Nanomaterials as drug delivery agents for overcoming the blood-brain barrier: A comprehensive review.

Background and Purpose: The blood-brain barrier (BBB), a critical interface of specialized endothelial cells, plays a pivotal role in regulating molecular and ion transport between the central nervous system (CNS) and systemic circulation. Experimental Approach: This review aims to delve into the intricate architecture and functions of the BBB while addressing challenges associated with delivering therapeutics to the brain. Historical milestones and contemporary insights underscore the BBB's significance in protecting the CNS. Key Results: Innovative approaches for enhanced drug transport include intranasal delivery exploiting olfactory and trigeminal pathways, as well as techniques like temporary BBB opening through chemicals, receptors, or focused ultrasound. These avenues hold the potential to reshape conventional drug delivery paradigms and address the limitations posed by the BBB's selectivity. Conclusion: This review underscores the vital role of the BBB in maintaining CNS health and emphasizes the importance of effective drug delivery through this barrier. Nanoparticles emerge as promising candidates to overcome BBB limitations and potentially revolutionize the treatment of CNS disorders. As research progresses, the application of nanomaterials shows immense potential for advancing neurological therapeutics, albeit with careful consideration of safety aspects.

Assessment of Real-World Escalation to Biologics in US Patients With Asthma.

BACKGROUND: Previous studies indicate that suboptimal medication adherence may contribute to uncontrolled asthma. Global Initiative for Asthma (GINA) guidelines recommend treatment escalation to biologics for patients with uncontrolled asthma despite adherence to high-dose maintenance medication and who have eosinophilic/allergic biomarkers or require maintenance oral corticosteroids. OBJECTIVE: This study aimed to describe the clinical status of patients with asthma escalated to biologic therapy. METHODS: This retrospective claims database analysis enrolled US patients with asthma who were escalated to biologics between January 2016 and June 2020. Exacerbations, control status, GINA step, and maintenance medication adherence during the 12 months before biologic therapy initiation were analyzed. Asthma control was assessed using both the European Respiratory Society/American Thoracic Society (ERS/ATS) and Stempel criteria. Adherence was defined as the proportion of days covered (PDC) by maintenance medication claims. RESULTS: Of 1786 patients escalated to biologics, 506 were included for analysis. During the 12 months before escalation, 346 patients had confirmed exacerbations. Uncontrolled asthma status was estimated in 55% and 70% of patients (ERS/ATS and Stempel criteria, respectively). GINA step was inferred for 395 patients: 154 were at step 2, 11 at step 3, 104 at step 4, and 126 at step 5. Of 403 patients with maintenance medication claims, 63% had suboptimal maintenance medication adherence (PDC <80%). CONCLUSION: In this study, most patients initiating biologic therapy had mild-to-moderate asthma or suboptimal maintenance medication adherence, possibly indicating inappropriate escalation. Incorporating objective medication adherence monitoring into existing guidelines may reduce inappropriate escalation to biologics.

Whole-body senescent cell clearance alleviates age-related brain inflammation and cognitive impairment in mice.

Cellular senescence is characterized by an irreversible cell cycle arrest and a pro-inflammatory senescence-associated secretory phenotype (SASP), which is a major contributor to aging and age-related diseases. Clearance of senescent cells has been shown to improve brain function in mouse models of neurodegenerative diseases. However, it is still unknown whether senescent cell clearance alleviates cognitive dysfunction during the aging process. To investigate this, we first conducted single-nuclei and single-cell RNA-seq in the hippocampus from young and aged mice. We observed an age-dependent increase in p16Ink4a senescent cells, which was more pronounced in microglia and oligodendrocyte progenitor cells and characterized by a SASP. We then aged INK-ATTAC mice, in which p16Ink4a -positive senescent cells can be genetically eliminated upon treatment with the drug AP20187 and treated them either with AP20187 or with the senolytic cocktail Dasatinib and Quercetin. We observed that both strategies resulted in a decrease in p16Ink4a exclusively in the microglial population, resulting in reduced microglial activation and reduced expression of SASP factors. Importantly, both approaches significantly improved cognitive function in aged mice. Our data provide proof-of-concept for senolytic interventions' being a potential therapeutic avenue for alleviating age-associated cognitive impairment.

Depot-specific adipocyte-extracellular matrix metabolic crosstalk in murine obesity.

Subcutaneous (SAT) and visceral (VAT) adipose tissues have distinct metabolic phenotypes. We hypothesized that the extracellular matrix (ECM) regulates depot-specific differences in adipocyte metabolic function in murine obesity. VAT and SAT preadipocytes from lean or obese mice were subject to adipogenic differentiation in standard 2D culture on plastic tissue culture plates or in 3D culture in ECM, followed by metabolic profiling. Adipocytes from VAT relative to SAT manifested impaired insulin-stimulated glucose uptake and decreased adipogenic capacity. In 3D-ECM-adipocyte culture, ECM regulated adipocyte metabolism in a depot-specific manner, with SAT ECM rescuing defects in glucose uptake and adipogenic gene expression in VAT adipocytes, while VAT ECM impaired adipogenic gene expression in SAT adipocytes. These findings demonstrate that ECM-adipocyte crosstalk regulates depot-specific differences in adipocyte metabolic dysfunction in murine obesity.

Reversibility of psychotropic medication induced weight gain among children and adolescents with bipolar disorders.

OBJECTIVE: To assess the reversibility of weight gain associated with psychotropic medications in children. METHODS: A retrospective cohort study was conducted using an ambulatory electronic medical records database. Individuals under 18 years of age were identified if they were initiating a new course of second generation/atypical antipsychotics (SGA) or mood stabilizers (MS) following a bipolar disorder diagnosis and subsequently discontinued treatment within 24 months of treatment initiation. RESULTS: Of the 297 children who had experienced positive BMI percentile increase (mean±SD: 8.71±11.94) during the treatment of SGA and/or MS, treatment discontinuation led to an average of 1.88 (±13.41) unit decrease in BMI percentile during a 12-month period since the treatment discontinuation. Repeated measure mixed model analysis showed that the reduction of BMI percentile after treatment discontinuation was neither associated with the treatment regimens patients previously received, nor associated with time since the treatment discontinuation. The three statistically significant predictors were baseline BMI percentile, BMI percentile gained during the treatment, and comorbid substance abuse disorder. CONCLUSION: Children with bipolar disorder were able to lose a fraction of weight gained during pharmacotherapy after the treatment discontinuation, however, their BMI percentile may not return to the prior treatment level within a year post-medication discontinuation.

Epidemiology of hyperhidrosis in 2 population-based health care databases.

BACKGROUND: Population-based and clinical case reports of hyperhidrosis (HH) provide prevalence estimates that vary widely across reported studies because of differences in case ascertainment. OBJECTIVE: In this study, we specify diagnostic, symptom, and prescription codes for HH to estimate incidence and prevalence for the United Kingdom and the United States. METHODS: Data from UK and US health care databases were analyzed to ascertain HH cases and estimate incidence and prevalence from health care records during calendar years 2011 through 2013. RESULTS: On the basis of 2013 data for the United States and United Kingdom, between 1.0% and 1.6% of these populations have health care records indicating diagnosis or treatment of HH. Women accounted for approximately 60% of incident and prevalent cases in both databases. LIMITATIONS: Because the case ascertainment methods rely on available data for those seeking health care, we may have underestimated the number of HH cases in both countries. CONCLUSIONS: The findings represent a plausible estimate for incidence and prevalence of HH among persons seeking medical care for excessive sweating. Improved practices for identifying HH in clinical settings may increase the sensitivity and specificity of future studies and improve characterization and quantification of the population burden of this significant disease.

Effect of Psychopharmacotherapy on Body Mass Index Among Children and Adolescents with Bipolar Disorders.

OBJECTIVE: To assess the long-term effect of all treatment options for pediatric bipolar disorders on body mass index (BMI) and to explore individual characteristics associated with less BMI increase during psychotropic medication exposures. METHODS: A retrospective cohort study was conducted by using the 1995 to 2010 General Electric Electronic Medical Record database. Individuals aged 18 years or younger who had a new bipolar disorder episode were identified. Treatment exposure was defined based on the medication regimens patients received, which include atypical antipsychotic (AT) monotherapy, mood stabilizer (MS) monotherapy, antidepressant (AD) monotherapy, AT+MS polytherapy, AT+AD polytherapy, MS+AD polytherapy, and no treatment. Both treatment exposure and BMI were coded as time varying, which could change from month to month. According to the duration of treatment and the availability of BMI measures, individuals were followed for up to 3, 6, 9, and 12 months since the treatment initiation. Repeated-measures mixed models were applied to compare the impact of different medication regimens and the length of drug exposure on BMI after adjusting for the baseline BMI, sociodemographic factors, comorbidities, and psychotherapy. RESULTS: A total of 2299 treated and 4544 untreated children and adolescents who met the inclusion criteria were identified. Analysis using repeated-measures mixed models showed that those on AT monotherapy (the reference group) had a gradually diminished, but statistically significant, monthly increase in BMI during all durations of drug exposure (3 months: 0.36 kg/m2, 6 months: 0.20 kg/m2, 9 months: 0.17 kg/m2, and 12 months: 0.16 kg/m2). As compared with AT monotherapy, the magnitude of increase in BMI associated with MS, AD monotherapy, and no treatment was significantly less at all time points, indicating less steep slopes of BMI change over time compared with AT monotherapy, especially during the short-term exposure. The combinations of AT with other psychotropic medications (ATMS, ATAD) were associated with a similar BMI increase as AT monotherapy. Individual characteristics found to be associated with a less increase in BMI during psychotropic medication exposure were being younger and having a higher baseline BMI. CONCLUSION: The long-term use of atypical antipsychotics, both as monotherapy or in combination with other psychotropic medications in children and adolescents with bipolar disorder, was associated with a steady and cumulative increase in BMI.

Care Provision and Prescribing Practices of Physicians Treating Children and Adolescents With ADHD.

OBJECTIVE: Care provision and prescribing practices of physicians treating children with attention-deficit hyperactivity disorder (ADHD) were compared. METHODS: A retrospective cohort study was conducted with the 1995-2010 General Electric Centricity Electronic Medical Record database. The sample included children (≤18 years) with newly diagnosed ADHD (ICD-9-CM code 314.XX) who received a prescription for a stimulant or atomoxetine. Identification of comorbid psychiatric disorders, duration from initial ADHD diagnosis to treatment, prescription of other psychotropic medications, and follow-up care during the ten months after the ADHD treatment initiation were compared across provider type (primary care physicians [PCPs], child psychiatrists, and physicians with an unknown specialty). The associations between provider type and practice variations were further determined by multivariate logistic regression accounting for patient demographic characteristics, region, insurance type, and prior mental health care utilizations. RESULTS: Of the 66,719 children identified, 75.8% were diagnosed by PCPs, 2.6% by child psychiatrists, and 21.6% by physicians whose specialty was unknown. Child psychiatrists were less likely than PCPs to initiate ADHD medication immediately after the diagnosis. However, once the ADHD treatment was initiated, they were more likely to prescribe psychotropic polytherapy even after analyses accounted for the comorbid psychiatric disorders identified. Only one-third of ADHD cases identified by both PCPs and child psychiatrists have met the HEDIS quality measure for ADHD medication-related follow-up visits. CONCLUSIONS: Differences were found by physician type in care of children with ADHD. Additional studies are needed to understand clinical consequences of these differences and the implications for care coordination across provider specialties.

Rising United States Hospital Admissions for Acute Bacterial Skin and Skin Structure Infections: Recent Trends and Economic Impact.

BACKGROUND: The number of ambulatory patients seeking treatment for skin and skin structure infections (SSSI) are increasing. The objective of this study is to determine recent trends in hospital admissions and healthcare resource utilization and identify covariates associated with hospital costs and mortality for hospitalized adult patients with a primary SSSI diagnosis in the United States. METHODS: We performed a retrospective cross-sectional analysis (years 2005-2011) of data from the US Healthcare Cost and Utilization Project National Inpatient Sample. Recent trends, patient characteristics, and healthcare resource utilization for patients hospitalized with a primary SSSI diagnosis were evaluated. Descriptive and bivariate analyses were conducted to assess patient and hospital characteristics. RESULTS: A total of 1.8% of hospital admissions for the years 2005 through 2011 were for adult patients with a SSSI primary diagnosis. SSSI-related hospital admissions significantly changed during the study period (P < .001 for trend) ranging from 1.6% (in 2005) to 2.0% (in 2011). Mean hospital length of stay (LOS) decreased from 5.4 days in the year 2005 to 5.0 days in the year 2011 (overall change, P < .001) with no change in hospital costs. Patients with postoperative wound infections had the longest hospital stays (adjusted mean, 5.81 days; 95% confidence interval (CI), 5.80-5.83) and highest total costs (adjusted mean, $9388; 95% CI, $9366-$9410). Year of hospital admission was strongly associated with mortality; infection type, all patient refined diagnosis related group severity of illness level, and LOS were strongly associated with hospital costs. CONCLUSIONS: Hospital admissions for adult patients in the United States with a SSSI primary diagnosis continue to increase. Decreasing hospital inpatient LOS and mortality rate may be due to improved early treatment. Future research should focus on identifying alternative treatment processes for patients with SSSI that could shift management from inpatient to outpatient treatment settings.

Comparative effectiveness of monotherapy with mood stabilizers versus second generation (atypical) antipsychotics for the treatment of bipolar disorder in children and adolescents.

OBJECTIVE: This study compared the effectiveness and safety of second generation (atypical) antipsychotic (SGA) versus traditional mood stabilizers (MS) in children and adolescents with bipolar disorder. METHODS: The study was a retrospective cohort study on 5 years (2003-2007) of Medicaid claims data from four geographically diversified states. Children and adolescents aged 6-18 years who initiated a new treatment episode for bipolar disorder on either an SGA or an MS were followed for 12 months to compare the effectiveness and safety between the two therapeutic categories for pediatric bipolar disorder (PBD). The outcome measures were psychiatric hospital admission, all cause medication discontinuation and treatment augmentation. Potential selection bias caused by unobserved confounding was addressed with instrumental variable methods, using physician prescribing preference and year of cohort entry as the instruments. Sensitivity analysis was conducted to test the robustness of findings against the uncertainties on PBD diagnosis. RESULTS: Of the 7423 bipolar children and adolescents identified, 66.60% started treatment on SGA, whereas 33.40% initiated on MS. Patients who initiated on MS and SGA had comparable risk of psychiatric hospital admission (HR=1.172, 95%CI: 0.827-1.660). However, as compared with those who initiated on MS, patients who initiated on SGA were less likely to discontinue the treatment (HR=0.634, 95%CI: 0.419-0.961) and less likely to receive treatment augmentation (HR=0.223, 95%CI: 0.103-0.484). CONCLUSION: As compared with MS monotherapy, SGA monotherapy could be a more effective and safer treatment option for PBD.