Anterior lamellar corneoscleral keratoplasty for the management of corneal thinning following treatment with mitomycin-C and interferon to treat highly suspected ocular surface squamous neoplasia: a case report

ABSTRACT A patient presented with corneoscleral thinning five months after the treatment of suspected ocular squamous surface neoplasia with mitomycin-C and interferon. For tectonic and aesthetic purposes, we decided to perform lamellar corneoscleral transplantation. The approach used established new tectonic support and corneal homeostasis. This technique might be an option in similar cases.

Empoderamento estrutural: potencializando as competências dos enfermeiros de um hospital de alta complexidade / Structural empowerment: enhancing the skills of nurses in a high-complexity hospital / Empoderamiento estructural: potenciar las competencias de los enfermeros en un hospital de alta complejidad

Objetivo: analisar o empoderamento estrutural de enfermeiros em um hospital de alta complexidade. Métodos: estudo quantitativo, analítico e transversal, realizado com 93 enfermeiros, utilizando um questionário sociodemográfico e ocupacional e o Questionário de Condições de Eficácia no Trabalho II. Os dados foram coletados entre fevereiro e março de 2023. A análise dos dados deu-se por meio de estatística descritiva, teste de Kolgomorov-Smirnov, teste do qui-quadrado e regressão de Poisson. Resultados: os enfermeiros apresentaram nível moderado de empoderamento estrutural, com média de 20,67 (p<0,000). O componente mais pontuado foi a oportunidade (4,22 dp±0,80). Não foram encontradas diferenças significativas nos níveis de empoderamento estrutural relacionadas às unidades de trabalho (p-Valor 0,381), vínculo empregatício (p-Valor 0,352) e grau de instrução (p-Valor 0,839). O modelo de regressão de Poisson indica que tanto pode haver altos ou baixos níveis de empoderamento a depender do setor. Conclusão: os enfermeiros demonstraram possuir níveis moderados de empoderamento estrutural.

Objective: to analyze the structural empowerment of nurses in a high-complexity hospital. Methods: a quantitative, analytical, cross-sectional study was carried out with 93 nurses, using a sociodemographic and occupational questionnaire and the Questionnaire of Conditions of Effectiveness at Work II. The data was collected between February and March 2023. The data was analyzed using descriptive statistics, the Kolgomorov-Smirnov test, the chi-square test, and Poisson regression. Results: the nurses had a moderate structural empowerment level, with a mean of 20.67 (p<0.000). The highest scoring component was opportunity (4.22 sd±0.80). No significant differences were found in the structural empowerment levels related to work units (p-Value 0.381), employment relationship (p-Value 0.352) and education level (p-Value 0.839). The Poisson regression model indicates that there can be either high or low empowerment levels depending on the sector. Conclusion: nurses showed moderate structural empowerment levels.

Objetivo: analizar el empoderamiento estructural del enfermero en un hospital de alta complejidad. Métodos: estudio cuantitativo, analítico y transversal, realizado con 93 enfermeros, utilizando un cuestionario sociodemográfico y ocupacional y el Cuestionario de Condiciones de Efectividad en el Trabajo II. Los datos se recolectaron entre febrero y marzo de 2023. El análisis de los datos se realizó mediante estadística descriptiva, prueba de Kolgomorov-Smirnov, prueba de chi-cuadrado y regresión de Poisson. Resultados: los enfermeros presentaron un nivel moderado de empoderamiento estructural, la media fue de 20,67 (p<0,000). El componente con mayor puntaje fue oportunidad (4,22 DE±0,80). No se encontraron diferencias significativas en los niveles de empoderamiento estructural relacionados con las unidades de trabajo (valor p 0,381), la relación laboral (valor p 0,352) y el nivel de formación (valor p 0,839). El modelo de regresión de Poisson indica que pueden existir niveles altos o bajos de empoderamiento dependiendo del sector. Conclusión: los enfermeros demostraron niveles moderados de empoderamiento estructural.

Optimizing Microfluidic Channel Design with High-Performance Materials for Safe Neonatal Drug Delivery.

INTRODUCTION: Designing the microfluidic channel for neonatal drug delivery requires proper considerations to enhance the efficiency and safety of drug substances when used in neonates. Thus, this research aims to evaluate high-performance materials and optimize the channel design by modeling and simulation using COMSOL multiphysics in order to deliver an optimum flow rate between 0. 3 and 1 mL/hr. METHOD: Some of the materials used in the study included PDMS, glass, COC, PMMA, PC, TPE, and hydrogels, and the evaluation criterion involved biocompatibility, mechanical properties, chemical resistance, and ease of fabrication. The simulation was carried out in the COMSOL multiphysics platform and demonstrated the fog fluid behavior in different channel geometries, including laminar flow and turbulence. The study then used systematic changes in design parameters with the aim of establishing the best implementation models that can improve the efficiency and reliability of the drug delivery system. The comparison was based mostly on each material and its appropriateness in microfluidic usage, primarily in neonatal drug delivery. The biocompatibility of the developed materials was verified using the literature analysis and adherence to the ISO 10993 standard, thus providing safety for the use of neonatal devices. Tensile strength was included to check the strength of each material to withstand its operation conditions. Chemical resistance was also tested in order to determine the compatibility of the materials with various drugs, and the possibility of fabrication was also taken into consideration to identify appropriate materials that could be used in the rapid manufacturing of the product. RESULTS: The results we obtained show that PDMS, due to its flexibility and simplicity in simulation coupled with more efficient channel designs which have been extracted from COMSOL, present a feasible solution to neonatal drug delivery. CONCLUSION: The present comparative study serves as a guide on the choice of materials and design of microfluidic devices to help achieve safer and enhanced drug delivery systems suitable for the delicate reception of fragile neonates.

Novel imaging techniques for tumor margin detection in basal cell carcinoma: a systematic scoping review of FDA and EMA-approved imaging modalities.

Mohs micrographic surgery (MMS) is the gold standard for removing basal cell carcinomas (BCCs) due to its ability to guarantee 100% margin evaluation through frozen section histopathology, offering the highest cure rate among current treatments. However, noninvasive imaging technologies have emerged as promising alternatives to clinical assessment for defining presurgical margins. This systematic scoping review examines the efficacy of these imaging modalities, focusing on those approved for clinical use by the United States Food and Drug Administration (FDA) or the European Medicines Agency (EMA). A systematic search of EMBASE, Scopus, PubMed, and the Cochrane Public Library databases identified 11 relevant studies out of 2123 records, encompassing 644 lesions across five imaging techniques. The findings suggest that dermoscopy, high-frequency ultrasound (HFUS), optical coherence tomography (OCT), line-field optical coherence tomography (LC-OCT), and reflectance confocal microscopy (RCM) show potential in detecting BCC margins, which could enhance MMS by providing better preoperative planning, informing patients of expected defect size, aiding in reconstruction decisions, and reducing overall procedure costs. This review discusses the benefits and limitations of each technique, offering insights into how these innovations could influence the future of BCC management. Emerging imaging techniques could enhance MMS by improving BCC margin assessment and reducing costs. Their adoption will depend on price and ease of use.

Veteran comfort and satisfaction with comprehensive geriatric assessment via video telehealth to home.

BACKGROUND: The purpose of this project was to measure satisfaction with virtual comprehensive geriatric assessments (CGA) among older Veterans (OVs). METHODS: The CGA involved five different healthcare providers and four one-hour VA Video Connect (VVC) calls. Using specific enrollment criteria, OVs were recruited in four cohorts separated by time. After completing the CGA, participants were asked to complete a 10-statement telephone questionnaire. Before analyses, responses to each statement were dichotomized as Agree (Agree/Strongly agree) or Do not Agree (Neutral/Disagree/Strongly Disagree). Descriptive statistics and Binomial generalized linear models (GLMs) were used to analyze the data. RESULTS: All 269 enrolled OVs completed all components of the CGA. This included 79, 57, 61, and 72 Veterans in cohorts 1 to 4, respectively. Their average age was 76.0 ± 5.9 years, and they were predominately white (82%), male (94%), and residents of rural settings (64%). Of the 236 (88%) OVs who completed the telephone survey, 57% indicated they were comfortable using VVC and 57% expressed willingness to use VVC again; 44% felt that VVC was easier than going to in-person visits. The OVs in Cohort 1 were more likely to agree with these statements than those in the remaining cohorts, especially Cohorts 2 and 4. Differences in demographics partially explained some of these findings. The majority (89% or higher) of survey participants agreed with the remaining seven survey statements indicating they were satisfied with the CGA program. CONCLUSION: OVs were very satisfied with their participation in a program of CGA, although not necessarily the mode of delivery. The percentage of participants who indicated discomfort using VVC for the CGA visits appeared to increase with time. Further work is needed to determine which OVs would be the best candidates to use VVC to complete all or part of a CGA.

Reducing unnecessary outpatient group and screen testing at a regional cancer center.

BACKGROUND: Unnecessary group and screens (G&S) can lead to unnecessary antibody investigations, use of technologist time, and laboratory resources. LOCAL PROBLEM: A baseline audit at our institution identified that 25% of G&S from the cancer center were unnecessary. We aimed to reduce the ratio of monthly G&S to CBC samples processed from the cancer center by 10% (from 0.034 to 0.031) by January 2024. METHODS: This represents an interrupted time series design from November 2022 to January 2024. Using Plan Do Study Act (PDSA) cycles, we aimed to increase the use of an existing reflex testing system, termed "do not test." When this option is selected, the blood bank will only process the G&S sample if specific CBC criteria are met (e.g., hemoglobin <9.0 g/dL). Educational sessions increased awareness of this feature and sought feedback from end-users on its usability. With feedback, the design was updated to include a modifiable hemoglobin threshold for G&S testing, automatic re-selection of the "do not test" feature for future G&S orders, and aesthetic changes to make the feature more visible. RESULTS: The percentage of samples with "do not test" selected increased from 7.2% to 63.0% (p < .0001) and the ratio of G&S to CBC specimens improved from 0.034 to 0.028, exceeding the target of 0.031. We noted an improvement in the appropriateness of G&S orders from 75% at baseline (n = 20) to 97.5% (n = 80) post intervention (p = .003). CONCLUSIONS: We describe an effective strategy to improve G&S utilization at our institution's cancer center using a reflex testing system.

Self-nanoemulsifying drug delivery system for nebulization: fabrication and evaluation for systemic delivery of atorvastatin.

The study undertakes the development of an atorvastatin-loaded self-nanoemulsifying drug delivery system (SNEDDS) to improve its bioavailability. The SNEDDS were fabricated using oleic acid, Tween 80, and Span 80 by spontaneous emulsification. The SNEDDS were assessed for their particle size distribution, zeta potential, morphology, drug content, surface tension, viscosity, and drug release. The aerodynamic performance of the SNEDDS was evaluated using an Andersen cascade impactor, while the lipid-lowering potential of the SNEDDS was determined in Wistar rats using the analyzer "Microlab 300." The particle size of the SNEDDS ranged from 36 to 311 nm, with a polydispersity index (PDI) of 0.25-0.40. The zeta potential of the SNEDDS fluctuated from - 29.22 to - 38.26 mV, which declined to - 4.55 mV in the case of F5. The chitosan-coated formulation (F5) exhibited a higher viscosity (22.12 mPa s) and lower surface tension (0.056 dyne/cm) than other formulations (F1-F4). The non-coated formulation exhibited a significantly higher burst drug release, followed by a sustained drug release pattern (p ≤ 0.05) as compared to the coated formulation (F5). The nebulized SNEDDS achieved a dispersed fraction of 87 to 97%, where notably higher aerosol dispersion from F4 was attributed to its smaller particle size and circularity. The inhaled fraction of nebulized SNEDDS was 74-87%. The size of the SNEDDS droplets was the primary determinant affecting the aerodynamic performance of the SNEDDS during nebulization. The chitosan-coated SNEDDS achieved a higher antihyperlipidemic effect than marketed tablets, which shows the suitability of F5 for effective systemic delivery of atorvastatin through the lung.

Recent opportunities and application of gellan gum based drug delivery system for intranasal route.

OBJECTIVES: In the recent years, in-situ hydrogel based on gellan gum has been investigated for delivery of various drug molecules particularly to treat neurological disorders via intranasal route. The major objective of the present manuscript is to review the recent research studies exploring gellan gum as ionic triggered in-situ gel for intranasal administration to enhance absorption of drugs and to increase their therapeutic efficacy. METHODS: This review include literature from 1982 to 2023 and were collected from various scientific electronic databases like Scopus, PubMed and Google Scholar to review source, chemistry, ionotropic gelation mechanism, and recent research studies for gellan gum based in-situ hydrogel for intransasl administration.Keywords such as gellan gum, in-situ hydrogel, intranasal administration and brain targeting were used to search literature. The present review included the research studies which explored gellan gum based in-situ gel for intranasal drug delivery. RESULTS: The findings have shown enhanced biavailability of various drugs upon intranasal administration using gellan-gum based in-situ hydrogel.Moreover, the review indicated that intranasal administration of in-situ hydrogel facilitate to overcome blood brain barrier effectively. Hence, significantly higher drug concentration was found to be achieved in brain tissues upon intranasal administration than that of other routes like oral and intravenous. CONCLUSION: The present work conducted a comprehensive review for gellan gum based in-situ hydrogel particularly for intransal administration to overcome BBB. The study concluded that gellan gum based in-situ hydrogel could be potential promising delivery system for intranasal administration to improve bioavailability and efficacy of drugs specifically to treat neurological disorders.

Efficacy of Rituximab Versus Cyclophosphamide and Mycophenolate for the Treatment of Interstitial Lung Disease in Systemic Sclerosis: A Systematic Review.

Interstitial lung disease (ILD) is a common complication of systemic sclerosis (SSc), contributing to significant morbidity and mortality in affected individuals. The optimal treatment approach for SSc-associated ILD remains uncertain, with rituximab, cyclophosphamide, and mycophenolate among potential therapeutic options. This systematic review aims to evaluate and synthesize the existing evidence on the efficacy of rituximab compared to cyclophosphamide and mycophenolate for the treatment of ILD in patients with systemic sclerosis. A comprehensive search of the following electronic databases, PubMed, Science Direct, Google Scholar, and Cochrane Library, has been conducted to identify relevant studies, including randomized controlled trials, systematic review and meta-analysis, prospective cohort studies, and retrospective cohort studies. Data on study characteristics, participant demographics, interventions, outcomes, and key findings have been extracted and synthesized. The risk of bias in the included studies has been assessed using appropriate tools such as the Cochrane Bias assessment tool for randomized controlled trials, the New Castle Ottawa tool for cohort studies, and the AMSTAR checklist for systematic reviews and meta-analysis. The research team ultimately selected 15 high-quality studies for review. Rituximab demonstrated similar efficacy to cyclophosphamide and mycophenolate in improving lung function (forced vital capacity (FVC) and diffusing capacity of the lung for carbon monoxide (DLCO)), with fewer severe adverse events. Cyclophosphamide, while effective, had higher toxicity, leading to more frequent adverse events such as leukopenia and infections. Mycophenolate showed comparable efficacy to cyclophosphamide but with fewer side effects, making it a well-tolerated alternative. The findings of this systematic review will provide valuable insights into the comparative efficacy of rituximab, cyclophosphamide, and mycophenolate in the management of ILD in systemic sclerosis, informing clinical decision-making and guiding future research in this area.

Pancreatitis Associated With Teduglutide: A Disproportionality Analysis via the Food and Drug Administration Adverse Event Reporting System (FAERS) Database.

Introduction Teduglutide is a glucagon-like peptide-2 analog that is indicated for the treatment of short bowel syndrome (SBS) by reducing patient dependence on parenteral support. Due to the rarity of SBS as well as the recent timeline of the adoption of teduglutide, the safety of teduglutide is relatively poorly understood. Several recent clinical case reports have highlighted elevated pancreatic enzymes and pancreatitis as a concerning complication of teduglutide. This prompts a systematic study of the association between pancreatitis and teduglutide. Methods This study conducts a case-control design disproportionality analysis by using data from the US Food and Drug Administration Adverse Event Reporting System (FAERS). Reports from the first quarter of 2020 through the first quarter of 2024 were retrieved from this database, and a disproportionality analysis was conducted. The analysis consisted of traditional methods of analyzing adverse drug events such as the reporting odds ratio (ROR) and proportional reporting ratio (PRR), as well as Bayesian methods such as the empirical Bayes geometric mean (EBGM) and information component (IC). A confidence interval for ROR and PRR that excludes a ratio of 1 or a confidence interval for IC that excludes a score of 0 was used as the criterion for a statistically significant association between pancreatitis risk and teduglutide use. Results Out of 11,696 reports of teduglutide adverse effects in over four years of adverse effects data drawn from the FAERS database, 79 cases of pancreatitis were identified. The disproportionality analysis revealed an ROR of 3.73 (95% CI (2.99, 4.66)), a PRR of 3.71 (95% CI (2.97, 4.63)), an EBGM of 3.70, and an IC of 1.84 (95% CI (1.51, 2.16)). All of these statistics indicate a statistically significant association between pancreatitis risk and teduglutide use. Conclusion The results reveal a statistically significant association between pancreatitis risk and teduglutide use. Our findings highlight the necessity for the careful monitoring of pancreatitis in patients undergoing teduglutide therapy going forward.

Efficacy of Rectal Versus Oral Chloral Hydrate in Pediatric Auditory Brainstem Response: Randomized Controlled Trial.

Objective: To compare sedation success rates between rectal (RCH) and oral chloral hydrate (OCH) administration in children undergoing auditory brainstem response (ABR) testing and assess the incidence of adverse effects. Study Design: Randomized controlled trial, performed between May 2023 and August 2023. Setting: Ear, Nose, and Throat Outpatient Department at tertiary care hospital. Methods: Pediatric patients aged 1 to 5 years, who were indicated for ABR testing were enrolled and randomly divided into 2 groups. The control group received 10% wt/vol chloral hydrate orally at a dose of 50 mg/kg, while the other group received the same dose through rectal administration. Onset of sedation, duration of sedation, recovery time, vital signs, and adverse effects were recorded and analyzed to assess sedative effectiveness and safety. Results: Eighty-eight children were randomly assigned to RCH or OCH administration groups, the sedation success rates of RCH and OCH groups were 84.09% and 90.91%, respectively (P = .33). Adverse effects were detected in 11 children (12.5%), with a vomiting rate of 20.45% in the oral group versus 0% in the rectal group (P = .002). The diarrhea rate was 4.55% in the rectal group versus 0% in the oral group (P = .16). In either group, no serious adverse effects were documented. Conclusion: RCH and OCH are both safe and effective for short-term sedation in pediatric patients during ABR testing. Interestingly, RCH administration offers a high success rate without vomiting or major adverse effects. This study established the effectiveness of RCH for sedation in children under specialized supervision.

Systemic administration of a potent mouse monoclonal antibody provides multisite protection against HPV16 infection.

Although preventive vaccines for Human Papillomaviruses (HPV) are available, a definitive cure for the viral infection itself is currently lacking. There is a sizable population that remains inaccessible to HPV vaccination due to reasons such as high costs or lack of availability of the vaccines. Therefore, there remains a significant population susceptible to HPV infection. Persistent multisite infections with high-risk HPV types can cause cancer at several different anatomic sites.Especially HPV16 is a key etiologic factor for cervical, other ano-genital and oropharyngeal cancers. Therefore, it is imperative to develop pharmaceutical interventions for the treatment of viral infections. In this study, a panel of 9 neutralizing antibodies was screened using the hybridoma technique, with 20F6 being identified as the representative antibody. The purified 20F6 exhibited an IC50 of 0.0011 µg/ml against HPV16, demonstrating potent viral inhibitory activity. Moreover, it displayed cross-neutralizing efficacy towards other Alphapapillom 9 subtypes including HPV31, HPV33, HPV52, and HPV58 with respective IC50 values of 2.0 µg/ml, 7.3 µg/ml, 1.7 µg/ml, and 3.0 µg/ml. 20F6 recognizes the linear epitope MSLW, the first four amino-acids located at the very N-terminus of the HPV16 L1 protein. Administration of 20F6, 24 h prior to and following HPV16 pseudo-virion (PSV) challenge, conferred protection against infection in mice at doses as low as 1 mg/kg. Following intraperitoneal administration of 20F6, neutralizing antibodies were consistently detected at both oral and vaginal sites, indicating that prophylactic systemic administration of 20F6 may confer efficient protection against multiple susceptible mucosal sites.

Bi-weekly irinotecan is an effective and convenient regimen in the treatment of relapsed or refractory small cell lung cancer.

BACKGROUND: Despite initial dramatic responses, metastatic small cell lung cancer (SCLC) invariably recurs. Irinotecan is one of the active agents for patients with recurrent SCLC. In the second line, weekly or three-weekly irinotecan regimens have been adopted, however, the optimal dose and schedule is not defined. In our institution, we use a bi-weekly regimen of irinotecan. In this study, we aimed to investigate the safety and efficacy of the bi-weekly irinotecan in the second- or third-line treatment of SCLC patients. METHODS: The study population consisted of advanced stage SCLC patients who were followed at Hacettepe University Cancer Institute between January 2007 and March 2021 and received salvage irinotecan 180 mg/m2 every two weeks, following progression after platinum-etoposide treatment. RESULTS: One hundred patients were included. At diagnosis, nineteen patients (19%) had limited stage and 81 patients (81%) had extensive stage SCLC. Objective response rates (ORR) were 44.6% and 46.2% for patients who received irinotecan treatment in second line, and in third line, respectively. Seventeen percent of all the patients had grade 3 and above adverse events during irinotecan treatment. In our study, 45.8% of patients were able to complete at least 6 cycles of irinotecan treatment and 69.8% were able to receive at least 3 cycles of irinotecan treatment without any dose interruption or reduction. CONCLUSIONS: Irinotecan 180 mg/m2 every two weeks appears to be safe and effective in the 2nd- and 3rd-line treatment of advanced stage SCLC. Bi-weekly administration allows G-CSF prophylaxis in between doses, leading to an uninterrupted administration.

Cost-effectiveness of mass drug administration for control of scabies in Ethiopia: a decision-analytic model.

Background: The strategies to control scabies in highly endemic populations include individual case/household management and mass drug administration (MDA). We used a decision-analytic model to compare ivermectin-based MDA and individual case/household management (referred to as "usual care") for control of scabies in Ethiopia at different prevalence thresholds for commencing MDA. Methods: A decision-analytic model was based on a repeated population survey conducted in Northern Ethiopia in 2018-2020, which aimed to evaluate the secondary impact of single-dose ivermectin MDA for the control of onchocerciasis on scabies prevalence. The model estimates the number of scabies cases and costs of two treatment strategies (MDA and usual care) based on their effectiveness, population size, scabies prevalence, compliance with MDA, medication cost, and other parameters. Results: In the base-case analysis with a population of 100,000 and scabies prevalence of 15%, the MDA strategy was both more effective and less costly than usual care. The probability of MDA being cost-effective at the current cost-effectiveness threshold (equivalent to the cost of usual care) was 85%. One-way sensitivity analyses showed that the MDA strategy remained dominant (less costly and more effective) in 22 out of 26 scenarios. MDA was not cost-effective at scabies prevalence <10%, MDA effectiveness <85% and population size <5,000. An increase in the cost of ivermectin from 0 (donated) to 0.54 US$/dose resulted in a decrease in the probability of MDA being cost-effective from 85% to 17%. At 0.25 US$/dose, the MDA strategy was no longer cost-effective. Conclusions: The model provides robust estimates of the costs and outcomes of MDA and usual care and can be used by decision-makers for planning and implementing scabies control programmes. Results of our analysis suggest that single-dose ivermectin MDA is cost-effective in scabies control and can be initiated at a scabies prevalence >10%.

Orbitofrontal cortex to dorsal striatum circuit is critical for incubation of oxycodone craving after forced abstinence.

Relapse is a major challenge in treating opioid addiction, including oxycodone. During abstinence, oxycodone seeking progressively increases, a phenomenon termed incubation of oxycodone craving. We previously demonstrated a causal role of orbitofrontal cortex (OFC) in this incubation. Here, we studied the interaction between glutamatergic projections from OFC and dopamine 1-family receptor (D1R) signaling in dorsal striatum (DS) in this incubation in male rats. We first examined the causal role of D1R signalling in DS in incubated oxycodone seeking. Next, we combined fluorescence-conjugated cholera toxin subunit B (CTb-555, a retrograde tracer) with Fos (a neuronal activity marker) to assess whether the activation of OFC→DS projections was associated with incubated oxycodone seeking. We then used a pharmacological asymmetrical disconnection procedure to examine the role of the interaction between projections from OFC and D1R signalling in DS in incubated oxycodone seeking. We also tested the effect of unilateral pharmacological inactivation of OFC or unilateral D1R blockade of DS on incubated oxycodone seeking. Finally, we assessed whether contralateral disconnection of OFC→DS projections impacted non-incubated oxycodone seeking on abstinence day 1. We found that D1R blockade in DS decreased incubated oxycodone seeking and OFC→DS projections were activated during incubated oxycodone seeking. Moreover, anatomical disconnection of OFC→DS projections, but not unilateral inactivation of OFC or unilateral D1R blockade in DS, decreased incubated oxycodone seeking. Lastly, contralateral disconnection of OFC→DS projections had no effect on oxycodone seeking on abstinence day 1. Together, these results demonstrated a causal role of OFC→DS projections in incubation of oxycodone craving.

Validation of drug-nondrug choice procedure to model maladaptive behavioural allocation to opioid use in rats.

Increased allocation of behaviour to substance abuse at the expense of personal and social rewards is a hallmark of addiction that is reflected in several of DSM-5 criteria for diagnosis of substance use disorder. Previous studies focused on refining the self-administration (SA) model to better emulate an addictive state in laboratory animals. Here, we employed concurrent SA of sucrose pellets and morphine as two competing natural and drug rewards, respectively, to validate the feasibility of capturing pathological behavioural allocation in rats. A custom-made three-lever operant chamber was used. With one active and one inactive lever presented, rats were trained to self-administer morphine (0.5 mg/kg/infusion; 2 h/day) under a fixed-ratio 1 (FR-1) schedule until a stable response was achieved. Next, they were trained to self-administer morphine in the presence of a third lever dispensing sucrose pellets (20 mg) under FR-1. Concurrent morphine-sucrose SA sessions (2 h/day) were continued until stable morphine taking behaviour was re-established. In another experiment, rats first established stable sucrose pellet SA (2 h/day, FR-1) and then were trained to take morphine (0.5 mg/kg/infusion; 2 h/day). Subsequently, all rats underwent extinction training, in which morphine was replaced with saline while sucrose pellets were still available upon lever pressing, followed by cue-induced reinstatement of morphine seeking behaviour. Results showed that rats retained morphine SA when sucrose pellets were also available, but they showed binge-like sucrose intake when morphine was removed during the extinction sessions. However, morphine SA did not develop in rats that had previously established sucrose pellet SA. In conclusion, morphine SA developed even in the presence of a potent competing nondrug reward in rats. Adding an effort-based contingent delivery of a natural reward to the standard SA model, this protocol may provide an improved model of drug addiction in laboratory animals.

The impact of supplementing vitamin D through different methods on the prognosis of COVID-19 patients: a systematic review and meta-analysis.

Objective: To analyze the impact of different methods of Vitamin D administration on the prognosis of COVID-19 patients. Methods: A comprehensive literature search was conducted across four databases: PubMed, Embase, Web of Science, and Cochrane, up to January 5, 2024. Eligible studies included randomized controlled trials and cohort studies that compared Vitamin D supplementation with control groups in COVID-19 patients. Outcomes of interest were mortality rate, ICU (Intensive Care Unit) admission rate, length of hospital stay, and endotracheal intubation rate. Subgroup analyses were performed based on the dosing regimen (single-dose vs. continuous-dose), total Vitamin D intake within 14 days (≥100,000 IU vs. <100,000 IU), and baseline serum Vitamin D levels (deficient group: 25OHD < 30 ng/mL vs. non-restricted group). A random-effects model was employed for meta-analysis to account for heterogeneity among studies. Results: A total of 21 studies involving 4,553 participants were included. In terms of mortality, Vitamin D supplementation significantly reduced the mortality rate (RR = 0.72, 95% CI: 0.54-0.94, I 2 = 54%, p = 0.02), with continuous dosing being more effective (RR = 0.53, 95% CI: 0.34-0.83, I 2 = 55%, p = 0.006) compared to single-dose (RR = 0.88, 95% CI: 0.69-1.12, I 2 = 21%, p = 0.3), and lower total doses (<100,000 IU) showing greater benefit (RR = 0.30, 95% CI: 0.21-0.44, I 2 = 0%, p < 0.0001). Mortality was significantly reduced in the Vitamin D-deficient group (25OHD < 30 ng/mL) (RR = 0.73, 95% CI: 0.59-0.89, I 2 = 0%, p = 0.002) but not in the non-restricted group. Regarding ICU admission, supplementation reduced ICU admission rates (RR = 0.58, 95% CI: 0.38-0.88, I 2 = 74%, p = 0.01), with continuous dosing (RR = 0.44, 95% CI: 0.22-0.90, I 2 = 74%, p = 0.02) being more effective than single-dose (RR = 0.79, 95% CI: 0.61-1.03, I 2 = 22%, p = 0.08), and lower doses (<100,000 IU) providing more significant reduction (RR = 0.31, 95% CI: 0.21-0.47, I 2 = 0%, p = 0.001). ICU admission rates were significantly reduced in the Vitamin D-deficient group (RR = 0.63, 95% CI: 0.42-0.93, I 2 = 0%, p = 0.02) but not in the non-restricted group (RR = 0.59, 95% CI: 0.32-1.11, I 2 = 86%, p = 0.1). For length of hospital stay, no significant differences were observed between Vitamin D and control groups (MD = -1, 95% CI: -2.16 to 0.16, p = 0.13), and subgroup analyses by dosing regimen, total dose, and baseline Vitamin D levels also showed no significant differences. Similarly, for endotracheal intubation, there was no significant difference in intubation rates between groups (RR = 0.78, 95% CI: 0.56-1.08, p = 0.13), and subgroup analyses confirmed no significant effect of different dosing strategies or baseline Vitamin D status on intubation rates. Conclusion: Vitamin D supplementation improves clinical outcomes in COVID-19 patients by reducing mortality and ICU admission rates, particularly when administered continuously with a total dose of less than 100,000 IU over 14 days, and among those with baseline Vitamin D deficiency (25OHD < 30 ng/mL). However, there were no significant effects on the length of hospital stay or endotracheal intubation rates, regardless of the dosing regimen or baseline Vitamin D levels. These findings emphasize the importance of considering both the total dose over 14 days and baseline Vitamin D status to optimize therapeutic benefits.

Alleviation of Allergic Rhinoconjunctivitis Symptoms in Participants Treated with a 0.005% Tacrolimus Eye-Drop Solution.

Purpose: This randomized, placebo-controlled, crossover, double-blind trial aimed to evaluate the efficacy and safety of Tacrosolv, a novel 0.005% tacrolimus eye-drop solution, in adults with grass pollen-induced allergic conjunctivitis. Methods: A total of 64 adult participants were randomized to receive 2.5 µg or 5 µg tacrolimus/eye/day or placebo treatment for 8 days, with grass pollen exposure on day 1 and day 8. After a 2-week washout period, placebo participants crossed over to Tacrosolv treatment and vice versa, with repeated treatment and exposure. During exposure, participants recorded ocular, nasal, and respiratory allergy symptoms every 15 minutes. The primary endpoint was the mean total ocular symptom score (TOSS) on day 8. Objective ocular safety parameters were assessed before, during, and after exposure. Adverse events were recorded throughout the study. Results: On day 8, high-dose Tacrosolv reduced the TOSS compared to placebo towards the end of exposure (p<0.05 at time points 3 hours, 45 minutes and 4 hours). A 26% reduction in baseline adjusted TOSS from day 1 to day 8 was observed in participants treated with high-dose Tacrosolv, whereas placebo-treated participants showed no difference in TOSS between day 1 and day 8. Nasal symptoms were reduced on both day 1 and day 8 in participants treated with high-dose Tacrosolv (p<0.05). No safety concerns were raised. All adverse events were resolved within the study period. Conclusion: High-dose Tacrosolv is safe and effective for alleviating symptoms of allergic rhinoconjunctivitis. Trial Registration: NCT04532710; EudraCT No. 2019-002847-62.

Utilization of Glucagon-Like Peptide-1 Receptor Agonist and Dipeptidyl Peptidase-4 Inhibitors at the Veterans Health Administration.

Background: Glucagon-like peptide-1 receptor agonists (GLP-1RA) and dipeptidyl peptidase-4 inhibitors (DPP-4i) are incretin-based therapies commonly used in the management of type 2 diabetes. Public interest in GLP-1RA soared after discovering their ability to lower body weight in patients without diabetes. Objective: To examine recent trends in usage of GLP-1RA and DPP-4i in the Veterans Health Administration (VHA). Methods: We extracted GLP-1RA and DPP-4i use from the national VHA Corporate Data Workhouse (CDW) between fiscal years (FYs) 2011 to 2021, which encompass medication class, name, dosage, date of filled prescription, and patients' characteristics. Results: A total of 3 037 006 prescriptions for DPP-4i and 2 183 294 prescriptions for GLP-1RA were filled during FY 2011 to 2021. More patients were prescribed DPP-4i (273 002 subjects) compared with GLP-1RA (157 209 subjects) from FY 2011 to 2021. Overall, 10.7% used DPP-4i for 90 days or less in comparison to 9.1% in GLP-1RA (P < 0.001). The proportion of patients prescribed DPP-4i who were 75 years of age or older was relatively stable over the years 2011 to 2021 (mean proportion = 19%). However, the proportion of patients who were 75 years of age or older prescribed GLP-1RA increased from 4.2% in 2011 to 16.9% in 2021. Conclusions: Incretin-based therapies have become a well-established class of drugs within the VHA. Even though DPP-4i usage in older adults has remained stable over the past 10 years, prescriptions for GLP-1RA in older adults have increased multifold over the last few years, which might be attributed to recent trial evidence showing benefit in cardiovascular outcomes and weight reduction.

Sex differences in nicotine intake and relapse behavior in nicotine-dependent adult wistar rats.

Introduction: Tobacco use is highly addictive and the leading cause of premature mortality in the world. Long-access nicotine self-administration procedures in rats closely model human smoking behavior. However, significant gaps remain in our understanding of sex differences in the development of dependence and relapse in adult rats. Methods: In the present study, we investigated operant responding for both nicotine and saline and the development of dependence in adult rats of both sexes. The rats had daily access to nicotine or saline for 6 h per day, 7 days per week. Dependence was assessed by evaluating precipitated and spontaneous somatic withdrawal signs, measuring locomotor activity in the small open field test, and assessing anxiety-like behavior in the large open field and elevated plus maze test. The sucrose preference test was used to determine if cessation of nicotine intake leads to anhedonia. It was also investigated if a period of forced abstinence affects nicotine-seeking behavior. Results: This study showed that nicotine intake is higher in females than in males when given daily long access to nicotine. Daily nicotine self-administration led to more precipitated and spontaneous somatic withdrawal signs compared to saline self-administration, with no sex differences observed. In addition, cessation of nicotine intake led to a similar increase in activity in both males and females in the small open field test. However, cessation of nicotine intake did not increase anxiety-like behavior or cause anhedonia in either males or females. A time course analysis revealed that the nicotinic acetylcholine receptor antagonist mecamylamine affected nicotine intake differently in males and females, increasing intake in males and decreasing intake in females. Three weeks of forced abstinence led to an increase in nicotine and saline-seeking behavior. The rats exhibited more nicotine than saline seeking, and the females displayed more nicotine seeking than the males. Discussion: The present findings demonstrate that females self-administer more nicotine and display more nicotine-seeking behavior than males. Furthermore, there were no sex differences in somatic withdrawal signs or activity during abstinence from nicotine. This work underscores the importance of considering sex differences across various aspects of addiction, including intake and relapse, when developing novel treatments for tobacco use disorder.