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L-citrulline is a precursor for endogenous arginine synthesis, supporting nitric oxide production and urea cycle function, yet its pharmacokinetics in neonatal calves are unknown. This study characterized and compared the pharmacokinetics of L-citrulline after intravenous (IV) and oral (PO) administration in healthy neonatal Holstein calves and evaluated associated amino acid responses and short-term clinical and laboratory tolerability. Six healthy male calves (2-4 weeks old) received a single 150 mg/kg dose of L-citrulline as extemporaneously prepared 5% (w/v) IV and 10% (w/v) PO formulations in a randomized 2-period crossover design with a 7-day washout. Blood samples were collected pre-dose and up to 48 h post-dose. Plasma amino acids were quantified by LC-MS/MS, and pharmacokinetic parameters were estimated using non-compartmental analysis. After IV administration, the highest observed total plasma L-citrulline concentration was detected at the first post-dose sampling time, 5 min after bolus administration (Cpeak 2213 ± 629 μmol/L; range, 1329-2830 μmol/L). After PO administration, Cmax was 1107 ± 371 μmol/L (range, 623-1478 μmol/L), with a median Tmax of 60 min (range, 45-120 min). Baseline-corrected non-compartmental analysis yielded t1/2 values of 2.32 ± 0.79 h after IV administration and 2.23 ± 0.60 h after PO administration, with AUC0-∞ values of 4130 ± 558 and 3444 ± 1067 μmol·h/L, respectively. Absolute oral bioavailability was 0.86 ± 0.32 (range, 0.52-1.28). Both routes increased plasma arginine (max +159% IV; +122% PO) and ornithine (max +132% IV; +149% PO) with no clinically relevant adverse effects or laboratory abnormalities during short-term monitoring of clinical, hematological, biochemical, blood gas/electrolyte, and coagulation variables. These findings support further evaluation of L-citrulline as a nutritional and/or therapeutic supplement in neonatal calves.

Pharmacist-led interventions significantly improved denosumab adherence in patients with osteoporosis at an academic medical center, reducing non-adherence from 20.8 to 4.9%. This quality improvement initiative included pharmacist-led medication counseling and laboratory monitoring, highlighting the effectiveness of pharmacist-physician collaboration in preventing rebound-associated vertebral fractures and enhancing patient outcomes. Interrupting or delaying denosumab beyond 7 months (210 days) from the last injection leads to transient increase in bone turnover known as rebound phenomenon, resulting in rapid loss of bone density and increased risk of vertebral fracture(s), now known as rebound-associated vertebral fractures (RAVF). Numerous studies suggest that clinical pharmacist participation in chronic disease state management leads to an increase in medication adherence and positive clinical outcomes. We evaluated the impact of a clinical pharmacist intervention on adherence to optimal denosumab timing for patients with osteoporosis. The model for improvement was used to design and evaluate this quality improvement project. This study analyzed 143 patients receiving denosumab therapy in an osteoporosis clinic every 6 months for the indication of osteoporosis. At baseline, 21% of patients receiving denosumab did not receive the medication at optimal time intervals for clinical effectiveness. An administration was considered correct or on time if denosumab was given within 210 days of the last injection received. If the injection was given outside this window, it was considered incorrect administration. The incidence of correct and incorrect administrations was gathered to calculate the non-adherence rate. Clinical pharmacist interventions included patient counseling and electronic dosing reminders and phone calls. The aim of this study was to reduce the nonadherence rate from 20.8% to less than 5.0% by July 31, 2023. With these interventions, the number of correct administrations between incorrect administrations improved from an average of 3.3 to 13.1. These effects became visible about 10 weeks after the second intervention and correspond to a reduction in nonadherence rate from 20.8 to 4.9% by July 31, 2023. Pharmacist-physician collaboration can reduce the nonadherence rate for drugs such as denosumab, interruption of which can result in serious consequences.

Antisense oligonucleotides (ASOs) are a rapidly growing therapeutic modality that directly modulate splicing or expression of disease-causing genes. ASOs are internalized through various endocytic mechanisms that converge on the endolysosomal pathway. Our work here aims to evaluate changes to the endolysosomal system following repeated ASO exposure. Histological examinations of nonhuman primates following repeated intrathecal administration of ASOs reveal dose-related neuronal microvesicular vacuolation in the hippocampus, cortex, and spinal cord. These changes are not associated with any neuronal degenerative changes or glial activation. Examination by electron microscopy reveals lysosomes containing stacked membranous material. We established an induced pluripotent stem cell-derived motor neuron (iPSC-MN) model that recapitulates these lysosome changes. ASO exposure did not cause any changes in iPSC-MN viability. To characterize lysosomal changes, we isolated lysosomes from iPSC-MNs after ASO treatment and quantified their protein and lipid contents by liquid chromatography-mass spectrometry. Our lipidomics studies documented increases in bis(monoacylglycerol)phosphate and lactosylceramide following ASO administration; proteomic analysis showed changes in several proteins, including decreases in four lysosomal hydrolases (Carboxypeptidase Q, ß-galactosidase, Cathepsin A, and α-l-Fucosidase). Altogether, this work advances our understanding of the cellular consequences following prolonged ASO administration and may guide further investigations to characterize these effects.

Nirsevimab is a monoclonal antibody with demonstrated efficacy in preventing respiratory syncytial virus (RSV) infections in infants. Because acute respiratory tract infections (ARTIs), including viral infections, often lead to antibiotic prescribing, we aimed to determine the effectiveness of nirsevimab on antibiotic prescribing among infants with medically attended ARTIs. A primary care attendee cohort was established using electronic health record data from 32 diverse practices across a healthcare network to emulate a target trial comparing nirsevimab to no treatment among infants <8 months. Eligible infants were seen at a primary care practice within 14 days of life. Primary outcomes included time to first antibiotic prescription for (1) outpatient ARTIs, (2) outpatient encounters for bronchiolitis, and (3) RSV-related hospitalizations. Nirsevimab effectiveness was calculated as 1 minus the risk ratio for each primary outcome. Among 15 341 patients who met inclusion criteria, 7413 received nirsevimab. Compared with no treatment, nirsevimab administration led to a 14.4% (95% CI: 7.8%, 20.6%) reduction in antibiotic prescribing for outpatient ARTIs, a 40.3% (95% CI: 25.1%, 52.5%) reduction in antibiotic prescribing for outpatient bronchiolitis, and a 69.4% (95% CI: 4.8%, 90.1%) reduction in antibiotic prescribing for RSV-related hospitalizations. Nirsevimab administration in primary care reduced antibiotic use for ARTIs in both ambulatory and inpatient settings.

To outline the current advances in food allergy. Food allergies have been increasing in prevalence and significantly affect the quality of life of both patients and their families. Over the past decades, there have been major changes to the recommendations for prevention and management of food allergies. These include timely introduction, various forms of immunotherapy, biologics, and epinephrine administration. As the effectiveness of many of these therapies are optimized in childhood, it is critical to be aware options are available. Shared decision-making is essential in navigating the current landscape of food allergy management.

Recent shifts in the geopolitical landscape, including the threat of nuclear conflict and the proliferation of nuclear materials, have heightened concerns about radiological emergencies. Acute radiation syndrome (ARS) is a major health consequence of such events, but effective medical countermeasures (MCMs) remain limited. Although several compounds have been approved as mitigators to treat ARS, there is currently no FDA-approved drug that can be used as a prophylaxis-administered before exposure to prevent or lessen the effects of radiation. One key mitigator is Nplate (romiplostim), a thrombopoietin receptor agonist currently approved for use as soon as possible after expected or confirmed exposure to myelosuppressive doses of radiation (2 Gray (Gy)). However, there is growing interest in expanding its utility beyond this narrow window. Our current research suggests that administering Nplate at later time points (e.g., 48 or 72 hours postexposure) could still provide a significant survival benefit. Furthermore, its potential as a prophylaxis is being explored, which could offer a vital layer of protection for first responders and military personnel in high-risk environments. This expansion would address a critical gap in current medical readiness and increase resilience in a radiologically contaminated environment. The efficacy of Nplate as both a mitigator and prophylaxis for ARS was evaluated in 2 separate studies using C57BL/6 mice. The first study used the Armed Forces Radiobiology Research Institute (AFRRI) cobalt-60 gamma irradiator to simulate nuclear fallout. Nplate was administered as a mitigator at 24, 48, and 72 hours postirradiation and as a prophylaxis at 6 and 12 hour preirradiation. The second study utilized the AFRRI Training, Research, Isotope, General Atomic (TRIGA) reactor to mimic nuclear detonation with mixed neutron-gamma radiation. All experiments were conducted under the oversight of the Uniformed Services University of the Health Sciences (USUHS) Institutional Animal Care and Use Committee (IACUC). When used as a mitigator for delayed administration, Nplate significantly enhanced the survival of both male and female subjects in a dose-dependent manner. In addition to improved survival rates, Nplate treatment led to the recovery of deficiencies in blood cell counts, an increase in colony-forming units (CFUs) in bone marrow, and a notable increase in megakaryocytes in sternal sections. Similarly, and even more pronounced, results were seen when Nplate was used as a prophylaxis. Prophylactic use resulted in a greater increase in overall survival, underscoring its potential to protect against the damaging effects of radiation. The data presented in this manuscript provides compelling evidence to support the expanded use of Nplate as a MCM against radiation exposure. Our findings demonstrate that Nplate's efficacy extends beyond its current approved use, remaining effective as a mitigator when administered at 24, 48, and even 72 hours postirradiation. Furthermore, the studies show that Nplate is a potent prophylaxis, offering significant protection for military personnel and first responders in the event of a radiological or nuclear incident. This data will be used to support continued interactions with the FDA to broaden Nplate's indications.

To characterize piperacillin population pharmacokinetics (PK) in critically ill children with and without extracorporeal membrane oxygenation (ECMO) support and to optimize piperacillin dosing regimens to attain the PK target of 100% free time above minimum inhibitory concentration (fT > minimum inhibitory concentration). Post hoc secondary analysis of a two-center, population PK modeling and simulation study (registered at clinicaltrials.gov, NCT02539407). PICUs at tertiary care centers, September 2015-November 2021. Thirty-three children supported with ECMO and 50 non-ECMO control patients treated with piperacillin (&#xb1; tazobactam). Administration of piperacillin at 300&#x2009;mg/kg/d by continuous infusion or 75&#x2009;mg/kg every 6 hours by intermittent infusion. A one-compartment linear-elimination model described best the piperacillin data. Clearance was driven by body weight and estimated glomerular filtration rate (eGFR). In a typical 11-kg patient, ECMO circuit volume-to-weight ratio increased the volume of distribution by 34%. Monte Carlo simulations across eGFR strata (30-60, 60-90, 90-150, 150-200, 200-300&#x2009;mL/min/1.73 m2) showed that a continuous infusion of 300&#x2009;mg/kg/d allowed greater than or equal to 90% of target attainment in all groups. Patients with an eGFR greater than 200&#x2009;mL/min/1.73 m2 required 400&#x2009;mg/kg/d to have 90% of target attainment. Continuous infusion of 300&#x2009;mg/kg/d piperacillin reliably achieves PK target across all renal-function ranges in children undergoing support with ECMO. Dose escalation to 400&#x2009;mg/kg/d is required for augmented renal clearance (eGFR > 200&#x2009;mL/min/1.73 m2).

Based on data from the U.S. Department of Defense Joint Trauma Registry, the Joint Trauma System has developed clinical practice guidelines for combat casualty care (CCC). As future high-intensity conflicts are likely to involve multinational operations, interoperability with allied nations-whose trauma systems may differ from established U.S. practices-is essential. This study aimed to compare key characteristics of French and U.S. military trauma systems to anticipate interoperability in CCC. This retrospective observational study included all U.S. and French service members (SMs) who sustained a severe battle injury requiring intensive care unit admission between 2009 and 2022. Demographics, prehospital management, and in-hospital interventions, including transfusions and tranexamic acid administration, were analyzed. A total of 734 U.S. and 98 French SMs met inclusion criteria. Most U.S. casualties occurred in Afghanistan (96.3%), whereas French casualties were mainly engaged in Africa after 2013 (51.0%). U.S. SMs sustained more improvised explosive device-related injuries (54.3% vs. 33.7%, P&#x2009;<&#x2009;.001) and fewer penetrating injuries (68.1% vs. 84.7%, P&#x2009;<&#x2009;.001) than French SMs. French SMs were more frequently managed by a prehospital physician (80.6% vs. 53.1%), received more prehospital transfusions (16.3% vs. 7.9%, P&#x2009;=&#x2009;.005), and more tranexamic acid (28.6% vs. 7.9%, P&#x2009;<&#x2009;.001). Median transport time from point of injury to surgical care was longer for French SMs (120 vs. 50 minutes). Both trauma systems emphasize early prehospital transfusion. Key differences include mechanisms of injury, the presence of a physician in prehospital teams, early tranexamic acid use, and evacuation timelines. Enhancing interoperability will require strengthened international data sharing, harmonization of competencies, and sustained collaboration in CCC.

Gepotidacin is a novel, first-in-class triazaacenaphthylene antibiotic that inhibits bacterial DNA replication through a distinct binding site and unique mechanism of action that provides well-balanced inhibition of two different type II topoisomerase enzymes (DNA gyrase and topoisomerase IV) for most pathogens. Gepotidacin was recently approved by the US Food and Drug Administration (FDA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) for the treatment of uncomplicated urinary tract infections (uUTI) and by the FDA for uncomplicated urogenital gonorrhea. This study investigated the in vitro time-kill kinetics, post-antibiotic effect (PAE), and sub-inhibitory MIC effect (PAE-SME) of gepotidacin, as well as interactions between gepotidacin and select marketed antibacterial agents for species where the published activity of gepotidacin was limited. Species included are those known to be associated with uUTI: Citrobacter freundii species complex, Enterobacter cloacae species complex, Klebsiella aerogenes, Klebsiella pneumoniae, Proteus mirabilis, Providencia rettgeri, Enterococcus faecalis, and Staphylococcus saprophyticus. Isolates were selected to represent various phenotypes, including wild type, extended-spectrum beta-lactamase positive (ESBL), and fluoroquinolone-resistant. Gepotidacin displayed concentration-dependent activity in time-kill, PAE, and PAE-SME experiments. Gepotidacin displayed bactericidal activity, often by 8 h, against 83% of isolates when tested at 4&#xd7; and 10&#xd7; MIC. In general, modest PAEs (>1-4 h) and extended PAE-SMEs (>4 h) were observed for gepotidacin. No antagonism was observed in broth microdilution checkerboard studies with marketed antibiotics, and the only consistent synergy observed was with gepotidacin and vancomycin against S. saprophyticus. These data add to the understanding of pharmacodynamics at play when treating with gepotidacin relevant uUTI species other than Escherichia coli. Antibiotic resistance continues to limit treatment options for common infections such as urinary tract infections (UTIs). Gepotidacin is a recently approved antibiotic that works in a new way compared with existing drugs, allowing it to remain active against bacteria that are resistant to many commonly used treatments. In this study, we examined how effectively gepotidacin kills several bacterial species that cause UTIs, including organisms that are resistant to fluoroquinolones or produce extended-spectrum &#x3b2;-lactamases. Gepotidacin was shown to rapidly reduce bacterial populations at clinically relevant concentrations and continued to suppress bacterial growth even after short exposures. Importantly, gepotidacin did not interfere with the activity of other commonly used antibiotics, suggesting it can potentially be used alongside existing therapies if needed. These findings provide additional evidence supporting the effectiveness of gepotidacin against a broad range of UTI pathogens and help improve our understanding of how this new antibiotic may perform in clinical treatment.

Minimally invasive cardiac surgery (MICS) offers faster recovery and improved patient satisfaction compared with sternotomy, but limited exposure makes myocardial protection challenging. Use of del Nido cardioplegia (DNC), originally developed for pediatrics, is increasing in adults due to its single-dose administration and prolonged arrest. Following PRISMA guidelines, PubMed was searched for studies published between September 1, 2015, and September 30, 2025, evaluating DNC in MICS or sternotomy-sparing cardiac surgery. Seven studies met inclusion criteria, including retrospective propensity-matched cohorts, 1 prospective randomized single-center trial, and 1 network meta-analysis. DNC was consistently linked to lower cardioplegia volume, fewer repeat doses, and shorter cross-clamp and bypass times compared with blood or histidine-tryptophan-ketoglutarate (HTK) solutions. Some studies reported reduced postoperative enzyme release, particularly with ischemic times <100 min. Safety outcomes, including mortality, complications, and recovery, were comparable across groups. Meta-analytic evidence suggested procedural efficiency advantages, while Custodiol ranked highest overall. DNC appears to be a safe alternative in MICS, offering workflow-related procedural efficiency while maintaining comparable myocardial protection. However, current evidence is mostly retrospective and single center. Large, multicenter, randomized trials are needed to establish its role versus HTK and Custodiol in sternotomy-sparing procedures.

In the aftermath of a nuclear detonation or other mass-casualty radiological event, thousands to millions of people may be exposed to high levels of radiation. Effective triage tools are needed to identify those with potentially life-threatening exposure requiring emergency medical care. To ensure these tools will be available to support a mass-casualty radiation event, US Food and Drug Administration (FDA) authorization is required. However, currently, no FDA-authorized biodosimetry tests are available to support a mass-casualty radiological event, due largely to the significant challenges in developing regulatory strategies for biodosimetry tests. We have developed a tool, called the CellRADx Software Application, to help address this mass-casualty triage need. CellRADx utilizes complete blood count (CBC) results from a single test, along with other inputs such as age and time post-exposure, to determine if an individual has absorbed more than 2 Gy of ionizing radiation. As part of the development of CellRADx, we have created a novel approach to facilitate the complete validation of the software device in compliance with FDA's medical device regulations. This novel approach employs a combination of real-world CBC data, an in silico radiation-induced cell depletion model, and nuclear event dose distribution models to validate clinical performance. Performance of CellRADx across the general population has been demonstrated with high sensitivity (92%) and high specificity (78%). Additional subpopulations with potentially confounding conditions were also tested using this approach and have demonstrated similar performance results. The ability to validate a biodosimetry device using a method that can support FDA authorization is a key enabling development that will facilitate implementation of tools that can improve preparedness for a mass-casualty nuclear event and help save many lives.

Congress, the United States Department of the Air Force (DAF) leadership, and other individuals frequently request military-specific cancer cluster investigations as concerns over cancer clusters within the military community continues to be a public health topic. The Intercontinental Ballistic Missile (ICBM) missile community is involved in the operation and maintenance of long-range ballistic missiles that have the capability to deliver nuclear warheads as part of the U.S. nuclear deterrence mission. They experience unique working conditions that are demanding and highly regulated due to the sensitive and critical nature of their work. The purpose of this study is to further evaluate cancer incidence and cancer mortality among missile community (MC) members serving from 1976 to 2010 utilizing multiple data sources from the Department of Defense (DoD) electronic health record, the Veteran's Administration (VA) electronic health record, both the DoD and VA cancer registries, and National Death Index data. For both incidence and mortality, an internal comparison (MC compared to DAF non-missile community [non-MC]) and an external comparison (MC compared to the U.S. general population) were conducted. For the internal comparisons, regression analyses were adjusted for sex, age, race, and rank (officer vs. enlisted). Incidence rate ratios (IRRs) and mortality rate ratios and corresponding 95% confidence intervals were estimated using the log link function, with individual person-years accounted for using the offset option. For the external comparisons, standardized incidence ratios and standardized mortality ratios were adjusted for age, sex, race, and year of death and were generated for the MC as compared to the U.S. general population for each of the 14 cancers individually and collectively. Males accounted for 92.92% of the MC, compared to 84.10% of the non-MC. Most individuals in both groups were White, accounting for 84.41% in the MC and 80.25% in the non-MC. Prostate cancer was the most common type among both the MC (n&#x2009;=&#x2009;577, 31.38%) and non-MC (n&#x2009;=&#x2009;16,845, 31.55%). Cancer incidence in the MC was statistically similar or lower compared to both the U.S. general population and the non-MC. Likewise, cancer mortality in the MC was statistically similar or lower compared to both comparison groups. Although this study did not find an increased risk of cancer incidence or mortality in the MC, additional analysis is planned using data from the Virtual Pooled Registry. Not only does this study provide a more comprehensive and reliable assessment of cancer risks in this military population than previous investigations, but it also informs important decisions about the design of future cancer epidemiology studies in military populations.

Alzheimer's disease (AD) remains a major cause of dementia, and currently available therapies provide only modest clinical benefit or are limited by intravenous administration and treatment-related adverse effects. Blarcamesine (ANAVEX 2-73) is an orally administered sigma-1 receptor (S1R) agonist that has demonstrated neuroprotective effects in preclinical studies and has progressed through Phase I, Phase II and Phase IIb/III clinical trials. This systematic review evaluated the current clinical evidence for the efficacy and safety of blarcamesine in early-stage and mild-to-moderate AD. A systematic literature search was conducted in PubMed (including MEDLINE), Scopus, and Google Scholar, together with clinical trial registries, with the final search performed in September 2025. Reference sections of manuscripts were searched, and authors were contacted for additional data. Studies investigating only blarcamesine in participants with mild-to-moderate AD were included. Blarcamesine for other diseases or severe AD were excluded. Data were summarised descriptively in accordance with PRISMA guidelines. The risk of bias was assessed using version 2 of the Cochrane Risk of Bias tool (RoB2) for randomised, placebo-controlled trials, and an adapted version of RoB2 for cross-over trials. One Phase I first-in-human study in healthy volunteers and ten reports describing two randomised clinical trials (NCT02244541, a randomised open-label study, and NCT03790709, a randomized placebo-controlled study) and their associated open-label extension studies (NCT02756858 and NCT04314934) were identified, including two peer-reviewed manuscripts, two preprints, and six conference abstracts. Thirty-two participants were enrolled in the Phase IIa open-label dose-finding study, where outcome measures were compared to baseline (NCT02244541). In the extended open-label study exploring the cognitive effect for another 52 weeks, 21 of 32 remained in the study (NCT02756858). The randomised placebo-controlled trial (NCT03790709) enrolled 509 participants and randomised them into three groups: 167 treated with 30 mg blarcamesine, 168 treated with 50 mg blarcamesine and 168 treated with placebo (for 30 mg blarcamesine, 112 completed the study; for 50 mg blarcamesine, 90 completed the study; and for placebo, 136 completed the study). Subsequently, 300 of 509 participants remained in the open-label extension (NCT04314934). Across these two studies, blarcamesine was generally well tolerated, with adverse events that were predominantly mild, transient, and dose-related. Treatment was associated with slower cognitive and functional decline, improvements in multiple clinical outcome measures, and reduced brain atrophy in genetically defined subgroups. Participants carrying the SIGMAR1 and COL24A1 wild-type genotypes were associated with greater therapeutic benefit, supporting the potential value of pharmacogenomic patient stratification. Current clinical evidence suggests that blarcamesine is a promising orally administered therapeutic candidate for early-stage AD with an acceptable safety profile and encouraging efficacy, particularly in genetically defined populations. However, the available evidence is derived from a limited number of clinical studies, including secondary analyses and conference reports. Additional independent randomised clinical trials are required to confirm these findings and further define the role of blarcamesine in the treatment of AD. CRD420251142826.

The KEYNOTE-689 trial demonstrated improved event-free survival with the addition of perioperative pembrolizumab to standard of care for patients with locally advanced head and neck squamous cell carcinoma (HNSCC), yet the cost-effectiveness remains unknown. To evaluate the cost-effectiveness of the KEYNOTE-689 perioperative pembrolizumab protocol. A partitioned survival model simulated the KEYNOTE-689 trial cohort with 3 mutually exclusive health states: event-free survival, disease progression, and death. Model inputs included Healthcare Cost and Utilization Project-derived and US Centers for Medicare & Medicaid Services-derived costs for drug acquisition (pembrolizumab and cisplatin), administration, surgery, radiation therapy, supportive care, management of serious adverse events, and disease progression. KEYNOTE-689 Kaplan-Meier survival estimates were digitized and data for the combined positive score (CPS) of 1 to 10 subgroup were derived from the reported CPS of 1 or greater and CPS of 10 or greater subgroups. Quality-adjusted life-year (QALY) values for different health states were sourced from published literature, with the US population preference-weighting algorithm applied to EuroQol 5-Dimension 3-Level health questionnaire data from the CheckMate 141 trial. The primary outcome was the incremental cost-effectiveness ratio (ICER) results stratified by programmed cell death 1 ligand 1 (PD-L1) combined positive score (CPS of 1 to 10 vs greater than 10). A probabilistic sensitivity analysis (PSA) was performed to evaluate parameter uncertainty. Subgroup analyses based on PD-L1 expression yielded divergent results. In the CPS greater than 10 cohort, perioperative pembrolizumab was cost-effective, producing approximately 1.35 additional QALYs at an incremental cost of $181&#x202f;900, resulting in an ICER of $134&#x202f;700. PSA showed a 57% probability that the pembrolizumab strategy was cost-effective at a $150&#x202f;000 willingness-to-pay (WTP) threshold. In the CPS of 1 to 10 cohort, perioperative pembrolizumab resulted in approximately 0.08 additional QALYs at an incremental cost of $166&#x202f;500, for an ICER of $2&#x202f;179&#x202f;400, with the PSA demonstrating an 11% probability of cost-effectiveness at a $150&#x202f;000 WTP threshold. In this economic evaluation, addition of perioperative pembrolizumab to standard treatment for locally advanced HNSCC may represent a cost-effective intervention for patients with a PD-L1 CPS greater than 10 if KEYNOTE-689 data are replicable in clinical practice. Perioperative pembrolizumab is not a cost-effective strategy for patients with a CPS less than 10 based on current data. Biomarker stratification may inform the value-based integration of immunotherapy among patients with HNSCC.

To investigate the effects and targets of cordycepin (COR) in alleviating non-alcoholic fatty liver disease (NAFLD). High-fat diet was used to induce NAFLD in mice, and after COR gavage administration, changes in liver function, glucose and lipid metabolism, and ferroptosis-related signaling were detected. In&#xa0;vitro, palmitic acid (PA) and oleic acid (PSA) were combined to induce hepatocyte lipid injury. The effect of COR on hepatocyte ferroptosis was examined. GCH1 conditional knockout mice (GCH1-CKO) and hepatocyte models were constructed, and AAV9-GCH1 was used to construct GCH1 overexpression mouse models to verify the effect of GCH1 on NAFLD. CETSA-WB, co-immunoprecipitation, and DARTS were employed in the COR-GCH1 interaction and mechanism studies to validate the targeted binding relationship between COR and GCH1. Animal-level studies showed that COR could improve glucose and lipid metabolism and liver function damage in mouse NAFLD, inhibit ferroptosis occurrence and lipid peroxidation injury. Cell-level results showed that COR could inhibit hepatocyte ferroptosis. The ferroptosis-inhibiting effect of GCH1 is independent of GPX4 and other signals; GCH1 directly inhibits reactive oxygen free radicals and suppresses lipid metabolism peroxidation damage. COR's effects are not related to classical anti-ferroptosis signals such as GPX4 and Nrf2, but only related to GCH1. COR can target the GCH1 K155 site, stabilize protein levels by inhibiting GCH1 ubiquitination degradation, and when GCH1 is knocked out, COR's effects are antagonized. GCH1 has a protective role in NAFLD, and this effect is independent of classical GPX4 signaling. COR can target the GCH1 K155 site, inhibit GCH1 ubiquitination thereby preventing protein degradation and exerting protein stabilization. COR elevates GCH1 levels to inhibit ferroptosis. COR is a small molecule with potential for treating NAFLD.

Military personnel are exposed to bouts of acute stress during their careers, in which cognitive processes associated with decision-making might simultaneously suffer. Currently, it is still unclear how hormones and neurotransmitters involved in the acute stress response specifically affect these decision-making subprocesses, particularly in the military. We aimed to expose military personnel to pharmacological stress, in which noradrenaline and/or cortisol activity was stimulated. Next, decision-making subprocesses (i.e. working memory, impulse control and risk-taking) were assessed. A sample of 100 Dutch military personnel were recruited. Noradrenaline and/or cortisol activity was stimulated through oral administration of yohimbine and hydrocortisone, respectively. Decision-making subprocesses were assessed through computerised tasks. Induction of stress was confirmed through psychophysiological measures. Working memory seemed subtly affected by stress, as heightened noradrenaline slowed recall while cortisol accelerated it. Inhibition was unaffected by acute stress. Risk-taking was enhanced solely by noradrenaline, contrasting earlier research positing cortisol as a predictor of amplified risk-taking in civilians. Our findings contribute to the existing literature of the effects of acute stress on cognitive processes associated with decision-making, emphasising intricacies of the effects of specific stress hormones and neurotransmitters. Future research is needed to further identify these differential intricacies on cognitive processes, keeping potential differences between demographic subgroups in mind.

Bruceantin (BCT), a natural product with promising anticancer properties, has limited clinical utility due to its hydrophobicity, low systemic bioavailability, and dose-limiting toxicity. Here, we report a redox-responsive polymeric nanoplatform based on a disulfide-linked diblock copolymer, poly(ethylene glycol)-block-poly(&#x3b5;-caprolactone) (PEG-SS-PCL), functionalized with luteinizing hormone-releasing hormone (LHRH) peptides for the targeted delivery of BCT to pancreatic cancer cells overexpressing LHRH receptors. The nanoplatform exhibits favorable physicochemical characteristics, including optimal particle size (45.7 nm), zeta potential (+3.5 mV), and high drug encapsulation efficiency (74.8%). Notably, it demonstrates redox-responsive drug release under glutathione-rich conditions that mimic the tumor microenvironment. In vitro assays highlight the superior cytotoxicity of the LHRH-targeted BCT formulation (IC50, 224.1 &#x3bc;g mL-1) compared to the non-targeted formulation (IC50, 279.5 &#x3bc;g mL-1). Biodistribution studies in an orthotopic pancreatic cancer murine model revealed substantial accumulation of LHRH-targeted nanoparticles primarily in tumors following systemic administration, with minimal hepatic deposition. Furthermore, BCT-loaded nanoplatforms reduced tumor growth by &#x223c;72.4% relative to controls, with no detectable adverse effects. Collectively, this work highlights the potential of LHRH-functionalized nanoplatforms as a promising strategy for the targeted treatment of pancreatic cancer with BCT, offering enhanced therapeutic efficacy with minimal systemic toxicity and paving the way for future clinical translation of this natural product.

Pyogenic spondylitis is treated with high-dose antibiotics for at least six weeks. In this study, we aimed to develop a novel therapeutic agent that can enhance bacterial targeting. We used solid lipid nanoparticles (SLNs) containing the antibiotic ampicillin (AMP), which were functionalized with the positively charged peptide LL-37. AMP-loaded SLNs (AMP-SLNs) were prepared, and LL-37 was attached to the AMP-SLNs (LL-37@AMP-SLNs). The physicochemical properties of the nanoparticles were characterized by particle size, zeta potential, morphology, drug release behavior, and hemocompatibility analyses. Furthermore, antibacterial activity, bacterial-targeting capability, and therapeutic efficacy were evaluated using Enterococcus faecalis-infected mesenchymal stem cells and a rat model of pyogenic spondylitis. The antibacterial performance of LL-37@AMP-SLNs was compared with that of SLNs and AMP-SLNs. The average size of the SLNs was approximately 342.66&#x2009;&#xb1;&#x2009;48.04&#xa0;nm, which increased to 528.58&#x2009;&#xb1;&#x2009;35.64&#xa0;nm after AMP loading and 695.58&#x2009;&#xb1;&#x2009;75.58&#xa0;nm following LL-37 modification. The LL-37@AMP-SLNs exhibited sustained AMP release over four days and demonstrated enhanced antibacterial activity and bacterial-targeting capability compared with unmodified SLNs and AMP-SLNs. LL-37@AMP-SLNs were shown to inhibit bacterial growth by targeting the cytoplasmic membrane and the cell walls of Gram-positive bacteria. Moreover, the LL-37@AMP-SLNs treatment led to significantly enhanced antibacterial effects. In vitro studies showed significantly greater inhibition of bacterial growth, while intravenous administration of LL-37@AMP-SLNs significantly reduced bacterial burden and improved therapeutic outcomes in the pyogenic spondylitis rat model compared with free AMP treatment. We suggest that LL-37@AMP-SLNs can be a useful therapeutic agent for targeting bacteria in pyogenic spondylitis.

Trust between healthcare providers is important in facilitating collaborative practices, especially in primary care, where disciplines collaborate across communities to deliver patient-centred care. To identify the facilitators and barriers that influence trust in interprofessional partnerships within primary care settings. We searched PubMed, PsycInfo, Embase, and CINAHL using key words to identify articles published up to 16 August 2023. Facilitators and barriers to trust were mapped onto the Consolidated Framework for Implementation Research (CFIR). Quality assessment utilized the Mixed Methods Appraisal Tool (MMAT). From 5750 screened articles, 11 studies were included. Sixteen facilitators and seven barriers were identified. Facilitators included co-location, familiarity, competence, professional identities, and effective communication. Barriers included perceived conflicts of interest, lack of familiarity, and transgressions of professional boundaries. Trust was often unbalanced, with a perception among non-medical healthcare professionals that they need to earn trust from medical healthcare professionals. Formation and nurturing of interprofessional trust is the foundation for building strong partnerships between healthcare professionals that promote collaborative practice in primary care. Future research should include non-English and grey literature and focus on the unequal trust dynamics.