods for chronic rhinosinusitis with nasal polyp after endoscopic sinus surgery (ESS). Methods: This was a randomized prospective study conducted from Oct 2019 to Jan, 2021. 35 patients who underwent ESS were randomly divided into 2 groups. Regular group (n = 18) received 0.4mg/kg/day of methylprednisolone orally for 10 days, tapering group (n = 17) received 0.4mg/kg/day of methylprednisolone orally for 7 days, followed by progressive reduction of 8 mg of methylprednisolone per week for 3 weeks. The visual analogue scale (VAS) score, the Lund-Kennedy endoscopy (LKE) score, and the E score were assessed preoperatively and at half and 1, 2, and 12 months postoperatively. Statistical analyses were performed using SPSS. Results: There was no statistical difference in the baseline characteristics between the 2 groups. The postoperative VAS scores and LKE scores of patients were significantly improved from those preoperatively (P-values < 0.05). There was no statistical difference in the LKE score, E score, and VAS score between the 2 groups both preoperatively and postoperatively (P-values > 0.05). There was no statistical difference in adverse events between the 2 groups (P-values > 0.05). Conclusions: The combination of OCSs and ESS can improve the clinical symptoms of patients and the recovery of nasal mucosa. There was no difference between the 2 drug withdrawal methods in efficacy and adverse events. Drug withdrawal gradually is more complicated therefore, in clinical practice, OCSs withdrawal directly would be the better option for patients. [ABSTRACT FROM AUTHOR]

Virtual reality (VR) technology plays a significant role in nursing education by enhancing the quality of training by applying knowledge, decision‐making, intervention completion and feedback. This study aims to examine nursing students' experiences and perceptions regarding the ventrogluteal injection training provided through VR technology. Conducted between May and June 2022, this qualitative descriptive phenomenology study took place at a state university in Turkey, involving 70 students who participated in Ventrogluteal Drug Administration training using VR glasses. The sample included 12 students selected via the Criterion Sampling Method. Data collection tools comprised the 'Descriptive Information Form' and a 'Semi‐Structured Questionnaire'. Qualitative data were analysed using the Content Analysis Method, while quantitative data were assessed through descriptive statistical methods (frequency, percentage, mean). The study identified 13 codes, four sub‐themes and two main themes from the students' evaluations. The first main theme, 'Weaknesses of Virtual Simulation', included two sub‐themes: 'Due to its Nature' and 'Due to its Technique', resulting in five codes. The second main theme, 'Strengths of Virtual Simulation', was divided into two sub‐themes: 'Permanence, Integrity, and Applicability' and 'Emotions towards Virtual Simulation', with eight codes identified. The findings indicate that students view VR technology positively in their education. However, they also highlighted specific issues related to the simulation's technique and inherent nature. [ABSTRACT FROM AUTHOR]

Health communication research applies communication science to develop generalizable knowledge capable of improving the health and well-being of individuals and communities. But to what extent does the knowledge generated by the health communication field actually achieve public health impact? To answer this question, we discuss the application of health communication science and research within a tobacco regulatory science framework. We describe three areas in which health communication research funded by the Food and Drug Administration (FDA) Center for Tobacco Products (CTP) contributed to 1) youth tobacco prevention campaigns, 2) cigarette health warnings, and 3) regulation of labeling, advertising, and marketing claims. These examples demonstrate how communication regulatory science achieves public health impact in the real world by informing national policies, regulatory actions, and public health practice. [ABSTRACT FROM AUTHOR]

Background: Surgical site infections (SSIs) represent a major challenge in spine surgery, leading to severe morbidity, mortality, and increased costs. The local application of antibiotics, particularly vancomycin, has emerged as a potential strategy. Individual randomized controlled trials (RCTs) have disagreed about the efficacy of topical vancomycin in preventing SSIs after spine surgery, and so a meta-analysis that pools data from those RCTs might be helpful to inform clinicians' decisions on the topic. Questions/purposes: This meta-analysis of RCTs asked: Does intrawound topical vancomycin reduce the risk of (1) SSIs, (2) deep SSIs, and (3) superficial SSIs in patients undergoing spine surgery? Methods: PubMed, Cochrane, and Google Scholar (pages 1-20) were searched up through March 13, 2024 (search performed on March 13, 2024). Inclusion criteria consisted of English or non-English-language RCTs comparing the implementation of topical vancomycin in spine surgery to its nonuse and assessing its efficacy in preventing SSI, while exclusion criteria consisted of nonrandomized comparative studies, single-arm noncomparative studies, comparative studies based on national databases or from the same center as other included studies, studies posted to preprint servers, studies reporting incomplete/nonrelevant outcomes, and studies adding another SSI preventive measure. The studies were assessed using the Cochrane Risk of Bias tool. Heterogeneity was evaluated by Q tests and I2 statistics. We used a random-effects model when considerable heterogeneity was observed (all SSIs, deep SSIs); otherwise, a fixed-effects model was used (all SSIs subanalysis, superficial SSIs). Furthermore, the fragility index was calculated for each of the assessed outcomes when there was no difference between the two groups to assess how many patients were needed to experience the outcomes for a difference to become present. The studied outcomes were the risks of SSIs, deep SSIs, and superficial SSIs. Deep SSIs were defined by the included trials as SSIs underneath the fascia, otherwise they were considered superficial. Six RCTs representing a total of 2140 patients were included, with 1053 patients in the vancomycin group and 1087 in the control group. Using an alpha of 0.05, our meta-analysis had 80% power to detect a risk difference of 1.5% for the primary outcome between patients who did and did not receive vancomycin. The age of the patients in the vancomycin group ranged from 37 to 52 years, while the age in the control group ranged from 34 to 52 years. The surgical procedures consisted of both instrumented and noninstrumented spinal procedures. Overall, the risk of bias in the included studies was either low or unclear, with none of the studies having a high risk of bias in any of the assessed categories (selection bias, performance bias, detection bias, attrition bias, and reporting bias). Results: We found no difference in the risk of SSI between the vancomycin and control groups (3.0% [32 of 1053] versus 3.9% [42 of 1087], relative risk 0.74 [95% CI 0.35 to 1.57]; p = 0.43). Ten additional patients (4.8% infection risk) in the control group would need to experience an SSI for a difference to be observed between the two groups. We found no difference in the risk of deep SSI between the vancomycin and control groups (1.8% [15 of 812] versus 2.7% [23 of 860], relative risk 0.69 [95% CI 0.24 to 2.00]; p = 0.50). Seven additional patients (3.5% infection risk) in the control group would need to experience a deep SSI for a difference to be observed between the two groups. We found no difference in the risk of superficial SSI between the vancomycin and control groups (1.0% [6 of 620] versus 1.4% [9 of 662], relative risk 0.68 [95% CI 0.25 to 1.89]; p = 0.46). Seven additional patients (2.4% infection risk) in the control group would need to experience a superficial SSI for a difference to be observed between the two groups. Conclusion: This meta-analysis of randomized trials examining use of topical vancomycin in spine surgery failed to show efficacy in reducing infection, and thus we do not recommend routine use of topical vancomycin for this indication. Future large-scale trials would be needed if surgeons believe that between-group differences smaller than those for which we were powered here (this meta-analysis had 80% power to detect a between-group difference of 1.5% in infection risk) are clinically important, and large database surveys may be informative in terms of assessing for postoperative adverse events associated with the use of vancomycin powder. Level of Evidence: Level I, therapeutic study. [ABSTRACT FROM AUTHOR]

Women going through menopause frequently experience vasomotor symptoms such as hot flashes, night sweats, and sleep disturbances, significantly influencing their quality of life. Hormonal therapy has been demonstrated to be beneficial in treating VMS. However, due to specific restrictions, it is not recommended for every woman. Fezolinetant, a neurokinin 3 antagonist and non-hormonal treatment for severe to moderate VMS, functions by inhibiting neuronal impulses originating from the hypothalamic thermoregulatory center. Current Skylight 2 and 4 trials statistically demonstrate the safety and acceptability of fezolinetant, with relatively few adverse effects reported. Fezolinetant has been shown great potential for treating menopausal-related VMS, supporting its further advancement. However, further investigation is required to thoroughly evaluate its safety, effectiveness, and its impact on sleep patterns. [ABSTRACT FROM AUTHOR]

Background: Glucagon‐like peptide‐1 receptor agonists (GLP‐1 RAs) are new anti‐hyperglycaemic drugs with proven cardiovascular (CV) benefit in diabetic and non‐diabetic patients at high CV risk. Despite a neutral class effect on arrhythmia risk, data on semaglutide suggest a possible drug‐specific benefit in reducing atrial fibrillation (AF) occurrence. Objective: To perform a meta‐analysis of randomized clinical trials (RCTs) to assess the risk of incident AF in patients treated with semaglutide compared to placebo. Methods and Results: Ten RCTs were included in the analysis. Study population encompassed 12,651 patients (7285 in semaglutide and 5366 in placebo arms), with median follow‐up of 68 months. A random effect meta‐analytic model was adopted to pool relative risk (RR) of incident AF. Semaglutide reduces the risk of AF by 42% (RR.58, 95% CI.40–.85), with low heterogeneity across the studies (I2 0%). At subgroup analysis, no differences emerged between oral and subcutaneous administration (oral: RR.53, 95% CI.23–1.24, I2 0%; subcutaneous: RR.59, 95% CI.39–.91, I2 0%; p‐value.83). In addition, meta‐regression analyses did not show any potential influence of baseline study covariates, in particular the proportion of diabetic patients (p‐value.14) and body mass index (BMI) (p‐value.60). Conclusions: Semaglutide significantly reduces the occurrence of incident AF by 42% as compared to placebo in individuals at high CV risk, mainly affected by type 2 diabetes mellitus. This effect appears to be consistent independently of the route of administration of the drug (oral or subcutaneous), the presence of underlying diabetes and BMI. [ABSTRACT FROM AUTHOR]