搜索结果：Stamford

Cariprazine is effective in a number of conditions and has shown efficacy in the treatment of negative symptoms. Data on its use as an adjunct to other antipsychotics is growing. To evaluate the effectiveness of add-on cariprazine in patients with predominant negative symptoms, we assessed a series of patients prescribed adjunctive cariprazine using the Schedule for the Assessment of Negative Symptoms (SANS). Patients had few positive symptoms, but negative symptoms were considered to have a major effect on functioning. SANS scores were calculated at baseline, 12 weeks and 24 weeks. We compared median scores using the Wilcoxon signed-rank test. Ten consecutive patients were evaluated. Median baseline SANS score was 87 (IQR 32), 66 (IQR 23) at week 12 (p = 0.002 vs baseline) and 57 (IQR 33) at week 24 (p = 0.006 vs baseline). At Week 12, 70% of the patients were still prescribed the initial starting dose of 1.5 mg daily, and at Week 24, 30% of the patients remained on the 1.5 mg/day dose. Adjunctive cariprazine was effective in the treatment of residual negative symptoms in people with minimal positive symptoms.

Time to onset of reversal is critical when treating opioid-induced respiratory depression and hypoxia. This study aimed to develop a formulation of the opioid antagonist nalmefene with an increased absorption rate and reduced time to onset of reversal following intramuscular administration. Several absorption enhancers were screened in rats, followed by confirmatory studies in dogs. Subsequently, nalmefene formulations with a range of MgCl2 concentrations were evaluated in a two-part translational clinical study in healthy participants. In Part 1 (N = 17), pharmacokinetic parameters were assessed following intramuscular injections of nalmefene formulated with MgCl2 (0.47%-4.7%) or NaCl (0.9%). In Part 2 (N = 6), participants received intravenous fentanyl to produce opioid-induced respiratory depression. They were then dosed with intramuscular nalmefene formulated with 0.94% MgCl2, intranasal naloxone or placebo (intramuscular saline) in a randomized six-period crossover sequence with each treatment administered on two separate occasions. Minute ventilation, oxygen saturation and carbon dioxide were monitored continuously, and pharmacokinetic and pharmacodynamic parameters were evaluated. Pharmacokinetic profiles from animals indicated that MgCl2 within a range of concentrations enhanced the nalmefene absorption rate. In the clinical studies, a nalmefene 1.5 mg formulation containing 0.94% MgCl2 demonstrated more rapid absorption compared with a formulation containing 0.9% NaCl and also produced faster, more robust reversal of opioid-induced respiratory depression compared with intranasal naloxone. These preclinical and clinical studies demonstrate that a nalmefene formulation containing magnesium chloride produced more rapid nalmefene absorption after intramuscular injection, which is advantageous for the treatment of opioid overdose in settings where life support is not immediately available.

Maris et al document important ethical challenges at the intersection of electronic health record data and artificial intelligence development, but existing governance frameworks designed for secondary data use are categorically insufficient for artificial intelligence model training, which creates persistent deployable artifacts that encode local clinical patterns as generalizable knowledge. Drawing on two decades of stewardship framework development, we propose extending governance from data stewardship to model stewardship.

The early-life rumen microbiome is highly dynamic, shaped by dietary transitions and maternal influences. Several dietary additives have been studied during the pre- and post-weaning periods to improve animal welfare, growth performance, and farming efficiencies. This study investigated microbial community assembly and growth performance of lambs provided with a mannan-rich fraction (MRF) supplement, either through maternal supplementation, directly, or via a combination of both. Using metagenomic sequencing and gas chromatography, we found differences in rumen microbial alpha and beta diversity related to both sampling time point and MRF supplementation (p < 0.05). At week 8, lamb microbiomes showed greater variance in their Shannon alpha diversity, with direct MRF supplementation only to the lamb resulting in a significantly greater diversity (p < 0.05). At week 20, combined maternal and lamb supplementation resulted in the highest Shannon diversity and was different compared to all other groups (p < 0.05). Beta diversity analyses combined with differential abundance analyses revealed that microbial community structures are driven by both diet and time, with maternal MRF supplementation associated with enrichment of taxa involved in carbohydrate fermentation and succinate metabolism, including Succiniclasticum ruminis, Succinovibrio dextrinosolvens, and Fibrobacter succinogenes. Generalized linear modeling identified significant associations between microbial alpha diversity metrics and total volatile fatty acids in lambs, particularly butyrate and valerate. Furthermore, at week 8, there was a significant positive correlation between alpha diversity metrics and propionate and valerate. In this study, lambs receiving MRF through maternal and direct supplementation had the highest growth performance, measured as the median average daily gains (kg) and final weights (kg) of lambs. These findings suggest that MRF supplementation, especially when provided both maternally and directly, may influence the lamb rumen microbiome and alter its metabolic potential with potential implications for optimizing early-life nutrition strategies in ruminant production systems.

Both untargeted "discovery" and targeted lipid analyses were performed on liver extracts obtained from mice, following the intravenous administration (10 mg/kg) of the tyrosine kinase inhibitor gefitinib, to maximize coverage of the liver lipidome. Untargeted lipid analysis by RP-UHPLC-IM-MS in both +ve and -ve ESI showed time-related changes in lipid profiles, including reductions in the abundances of PCs and PEs and a concomitant rise in the LPCs. Targeted analysis by HILIC-UHPLC-MS using +ve ESI also showed time-related effects on the lipid profiles of gefitinib-dosed mice with PCs, SMs, TGs, and LPCs, particularly for the lipids PC(34:1), PC(32:1), SM(40:1), TG(48:1), and PC(32:0), and effects on a number of acyl carnitines were also noted. In addition, time-related effects were seen using -ve ESI on a range of lipids, including PGs, PCs, LPEs, PEs, and FFAs. The resulting data suggest widespread effects on fatty acid utilization and metabolism may occur in the liver of mice as a result of exposure to gefitinib.

To perform an updated systematic review and meta-analysis of the efficacy and safety of intensive (INT) vs. conventional (CONV) blood glucose (BG) targets for critically ill adults on insulin infusions. We conducted a comprehensive search of Embase and OVID Medline databases from inception to October 16, 2023. We manually excluded studies published before 2000 due to potential lack of relevance as glycemic control in the ICU was not routinely practiced before 2000. We included randomized controlled trials (RCTs) evaluating adult, critically ill patients on insulin infusions comparing INT vs. CONV targets for efficacy and safety outcomes. Data were screened and extracted with accuracy confirmed by a second reviewer. Study methodological characteristics, patient population, interventions, and outcome data were recorded. Studies without numerical outcomes were summarized as text statements. Forty-five RCTs were included involving 32,215 patients. No differences were seen between INT and CONV targets for hospital mortality or ICU mortality. INT targets were associated with lower ICU length of stay (LOS), infections, and critical illness polyneuropathy (CIP); however, INT targets demonstrated a 3.6-fold higher risk of severe hypoglycemia. Most of the studies with significant differences contained serious inconsistencies or risk of bias. In the subgroup analyses, INT targets demonstrated favorable neurologic outcomes in neurologic ICU patients, lower ICU LOS in mixed ICU patients, and lower ICU mortality in the cardiac surgery subgroup. INT BG targets demonstrated mild to moderate improvements in several important morbidity secondary outcomes, including LOS, infections, and CIP, but were associated with a 3.6-fold higher risk of severe hypoglycemia. No differences were seen in ICU or hospital mortality. INT targets should not be routinely used over CONV targets when trying to minimize hypoglycemia as a marker of patient safety. However, as stated in the Society of Critical Care Medicine guidelines, a lower target within the INT range (110-140&#x2009;mg/dL; 6.1-7.8 mmol/L) may be considered acceptable in select centers where the risk of hypoglycemia is documented to be negligible based on routine assessment and with the use of optimized glycemic management protocols.

Naturalistic studies examining paliperidone palmitate 3-monthly (PP3M) long-acting injection have proven PP3M to be a safe and effective maintenance treatment for patients with schizophrenia. The aim of this study is to explore patients' views and experiences with PP3M. This was a cross-sectional, non-interventional, one-time questionnaire which was designed by pharmacists in collaboration with clinicians experienced in the use of long-acting antipsychotic injections. Eligible patients were adults currently prescribed PP3M who were attending their routine long-acting injection administration appointment at their community mental health team (CMHT). Of 172 patients who were due PP3M during the study period, 68 (39.5%) completed the questionnaire. Of these, 31.3% found PP3M extremely helpful, 43.3% found it very helpful, 17.9% somewhat helpful, 3% slightly helpful and 4.5% not helpful at all. The majority of respondents (83.8%) preferred PP3M over PP1M, with convenience being cited as the main reason for preference (62.9%). The majority reported mild (35.4%) or no injection pain (30.8%) and no new side effects on PP3M (80.6%). For those experiencing side effects, they were largely not considered troubling (24.6%). CMHT contact remained unchanged since switching to PP3M (56.9%). In-person appointments were considered important (33.8%) or very important (35.4%). Most patients either had no preference (40.3%) or were opposed to having a monthly appointment (32.3%). When asked about preferred injection frequency, patients overwhelmingly selected the 3-monthly (62.5%) or 6-monthly option (35.9%). Patients generally reported high levels of satisfaction with PP3M and perceived the treatment to be helpful and well-tolerated, with most expressing a preference for PP3M compared with a 1-monthly injection. Patient views on paliperidone palmitate 3-monthly injection People living with schizophrenia often need long-term medication to stay well. Some medicines are available as long-acting injections that are given monthly or every few months. Paliperidone palmitate 3- monthly (PP3M) is an injection given once every three months. This means patients need four injections per year. Whilst studies have shown that PP3M is an effective and convenient treatment for many people, little is known about how patients themselves feel about it. This study has asked patients in community mental health teams across South London to share their views and experience of PP3M. A short questionnaire was completed by 68 patients who were receiving PP3M as part of their usual care. Questions covered helpfulness of treatment, side effects, pain at the injection site, contact with healthcare staff and preferred injection frequency. Most patients said that PP3M was very or extremely helpful and that they preferred it over their previous monthly injection. Convenience was the most common reason for preferring PP3M. The majority reported mild or no injection pain and no new side effects. Contact with their community mental health team generally stayed the same after switching to PP3M. Seeing their team in person was considered important, and most preferred their injection frequency to remain every three months followed by every six months. Overall, this study suggests that patients find PP3M convenient, well-tolerated and acceptable in routine clinical practice. Understanding patient views is important to ensure that treatment plans both support effectiveness of treatment and patient quality of life.

The objective of this analysis was to describe the effects of methylphenidate-mediated symptom improvement on functional impairments in adults with ADHD. This is an exploratory study of self-reported functional impairment on the Weiss Functional Impairment Rating Scale (WFIRS-S) in 351 ADHD adults treated in a forced dose, double blind (DB), randomized, parallel clinical trial of a 16-hr methylphenidate stimulant (PRC-063) for 4 weeks followed by open-label (OL; N = 147) for 6 months. During the 4-week DB period, there was a statistically significant response to medication versus placebo in the WFIRS-S domain of "work." Forty percent of DB subjects, assigned a random dose of medication, showed functional improvement as defined by the Minimal Clinical Important Differences (MCID) of the WFIRS. At the end of DB, one third of subjects had scores below symptomatic and functional impairment thresholds and two thirds by the end of OL. Although the OL period was uncontrolled, when all subjects had been dose optimized with sufficient time for functional impairment to manifest, all WFIRS functional domains showed clinically-relevant improvements from baseline to end of the 6-month OL (p&#x2009;<&#x2009;.0001). There was a fair-to-moderate correlation between change in symptoms and change in function, but ADHD symptoms were about twice as sensitive to change. The strongest predictor of improvement in function was greater improvement in ADHD symptoms. Younger age predicted greater functional impairment. This study of the relationship between change in symptoms and functional outcome illustrates that improvement in symptoms may be associated with an almost cotemporaneous improvement in function, that increases over time. Identification of subjects who are symptom responders with residual functional impairment suggests the need for additional intervention to target residual functional difficulty. Further research needs to replicate this methodology using an individually dose optimized design to demonstrate full potential for change and to confirm the domains of functioning in adults with ADHD that are most responsive to stimulant treatment. https://clinicaltrials.gov/study/NCT02139124.

We report a novel Efflux Resistance Breaker (ERB) strategy for designing antibiotics intrinsically resistant to efflux, using fluoroquinolones as a model class. ERB-modified fluoroquinolones showed enhanced intracellular accumulation and markedly improved antibacterial activity, with up to 512-fold reduction in MIC (MIC90 0.03-2 &#x3bc;g/mL) across multidrug-resistant bacteria. Lead compounds KSN-L22 (46) and BL-7 (50) demonstrated potent activity against MRSA, Streptococcus pneumoniae (including MDR and PRSP), Enterococcus faecalis and E. faecium (VanA, VanB and VanD), as well as Acinetobacter baumannii and Escherichia coli. The compounds inhibited both wild-type and S84L mutant DNA gyrase (IC50 &#x223c; 3.8 &#x3bc;g/mL) and achieved a > 4-log bacterial load reduction in a murine thigh infection model at oral doses of 50 mg/kg. Favorable oral and intravenous PK/PD profiles, absence of toxicity at 1200 mg/kg/day, and no hERG, CYP450, or off-target liabilities were observed. ERB technology provides a promising strategy for designing antibiotics that are intrinsically less susceptible to efflux.

This multi-institutional randomized phase II clinical trial (NCT03414684) investigated the efficacy and safety of carboplatin plus nivolumab compared to carboplatin in metastatic triple-negative breast cancer (mTNBC). The primary endpoint was progression-free survival (PFS) in a modified intention-to-treat (mITT) population of patients with chemotherapy-na&#xef;ve (i.e., first-line) mTNBC. Secondary endpoints included overall survival (OS), confirmed objective response rate, confirmed clinical benefit rate, time to and duration of confirmed objective response, safety, and tolerability. Clinical outcomes were evaluated in the PD-L1-positive subgroup (&#x2009;&#x2265;&#x2009;1% immune cells; SP142 clone) per central review. Biospecimens were collected for correlative analyses. 75 patients were enrolled and treated between 2/2018-9/2020. Among the mITT population (n&#x2009;=&#x2009;62), median PFS was 4.2 months with carboplatin plus nivolumab vs 5.5 months with carboplatin. Median OS did not significantly differ between arms (16.8 vs 11.1 months, respectively). In PD-L1-positive mTNBC patients (n&#x2009;=&#x2009;24), median PFS was 8.3 vs 4.7 months; median OS was 17.6 vs 10.7 months. Grade &#x2265;3 adverse events occurred in 56.8% of patients in the combination arm and 65.8% in the carboplatin arm. Carboplatin plus nivolumab did not significantly improve PFS compared to carboplatin in patients overall; however, a trend toward improved outcomes was observed in PD-L1-positive mTNBC patients. High mutational burden, interferon-gamma signaling, early circulating tumor&#xa0;DNA reduction, low baseline serum thymidine kinase activity, and urea cycle dysregulation in the microbiome emerged as potential predictors of response to immune checkpoint inhibitors with platinum.

Background: Cyclosporine is widely used to prevent transplant rejection; however, its systemic administration is associated with low bioavailability and a risk of severe adverse side effects. In the context of lung transplantation, local pulmonary delivery represents a promising strategy to reduce the required dose while enhancing local anti-inflammatory efficacy and limiting systemic toxicity. Methods: In this study, cyclosporine was encapsulated in liposomes coated with calcium phosphate to improve cellular uptake. The liposomal formulation was subsequently converted into a dry powder for inhalation to enable pulmonary administration, combining cyclosporine-loaded liposomes with a calcium phosphate coating, extending prior work on inhaled liposomal cyclosporine and mineral-coated liposomes into a single platform. The cyclosporine loading was optimised to achieve an efficient drug content in the final formulation. Results: The presence of the calcium phosphate coating on the liposomal surface was confirmed by the shift in zeta potential and by cryo-transmission electron microscopy. The resulting dry powder exhibited suitable aerodynamic properties for pulmonary delivery with a fine particle fraction of 33.6 &#xb1; 1.6%. In vitro biocompatibility studies performed on A549 epithelial cells and THP-1 monocytic cells demonstrated that the formulation did not affect cell viability. Furthermore, the formulation containing calcium phosphate-coated liposomes showed a stronger anti-inflammatory effect compared with both uncoated liposomal formulations and the corresponding raw material, consisting of a physical mixture of phospholipids and cyclosporine. Conclusions: Overall, despite limitations on respirability and efficacy that will require further in vivo studies, this calcium phosphate-coated liposomal dry powder could represent a promising strategy for targeted pulmonary delivery of cyclosporine, with potential to improve the prevention of lung transplant rejection while minimising systemic side effects.

To compare the effects of different exercise modalities on lower-limb balance and functional motor performance after stroke and to examine their nonlinear dose-response relationships to identify potentially optimal exercise doses using a Bayesian network meta-analysis. A systematic search of PubMed, Embase, Web of Science, the Cochrane Library, and SPORTDiscus identified 54 randomized controlled trials (RCTs). A Bayesian random-effects dose-response network meta-analysis examined associations between total exercise dose, exercise modalities, and lower-limb balance and functional mobility after stroke. Both lower-limb balance and functional movement outcomes showed clear nonlinear improvements with increasing total exercise doses, peaking at approximately 1,800-2,200&#x2009;MET&#xd7;min/week. Beyond this range, marginal benefits plateaued or declined, with greater inter-individual variability. For lower-limb balance, gains stabilized or slightly decreased past 2,200&#x2009;MET&#xd7;min/week. Functional movement improvements formed an early plateau at around 1,800&#x2009;MET&#xd7;min/week, sustained up to 2,200, then gradually diminished. Exercise modalities displayed distinct dose sensitivities: integrated aerobic training (IAT) rapidly achieved peak benefits at moderate loads, supporting early rehabilitation; motor control training (MCT) maintained stable effects over a broader range, facilitating long-term neuromuscular reinforcement; virtual reality training (VRT) showed localized peaks at low to moderate doses but exhibited increased uncertainty at higher levels. This study suggests that moderate weekly exercise doses may improve lower-limb balance and functional mobility after stroke, with dose-response patterns differing across exercise modalities. These findings support dose regulation and individualized exercise prescription, although further high-quality trials are needed to confirm the observed dose ranges and modality-specific effects. This study is the first to apply a Bayesian non-linear network meta-analysis to model the joint effects of exercise dose and training modality in stroke rehabilitation, addressing the critical gap in prior research that lacked integrated, quantitative guidance for optimizing intervention strategies.It identifies an optimal total exercise dose of approximately 1800&#x2013;2200&#x2009;MET&#xd7;min/week for improving lower-limb balance and functional motor performance in stroke patients. Beyond this threshold, benefits plateau or slightly decline, accompanied by increased interindividual variability.It demonstrates distinct dose-response profiles across modalities: integrated aerobic training (IAT) peaks at moderate doses, motor control training (MCT) sustains effects over a broader range, and virtual reality training (VRT) shows localized benefits at low-to-moderate doses with greater variability in outcomes.

Antimicrobial resistance (AMR) is a critical global health challenge that compromises the effectiveness of widely used biocides such as chlorhexidine (CHX). The emergence of CHX-resistant bacterial strains, often mediated by efflux mechanisms and membrane adaptations, necessitates the development of new chemical entities capable of overcoming these resistance pathways. Here, we report the rational design, synthesis, and biological evaluation of structurally modified CHX analogues. These analogues were designed by substituting the terminal chlorophenyl rings of CHX with strategically selected aromatic groups bearing fluorine and methyl substituents to enhance membrane permeability, modulate physicochemical properties, and reduce efflux susceptibility. A library of 13 compounds was prepared using biscyanoguanidine chemistry and aniline-based substitutions via microwave-assisted synthesis, and was fully characterized by LC-MS, HRMS, and NMR. Antibacterial activity was assessed using minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) assays against a panel of Gram-positive and Gram-negative bacteria, including CHX-resistant Klebsiella pneumoniae and Pseudomonas aeruginosa strains harboring smvR, phoQ, and pmrB mutations. Selected analogues, particularly compounds 8 and 11, demonstrated potent antibacterial activity. Compound 11 showed MIC values predominantly in the range of 4-8 &#x3bc;g/mL across wild-type strains and retained activity in resistant isolates, with MIC values of 4-8 &#x3bc;g/mL in P. aeruginosa and 64 &#x3bc;g/mL in CHX-resistant K. pneumoniae. MBC values were generally comparable to MIC values for the fluorinated analogues, consistent with a biocidal mode of action, while chlorhexidine showed elevated MBC values in resistant strains. Molecular modeling suggests that these compounds form favorable interactions within hydrophobic regions of the SmvA efflux pump in K. pneumoniae, potentially reducing efflux susceptibility. Structure-activity relationship analysis highlights the importance of combining fluorine and methyl substituents to optimize physicochemical properties associated with antibacterial activity and resistance bypass. Collectively, these findings establish a foundation for the development of next-generation CHX-based biocides with improved efficacy against multidrug-resistant pathogens and support further translational evaluation.

The advancement of synthetic biology and the rise of antimicrobial resistance have led to the development of bacteriophage therapy for more than antibacterial applications. This review focuses on applications to multidrug-resistant infections, biofilm diseases, cancer research, veterinary medicine and animal production. Recent research suggests phages can be used in combination with antibiotics to enhance treatment of large multidrug resistant pathogens such as Pseudomonas aeruginosa, Acinetobacter baumannii and Klebsiella pneumoniae. This could also help to restore antibiotic sensitivity by making bacteria change resistance related structures or mechanisms. Despite this, there are several challenges for the use of phage therapy prior to its widespread clinical application, including phage resistance, difference in patient response, unknown pharmacokinetic parameters, immune issues, and unclear regulatory guidelines. Additionally, in some cases, phages could also play a role in horizontal gene transfer, raising further safety concerns. Beyond antimicrobial therapy, phage display platforms derived from M13, T7 and &#x3bb; phages have enabled the identification of tumor-targeting peptides, the development of immunomodulatory constructs, and targeted delivery of therapeutic molecules. Over 100 clinical cases and 44 registered trials support the generally favorable safety profile of personalized phage therapy, and highlight the need for better treatment standardization, controlled clinical evaluation, and better regulatory processes. Additionally, engineered phages expressing biofilm degrading enzymes represent promising tools for disrupting matrix-embedded bacterial communities associated with chronic infections and medical devices. In summary, CRISPR-based engineering and genome refactoring highlight the potential of phage-based therapeutics as complements to conventional antimicrobial therapy, although their broader use depends on overcoming biological, clinical, and regulatory challenges.

Migraine is a highly disabling neurological condition that requires effective preventive treatment options. We developed CT-132, a digital therapeutic that delivers clinically validated cognitive behavioral therapeutic interventions, as an adjunct to existing migraine therapies. We evaluated CT-132 for the preventive treatment of migraine in two randomized controlled trials, and this report is an integrated analysis of the two similarly designed trials: ReMMi-D (n&#x2009;=&#x2009;568), which included patients on prescription migraine medications (not migraine-specific), and ReMMiD-C, a study (n&#x2009;=&#x2009;110), in patients taking migraine-specific medications (i.e., CGRPi). Pooled data (N&#x2009;=&#x2009;678) from these post-hoc analyses demonstrated that CT-132 significantly reduced monthly migraine days (LS mean difference, -0.86 days; p&#x2009;=&#x2009;0.003) and improved secondary outcomes, had high engagement, and no device-related safety concerns. This data supports that CT-132 is an effective and safe digital therapeutic when used as an adjunct to medication for patients with episodic migraine. ReMMi-D: ClinicalTrials.gov NCT05853900 https://clinicaltrials.gov/study/NCT05853900?term=NCT05853900&rank=1 . REMMiD-C: ClinicalTrials.gov NCT06004388 https://clinicaltrials.gov/study/NCT06004388?term=NCT06004388&rank=1.

Environmental exposures play a pivotal role in carcinogenesis, yet their molecular imprints in human tissues remain incompletely understood. Here, we present an extensive catalog of mutational signatures induced by a panel of environmental carcinogens using human tissue-derived organoids coupled with high-fidelity duplex sequencing (NanoSeq). This unique combination enables direct detection of mutations without clonal expansion and reveals consistent carcinogen-specific signatures across multiple organ types (i.e., colon, stomach, liver, kidney, and pancreas). We identify mutational signatures for agents such as benzo[a]pyrene, aflatoxin B1, aristolochic acid I, and alkylating agents, some of which show strong concordance with known tumor signatures (e.g., SBS4, SBS11, SBS22, and SBS24) and previous experimentally-derived signatures. Our findings validate organoid models as physiologically relevant platforms for chemical mutagenesis and provide a foundational resource for decoding the environmental origins of human cancer.

Skin swab sampling provides an accessible, noninvasive method for collecting lipid-rich material from the skin surface, with growing potential for biomarker discovery and diagnostic testing. However, quantitative sebum analysis remains challenging because of variability in the amount collected and the complexity of the lipid matrix. This study evaluates the robustness of skin swab sampling for lipid analysis and the feasibility of quantifying skin-surface components using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Multiple reaction monitoring was used to assess analytical linearity, matrix effects, and recovery following established protocols for swab collection, storage, and extraction. Robust linearity was observed for both spiked isotope-labeled internal standards (IS) and endogenous lipids across concentrations of 0.15-550 ng/mL (R2 > 0.97). IS recovery varied between lipid classes, with consistent under-recovery. Although IS corrected for analytical variability during extraction and analysis, it could not fully account for differences in the amount of material collected. Endogenous lipids were, therefore, evaluated as normalization markers. Ratios between selected triacylglycerol (TG) species were highly conserved across samples, with coefficients of variation below 15% for TG 45:1/TG 47:1, TG 46:1/TG 48:1, and TG 47:1/TG 48:1. These ratios were stable across individuals and were independent of disease status. The reproducibility of TG recovery and stability of TG ratios suggest that endogenous lipid normalization can mitigate sampling and extraction variability. This approach provides a framework for improving quantitative reliability in skin swab lipidomics and represents a big step toward the development of reproducible mass spectrometry workflows for skin-swat-based biomarker studies.

This Research Communication addresses the hypothesis that calf faeces can be used as a microbial inoculum in the in vitro gas production (GP) technique to model rumen digestibility in calves. In vitro GP is a valuable method of screening dietary interventions in ruminants. However, the technique requires a microbial inoculum, typically obtained from the rumens of fistulated animals. Using faecal inocula that can be collected non-invasively would be ethically and economically preferable, if it provided equivalent results. The aim of this pilot study was to compare in vitro GP from faecal and ruminal inocula obtained from dairy calves that were killed either pre-weaning or post-weaning. Ruminal content and faeces were collected from calves aged 4, 7 and 13&#xa0;weeks old, and incubated with calf starter concentrates in the ANKOMRF system. A weak relationship between inocula was seen for all modelled GP kinetic parameters (R2 < 0.53), although modelling indicated that incubations using faecal and rumen inocula from pre-weaned calves had similar lag times and rates of degradation. In weaned calves, aged 13&#xa0;weeks, faecal incubations produced less gas, lag times were longer, and the rate of degradation of the slowly degradable fraction of calf starter was slower, compared to rumen incubations. Weak relationships, and kinetic differences, between rumen and faecal inocula would likely hinder the use of faeces to model calf rumen fermentation.

BackgroundThis study compared treatment persistence of individuals newly initiating treatment with rimegepant or lasmiditan for the acute treatment of migraine.MethodsA retrospective cohort analysis was conducted on individuals from MarketScan (commercial and managed Medicare) newly initiating treatment with rimegepant or lasmiditan between March 2020 and December 2022. Treatment persistence was defined as the proportion of individuals with &#x2265;1 medication refill within 12 months of the index prescription. Subgroups included individuals with chronic migraine, index lasmiditan dose (50 and 100&#x2005;mg) and individuals with a history of two or more uses of controlled substances (prior repeated use of controlled substances [PRUCS] defined here as opioids, butalbital, nausea medications with central nervous system action). Treatment persistence was compared between inverse probability of treatment weighting (IPTW)-adjusted cohorts using odds ratios (ORs) and 95% confidence intervals (CIs).ResultsThe primary analysis included 16,603 rimegepant and 716 lasmiditan users. A significantly higher proportion of individuals in the rimegepant cohort were treatment persistent compared with the lasmiditan cohort (OR 3.79 [95% CI 3.23-4.41]). This finding remained consistent across lasmiditan dosages (50&#x2005;mg: 5.05 [3.87-6.60]; 100&#x2005;mg: 3.33 [2.78-4.00]), chronic migraine diagnosis (3.89 [3.21-4.71]), or PRUCS (ORs ranged from 2.78 to 4.63; all statistically significant).ConclusionRimegepant users demonstrated higher treatment persistence over 12 months compared to lasmiditan users, which could reflect better real-world treatment satisfaction.