The Cerebellar Cognitive Affective/Schmahmann Syndrome Scale in Spinocerebellar Ataxias.

The Cerebellar Cognitive Affective/Schmahmann Syndrome (CCAS) manifests as impaired executive control, linguistic processing, visual spatial function, and affect regulation. The CCAS has been described in the spinocerebellar ataxias (SCAs), but its prevalence is unknown. We analyzed results of the CCAS/Schmahmann Scale (CCAS-S), developed to detect and quantify CCAS, in two natural history studies of 309 individuals Symptomatic for SCA1, SCA2, SCA3, SCA6, SCA7, or SCA8, 26 individuals Pre-symptomatic for SCA1 or SCA3, and 37 Controls. We compared total raw scores, domain scores, and total fail scores between Symptomatic, Pre-symptomatic, and Control cohorts, and between SCA types. We calculated scale sensitivity and selectivity based on CCAS category designation among Symptomatic individuals and Controls, and correlated CCAS-S performance against age and education, and in Symptomatic patients, against genetic repeat length, onset age, disease duration, motor ataxia, depression, and fatigue. Definite CCAS was identified in 46% of the Symptomatic group. False positive rate among Controls was 5.4%. Symptomatic individuals had poorer global CCAS-S performance than Controls, accounting for age and education. The domains of semantic fluency, phonemic fluency, and category switching that tap executive function and linguistic processing consistently separated Symptomatic individuals from Controls. CCAS-S scores correlated most closely with motor ataxia. Controls were similar to Pre-symptomatic individuals whose nearness to symptom onset was unknown. The use of the CCAS-S identifies a high CCAS prevalence in a large cohort of SCA patients, underscoring the utility of the scale and the notion that the CCAS is the third cornerstone of clinical ataxiology.

The S-Factor, a New Measure of Disease Severity in Spinocerebellar Ataxia: Findings and Implications.

Spinocerebellar ataxias (SCAs) are progressive neurodegenerative disorders, but there is no metric that predicts disease severity over time. We hypothesized that by developing a new metric, the Severity Factor (S-Factor) using immutable disease parameters, it would be possible to capture disease severity independent of clinical rating scales. Extracting data from the CRC-SCA and READISCA natural history studies, we calculated the S-Factor for 438 participants with symptomatic SCA1, SCA2, SCA3, or SCA6, as follows: ((length of CAG repeat expansion - maximum normal repeat length) /maximum normal repeat length) × (current age - age at disease onset) × 10). Within each SCA type, the S-Factor at the first Scale for the Assessment and Rating of Ataxia (SARA) visit (baseline) was correlated against scores on SARA and other motor and cognitive assessments. In 281 participants with longitudinal data, the slope of the S-Factor over time was correlated against slopes of scores on SARA and other motor rating scales. At baseline, the S-Factor showed moderate-to-strong correlations with SARA and other motor rating scales at the group level, but not with cognitive performance. Longitudinally the S-Factor slope showed no consistent association with the slope of performance on motor scales. Approximately 30% of SARA slopes reflected a trend of non-progression in motor symptoms. The S-Factor is an observer-independent metric of disease burden in SCAs. It may be useful at the group level to compare cohorts at baseline in clinical studies. Derivation and examination of the S-factor highlighted challenges in the use of clinical rating scales in this population.

The long term vaccine-induced anti-SARS-CoV-2 immune response is impaired in quantity and quality under TNFα blockade.

The humoral immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination in patients with chronic inflammatory disease (CID) declines more rapidly with tumor necrosis factor-α (TNF-α) inhibition. Furthermore, the efficacy of current vaccines against Omicron variants of concern (VOC) including BA.2 is limited. Alterations within immune cell populations, changes in IgG affinity, and the ability to neutralize a pre-VOC strain and the BA.2 virus were investigated in these at-risk patients. Serum levels of anti-SARS-CoV-2 IgG, IgG avidity, and neutralizing antibodies (NA) were determined in anti-TNF-α patients (n = 10) and controls (n = 24 healthy individuals; n = 12 patients under other disease-modifying antirheumatic drugs, oDMARD) before and after the second and third vaccination by ELISA, immunoblot and live virus neutralization assay. SARS-CoV-2-specific B- and T cell subsets were analysed by multicolor flow cytometry. Six months after the second vaccination, anti-SARS-CoV-2 IgG levels, IgG avidity and anti-pre-VOC NA titres were significantly reduced in anti-TNF-α recipients compared to controls (healthy individuals: avidity: p ≤ 0.0001; NA: p = 0.0347; oDMARDs: avidity: p = 0.0012; NA: p = 0.0293). The number of plasma cells was increased in anti-TNF-α patients (Healthy individuals: p = 0.0344; oDMARDs: p = 0.0254), while the absolute number of SARS-CoV-2-specific plasma cells 7 days after 2nd vaccination were comparable. Even after a third vaccination, these patients had lower anti-BA.2 NA titres compared to both other groups. We show a reduced SARS-CoV-2 neutralizing capacity in patients under TNF-α blockade. In this cohort, the plasma cell response appears to be less specific and shows stronger bystander activation. While these effects were observable after the first two vaccinations and with older VOC, the differences in responses to BA.2 were enhanced.

The Contribution of First-name Information to the Accuracy of Racial-and-Ethnic Imputations Varies by Sex and Race-and-Ethnicity Among Medicare Beneficiaries.

BACKGROUND: Data on race-and-ethnicity that are needed to measure health equity are often limited or missing. The importance of first name and sex in predicting race-and-ethnicity is not well understood. OBJECTIVE: The objective of this study was to compare the contribution of first-name information to the accuracy of basic and more complex racial-and-ethnic imputations that incorporate surname information. RESEARCH DESIGN: We imputed race-and-ethnicity in a sample of Medicare beneficiaries under 2 scenarios: (1) with only sparse predictors (name, address, sex) and (2) with a rich set (adding limited administrative race-and-ethnicity, demographics, and insurance). SUBJECTS: A total of 284,627 Medicare beneficiaries who completed the 2014 Medicare Consumer Assessment of Healthcare Providers and Systems survey and reported race-and-ethnicity were included. RESULTS: Hispanic, non-Hispanic Asian/Pacific Islander, and non-Hispanic White racial-and-ethnic imputations are more accurate for males than females under both sparse-predictor and rich-predictor scenarios; adding first-name information increases accuracy more for females than males. In contrast, imputations of non-Hispanic Black race-and-ethnicity are similarly accurate for females and males, and first names increase accuracy equally for each sex in both sparse-predictor and rich-predictor scenarios. For all 4 racial-and-ethnic groups, incorporating first-name information improves prediction accuracy more under the sparse-predictor scenario than under the rich-predictor scenario. CONCLUSION: First-name information contributes more to the accuracy of racial-and-ethnic imputations in a sparse-predictor scenario than in a rich-predictor scenario and generally narrows sex gaps in accuracy of imputations.

Immunogenicity and safety of anti-SARS-CoV-2 mRNA vaccines in patients with chronic inflammatory conditions and immunosuppressive therapy in a monocentric cohort.

INTRODUCTION: In light of the SARS-CoV-2 pandemic, protecting vulnerable groups has become a high priority. Persons at risk of severe disease, for example, those receiving immunosuppressive therapies for chronic inflammatory cdiseases (CIDs), are prioritised for vaccination. However, data concerning generation of protective antibody titres in immunosuppressed patients are scarce. Additionally, mRNA vaccines represent a new vaccine technology leading to increased insecurity especially in patients with CID. OBJECTIVE: Here we present for the first time, data on the efficacy and safety of anti-SARS-CoV-2 mRNA vaccines in a cohort of immunosuppressed patients as compared with healthy controls. METHODS: 42 healthy controls and 26 patients with CID were included in this study (mean age 37.5 vs 50.5 years). Immunisations were performed according to national guidelines with mRNA vaccines. Antibody titres were assessed by ELISA before initial vaccination and 7 days after secondary vaccination. Disease activity and side effects were assessed prior to and 7 days after both vaccinations. RESULTS: Anti-SARS-CoV-2 antibodies as well as neutralising activity could be detected in all study participants. IgG titres were significantly lower in patients as compared with controls (2053 binding antibody units (BAU)/mL ±1218 vs 2685±1102). Side effects were comparable in both groups. No severe adverse effects were observed, and no patients experienced a disease flare. CONCLUSION: We show that SARS-CoV-2 mRNA vaccines lead to development of antibodies in immunosuppressed patients without considerable side effects or induction of disease flares. Despite the small size of this cohort, we were able to demonstrate the efficiency and safety of mRNA vaccines in our cohort.

Bridging research and practice in conservation.

Calls for biodiversity conservation practice to be more evidence based are growing, and we agree evidence use in conservation practice needs improvement. However, evidence-based conservation will not be realized without improved access to evidence. In medicine, unlike in conservation, a well-established and well-funded layer of intermediary individuals and organizations engage with medical practitioners, synthesize primary research relevant to decision making, and make evidence easily accessible. These intermediaries prepare targeted evidence summaries and distribute them to practitioners faced with time-sensitive and value-laden decisions. To be effective, these intermediaries, who we refer to as evidence bridges, should identify research topics based on the priorities of practitioners; synthesize evidence; prepare and distribute easy-to-find and easy-to-use evidence summaries; and develop and maintain networks of connections with researchers and practitioners. Based on a review of the literature regarding evidence intermediaries in conservation and environmental management, as well as an anonymous questionnaire searching for such organizations, we found few intermediaries that met all these criteria. Few evidence bridges that do exist are unable to reach most conservation practitioners, which include resource managers in government and industry, conservation organizations, and farmers and other private landowners. We argue that the lack of evidence bridges from research to practitioners contributes to evidence complacency and limits the use of evidence in conservation action. Nevertheless, several existing organizations help reduce the gap between evidence and practice and could serve as a foundation for building additional components of evidence bridges in conservation. Although evidence bridges need expertise in research and evidence synthesis, they also require expertise in identifying and communicating with the community of practitioners most in need of clear and concise syntheses of evidence. Article Impact Statement: Evidence-based conservation will not be realized without improved access to evidence. We call for intermediary evidence bridges.

Vinculación entre la Investigación y la Práctica en la Conservación Resumen Cada vez existen más peticiones para que las prácticas de conservación de la biodiversidad estén más basadas en evidencias, además de que apoyamos la idea de que el uso de evidencias en la práctica de la conservación necesita mejorar. Sin embargo, la conservación basada en la evidencia no se logrará sin un acceso mejorado a las evidencias. En la medicina, no como en la conservación, un estrato bien establecido y financiado de individuos y organizaciones intermediarias interactúan con los médicos, sintetizan las investigaciones primarias relevantes para la toma de decisiones y hacen que las evidencias sean de fácil acceso. Estos intermediarios preparan resúmenes de evidencias específicas y los distribuyen a los médicos que enfrentan decisiones urgentes y muy valiosas. Para que sean efectivos, estos intermediarios, a quienes nos referimos como puentes de evidencias, deben poder identificar los temas de estudio con base en las prioridades de los practicantes, sintetizar evidencias, preparar y distribuir resúmenes fáciles de encontrar y fáciles de usar, y desarrollar y mantener redes de conexiones con los investigadores y los practicantes. Con base en una revisión de la literatura correspondiente a los intermediarios de evidencias en la conservación y el manejo ambiental, así como en un cuestionario anónimo que busca a dichas organizaciones, encontramos a pocos intermediarios que cumplieran con estos criterios. Los pocos puentes de evidencias que existen no son capaces de llegar a la mayoría de los practicantes de la conservación, los cuales incluyen a los gestores de recursos en el gobierno y en la industria, a las organizaciones de conservación y a los agricultores y otros terratenientes privados. Argumentamos que la falta de puentes de evidencia entre los investigadores y los practicantes contribuye a la indulgencia de evidencias y limita el uso de evidencias en las acciones de conservación. Sin embargo, varias organizaciones existentes ayudan a reducir la brecha entre la evidencia y la práctica y podrían funcionar como base para la construcción de componentes adicionales para los puentes de evidencia en la conservación. Aunque los puentes de evidencias necesitan experiencia con la investigación y con la síntesis de evidencias, también requieren experiencia con la identificación de y comunicación con la comunidad de practicantes que más necesitan una síntesis clara y concisa de la evidencia.

Mortality in infantile spasms: A hospital-based study.

OBJECTIVE: To determine risk factors and causes for mortality during childhood in patients with infantile spasms (IS). We describe the overall goals of care for those who died. METHODS: This is a retrospective chart review of IS patients born between 2000 and 2011. We examined potential risk factors for mortality, including etiology, neurologic impairment, medication use, persistence of epileptic spasms, and comorbid systemic involvement (requirement for G-tube feedings, respiratory interventions). For patients who died, we describe cause of death and resuscitation status or end-of-life care measures. RESULTS: We identified 150 IS patients with median follow-up of 12 years. During the study period, 25 (17%) patients died, 13 before 5 years of age. Univariate analysis demonstrated that developmental delay, identifiable etiology, hormonal use for IS, persistence of epileptic spasms, polypharmacy with antiseizure medications, refractory epilepsy, respiratory system comorbidity, and the need for a G-tube were significant risk factors for mortality. In a multivariate analysis, mortality was predicted by persistence of epileptic spasms (odds ratio [OR] = 4.30, 95% confidence interval [CI] = 1.11-16.67, P = .035) and significant respiratory system comorbidity (OR = 12.75, 95% CI = 2.88-56.32, P = .001). Mortality was epilepsy-related in one-third of patients who died with sudden unexpected death in epilepsy (SUDEP), accounting for 88% of epilepsy-related deaths. Most deaths before age 5 years were related to respiratory failure, and SUDEP was less common (17%) whereas SUDEP was more common (45%) with deaths after 5 years. For the majority (67%) of patients with early mortality, an end-of-life care plan was in place (based on documentation of resuscitation status, comfort measures, or decision not to escalate medical care). SIGNIFICANCE: Mortality at our single-center IS cohort was 17%, and persistence of epileptic spasms and comorbid respiratory system disorders were the most important determinants of mortality. Early deaths were related to neurological impairments/comorbidities. SUDEP was more common in children who died after 5 years of age than in those who died younger than 5 years.

In Vitro Topical Delivery of Chlorhexidine to the Cornea: Enhancement Using Drug-Loaded Contact Lenses and ß-Cyclodextrin Complexation, and the Importance of Simulating Tear Irrigation.

Microbial keratitis is a severe, sight-threatening condition caused by various pathogens. Eyedrops are the standard delivery modality for treating these disorders; however, blinking reflex, elevated tear production, and nasolacrimal drainage eliminate much of the instilled dose within a few seconds. Therefore, eyedrops must be applied repeatedly for prolonged periods. The present study aimed to probe more effective ocular delivery of chlorhexidine based upon drug-loaded hydrogel contact lenses and ß-cyclodextrin (ß-CD), while also determining the effect of constant irrigation with simulated tear fluid (STF) in in vitro experiments. Chlorhexidine digluconate (as 0.2 and 2% solutions, ß-CD inclusion complexes, and loaded hydrogel contact lenses) were applied to enucleated porcine eyes as single or multiple 10 µL doses, or as drug-loaded contact lenses, with and without ß-CD. The corneas were then excised and drug-extracted quantified by high-performance liquid chromatography (HPLC). The effect of constant irrigation by STF was evaluated to test the effect of increased tear production on corneal delivery. Potential antimicrobial activity of the delivered drug was also assessed. Results showed that drug-loaded contact lenses delivered the greatest amount of chlorhexidine into the cornea over a 24 h period, while the eyedrop solution comparator delivered the least. The ß-CD significantly enhanced chlorhexidine delivery to the cornea from eyedrop solution, although contact lenses loaded with chlorhexidine-ß-CD failed to enhance delivery. ß-CD within the hydrogel matrix impeded drug release. Constant irrigation with STF significantly reduced the amount of drug delivered to the cornea in all cases. Chlorhexidine retained antimicrobial activity in all delivery methods. Hydrogel contact lenses loaded with chlorhexidine delivered significantly higher levels to the cornea compared to eyedrops, either multiple hourly doses or a single dose. They also offer reduced application, in particular, to a nonulcerated corneal infection. Finally, the importance of fully accounting for tear production in in vitro ocular delivery experiments was highlighted.

A Comparison of Methods for Classifying and Modeling Respondents Who Endorse Multiple Racial/Ethnic Categories: A Health Care Experience Application.

BACKGROUND: Race/ethnicity information is vital for measuring disparities across groups, and self-report is the gold standard. Many surveys assign simplified race/ethnicity based on responses to separate questions about Hispanic ethnicity and race and instruct respondents to "check all that apply." When multiple races are endorsed, standard classification methods either create a single heterogenous multiracial group, or attempt to impute the single choice that would have been selected had only one choice been allowed. OBJECTIVES: To compare 3 options for classifying race/ethnicity: (a) hierarchical, classifying Hispanics as such regardless of racial identification, and grouping together all non-Hispanic multiracial individuals; (b) a newly proposed additive model, retaining all original endorsements plus a multiracial indicator; (c) an all-combinations approach, separately categorizing every observed combination of endorsements. RESEARCH DESIGN: Cross-sectional comparison of racial/ethnic distributions of patient experience scores; using weighted linear regression, we model patient experience by race/ethnicity using 3 classification systems. SUBJECTS: In total, 259,763 Medicare beneficiaries age 65+ who responded to the 2017 Medicare Consumer Assessments of Healthcare Providers and Systems Survey and reported race/ethnicity. MEASURES: Self-reported race/ethnicity, 4 patient experience measures. RESULTS: Additive and hierarchical models produce similar classifications for non-Hispanic single-race respondents, but differ for Hispanic and multiracial respondents. Relative to the gold standard of the all-combinations model, the additive model better captures ratings of health care experiences and response tendencies that differ by race/ethnicity than does the hierarchical model. Differences between models are smaller with more specific measures. CONCLUSIONS: Additive models of race/ethnicity may afford more useful measures of disparities in health care and other domains. Our results have particular relevance for populations with a higher prevalence of multiracial identification.

Characterization of Endocannabinoid-Metabolizing Enzymes in Human Peripheral Blood Mononuclear Cells under Inflammatory Conditions.

Endocannabinoid-metabolizing enzymes are downregulated in response to lipopolysaccharide (LPS)-induced inflammation in mice, which may serve as a negative feedback mechanism to increase endocannabinoid levels and reduce inflammation. Increased plasma levels of the pro-inflammatory cytokine interleukin-6 (IL-6) and decreased fatty acid amide hydrolase (FAAH) activity in peripheral lymphocytes from individuals diagnosed with Huntington's disease (HD) suggests that a similar negative feedback system between inflammation and the endocannabinoid system operates in humans. We investigated whether CpG- (unmethylated bacterial DNA) and LPS-induced IL-6 levels in peripheral blood mononuclear cells (PBMCs) from non-HD and HD individuals modulated the activities of endocannabinoid hydrolases monoacylglycerol lipase (MAGL) and carboxylesterase (CES). Baseline plasma IL-6 levels and 2-arachidonoylglycerol (2-AG) hydrolytic activity in PBMC lysates were not different in HD and non-HD individuals. Inhibition of MAGL and CES1 activity in PBMCs using the inhibitors JZL184 and WWL113, respectively, demonstrated that MAGL was the dominant 2-AG hydrolytic enzyme in PBMCs, regardless of disease state. Correlative analyses of 2-AG hydrolytic activity versus enzyme abundance confirmed this conclusion. Flow cytometric analysis of PBMCs showed that MAGL and CES1 were primarily expressed in monocytes and to a lesser extent in lymphocytes. In conclusion, these data suggest that IL-6 did not influence 2-AG hydrolytic activity in human PBMCs; however, monocytic MAGL was shown to be the predominant 2-AG hydrolytic enzyme.

Crown Ethers: Novel Permeability Enhancers for Ocular Drug Delivery?

Crown ethers are cyclic molecules consisting of a ring containing several ether groups. The most common and important members of this series are 12-crown-4 (12C4), 15-crown-5 (15C5), and 18-crown-6 (18C6). These container molecules have the ability to sequester metal ions, and their complexes with drugs are able to traverse cell membranes. This study investigated 12C4, 15C5, and 18C6 for their ability to increase solubility of ocular drugs and enhance their penetration into the cornea. Phase solubility analysis determined crown ethers' ability to enhance the solubility of riboflavin, a drug used for the therapy of keratoconus, and these solutions were investigated for ocular drug permeation enhancing properties. Atomic absorption spectroscopy demonstrated crown ether solutions' ability to sequester Ca2+ from corneal epithelia, and crown ether mediated adsorption of riboflavin into the stroma was investigated. Induced corneal opacity studies assessed potential toxicity of crown ethers. Crown ethers enhanced riboflavin's aqueous solubility and its penetration into in vitro bovine corneas; the smaller sized crown ethers gave greatest enhancement. They were shown to sequester Ca2+ ions from corneal epithelia; doing so loosens cellular membrane tight junctions thus enhancing riboflavin penetration. Induced corneal opacity was similar to that afforded by benzalkonium chloride and less than is produced using polyaminocarboxylic acids. However, in vivo experiments performed in rats with 12C4 did not show any statistically significant permeability enhancement compared to enhancer-free formulation.

Differential Requirements for IL-17A and IL-22 in Cecal versus Colonic Inflammation Induced by Helicobacter hepaticus.

Type 17 helper T-cell cytokines have been implicated in the pathogenesis of inflammatory bowel disease, a chronic condition affecting the gastrointestinal tract, but information regarding their contribution to pathology in different regions of the gut is lacking. By using a murine model of bacteria-induced typhlocolitis, we investigated the role of IL-17A, IL-17F, and IL-22 in cecal versus colonic inflammation. Cecal, but not colonic, pathology in C57BL/6 mice inoculated with Helicobacter hepaticus plus anti-IL-10 receptor (IL-10R) monoclonal antibody was exacerbated by co-administration of anti-IL-17A monoclonal antibody, suggesting a disease-protective role for IL-17A in the cecum. In contrast, anti-IL-17F had no effect on H. hepaticus-induced intestinal pathology. Neutralization of IL-22 prevented the development of colonic, but not cecal, inflammation in H. hepaticus-infected anti-IL-10R-treated mice, demonstrating a pathogenic role for IL-22 in the colon. Analysis of transcript levels revealed differential expression of IL-22R, IL-22 binding protein, and IL-23R between cecum and colon, a finding that may help explain why these tissues respond differently after anti-IL-22 treatment. Analysis of microarray data from healthy human intestine further revealed significant differences in cytokine receptor transcript levels (including IL-22RA1 and IL-23R) in distinct parts of the human gut. Together, our findings demonstrate that individual type 17 helper T-cell cytokines can have proinflammatory or anti-inflammatory effects in different regions of the intestine, an observation that may have implications for interventions against human inflammatory bowel disease.

IL-22 fate reporter reveals origin and control of IL-22 production in homeostasis and infection.

IL-22 is a cytokine that regulates tissue homeostasis at barrier surfaces. A variety of IL-22-producing cell types is known, but identification on the single-cell level remains difficult. Therefore, we generated a fate reporter mouse that would allow the identification of IL-22-producing cells and their fate mapping in vivo. To trace IL-22-expressing cells, a sequence encoding Cre recombinase was cloned into the Il22 locus, and IL22(Cre) mice were crossed with reporter mice expressing enhanced yellow fluorescence protein (eYFP) under control of the endogenous Rosa26 promoter. In IL22(Cre)R26R(eYFP) mice, the fluorescent reporter permanently labels cells that have switched on Il22 expression, irrespective of cytokine production. Despite a degree of underreporting, eYFP expression was detectable in nonimmune mice and restricted to group 3 innate lymphoid cells (ILC3) in the gut and γδ T cells in skin or lung. Upon skin challenge with imiquimod, eYFP(+) γδ and CD4 T cells expanded in the skin. Infection with Citrobacter rodentium initially was controlled by ILC3, followed by expansion of eYFP(+) CD4 T cells, which were induced in innate lymphoid follicles in the colon. No eYFP expression was detected in small intestinal Th17 cells, and they did not expand in the immune response. Colonic eYFP(+) CD4 T cells exhibited plasticity during infection with expression of additional cytokines, in contrast to ILC3, which remained largely stable. Single-cell quantitative PCR analysis of eYFP(+) CD4 T cells confirmed their heterogeneity, suggesting that IL-22 expression is not confined to particular subsets or a dedicated Th22 subset.

On the barrier properties of the cornea: a microscopy study of the penetration of fluorescently labeled nanoparticles, polymers, and sodium fluorescein.

Overcoming the natural defensive barrier functions of the eye remains one of the greatest challenges of ocular drug delivery. Cornea is a chemical and mechanical barrier preventing the passage of any foreign bodies including drugs into the eye, but the factors limiting penetration of permeants and nanoparticulate drug delivery systems through the cornea are still not fully understood. In this study, we investigate these barrier properties of the cornea using thiolated and PEGylated (750 and 5000 Da) nanoparticles, sodium fluorescein, and two linear polymers (dextran and polyethylene glycol). Experiments used intact bovine cornea in addition to bovine cornea de-epithelialized or tissues pretreated with cyclodextrin. It was shown that corneal epithelium is the major barrier for permeation; pretreatment of the cornea with ß-cyclodextrin provides higher permeation of low molecular weight compounds, such as sodium fluorescein, but does not enhance penetration of nanoparticles and larger molecules. Studying penetration of thiolated and PEGylated (750 and 5000 Da) nanoparticles into the de-epithelialized ocular tissue revealed that interactions between corneal surface and thiol groups of nanoparticles were more significant determinants of penetration than particle size (for the sizes used here). PEGylation with polyethylene glycol of a higher molecular weight (5000 Da) allows penetration of nanoparticles into the stroma, which proceeds gradually, after an initial 1 h lag phase.

Pharmacological Treatment of Tourette Disorder in Children.

Background: Tourette disorder (TD) is a neurodevelopmental disorder characterized by childhood onset of tics lasting more than one year, with multiple motor tics and at least one phonic tic at some point during the course of the symptoms. Treatment of tics may include psychoeducation, non-pharmacologic treatment, or pharmacologic treatment. We review pharmacologic treatment here. Methods: We performed a literature review on pharmacologic treatments for TD. Results: There is no current evidence to suggest that medications impact the prognosis of tic disorders, so current clinical guidelines recommend reassurance of the patient and family and monitoring if there is no change in function or quality of life due to tics. If treatment is indicated, it must be chosen based on the needs of each individual patient. Comprehensive behavioral intervention for tics (CBIT) is considered first-line management for most individuals with bothersome tics, especially if they are mild to moderate in severity. Pharmacotherapy should be considered when tics are impairing daily functioning, causing social problems, accompanied by other neuropsychiatric symptoms, or when the patient is not likely to benefit from CBIT. Current recommended pharmacotherapy options include alpha-2 adrenergic agonists, dopamine modulators, GABAergic medications, dopamine depleters, and botulinum toxin injections. Additionally, there are other novel medications that are being studied in ongoing clinical trials. Conclusions: This review summarizes available pharmacotherapy options for TD in children. It provides an overview of new medications and offers guidance to physicians when selecting appropriate treatments. If medications are indicated for tic management, treatment should be chosen based on the needs of the individual patient.

Performance of a Tic Screening Tool (MOVeIT) in Comparison to Expert Clinician Assessment in a Developmental-Behavioral Pediatrics Clinic Sample.

Youth with intellectual and developmental disabilities typically have higher rates of tics and stereotypies compared to children with otherwise typical development. Differentiating between these two pediatric movement disorders can be challenging due to overlapping clinical features, but is relevant due to distinct treatment modalities. The current study evaluated sensitivity and specificity of a tic screening measure, the Motor or Vocal Inventory of Tics (MOVeIT) in a pediatric sample enriched for stereotypy and tics. Children (n=199, age 2-15 years old) receiving care in a developmental-behavioral pediatrics clinic underwent a gold-standard diagnostic assessment by a tic expert; these evaluations were compared to the MOVeIT. The MOVeIT demonstrated good sensitivity (89.8%) and relatively lower specificity (57.1%) compared to tic expert for detecting tics in the overall sample. Specificity of the MOVeIT to identify tics improved to 75% when excluding children with co-occurring stereotypy. For children with tics and co-occurring stereotypy, sensitivity remained high (91.9%) but specificity was low (39.1%). The area under the curve (AUC) value to detect tics on the MOVeIT compared to the tic expert gold standard was significantly higher for children without stereotypy (AUC=85.7%) than those with stereotypy (AUC=64.3%, p <0.01). Overall, the ability to detect tics was better in those without co-occurring stereotypy symptoms. Further work is needed to establish the utility of the MOVeIT in populations where there is a high likelihood of co-occurring tics and stereotypy and in general population settings. Accurate distinction between tics and stereotypy will guide choices for intervention and anticipatory guidance for families.

Cyclodextrin-mediated enhancement of riboflavin solubility and corneal permeability.

Cyclodextrins are water-soluble cyclic oligosaccharides consisting of six, seven, and eight α-(1,4)-linked glucopyranose subunits. This study reports the use of different cyclodextrins in eye drop formulations to improve the aqueous solubility and corneal permeability of riboflavin. Riboflavin is a poorly soluble drug with a solubility up to 0.08 mg mL(-1) in deionized water. It is used as a drug topically administered to the eye to mediate UV-induced corneal cross-linking in the treatment of keratoconus. Aqueous solutions of ß-cyclodextrin (10-30 mg mL(-1)) can enhance the solubility of riboflavin up to 0.12-0.19 mg mL(-1), whereas the higher concentration of α-cyclodextrin (100 mg mL(-1)) achieved a lower level of enhancement of 0.11 mg mL(-1). The other oligosaccharides were found to be inefficient for this purpose. In vitro diffusion experiments performed with fresh and cryopreserved bovine cornea have demonstrated that ß-cyclodextrin enhances riboflavin permeability. The mechanism of this enhancement was examined through microscopic histological analysis of the cornea and is discussed in this paper.

E-mail management of the modified Atkins Diet for adults with epilepsy is feasible and effective.

PURPOSE: The modified Atkins Diet (MAD) is an effective dietary treatment for children with epilepsy. However, adults may have limited access to this therapy because of lack of availability of dietitian or nutrition support or familiarity with the diet by their treating neurologist. This study was designed to investigate the tolerability and efficacy of the MAD administered solely via e-mail to adults with pharmacoresistant epilepsy. METHODS: A prospective, open-label, proof-of-principle 3-month study design was employed. Adults were enrolled, instructed on how to self-administer a 20 g carbohydrate per day MAD, and followed by the investigators only via e-mail. There were no clinic visits or dietitian contacts during the study period. KEY FINDINGS: Twenty-five participants (median age 30 years [range 18-66 years], 68% female) consented and 22 started the MAD. The median prior anticonvulsants was 5 (range 2-10) and seizure frequency was 5 per week (range 1-140). Urinary ketosis was achieved in 21 participants (95%), of which 16 (76%) reported at least 40 mg/dl (moderate). Twenty-one participants (95%) remained on the MAD at 1 month and 14 (64%) at 3 months. After 1 month, 9 (41%) had >50% seizure reduction including one (5%) with >90% seizure reduction using intent-to-treat analysis. After 3 months, 6 (27%) had >50% seizure reduction including 3 (14%) with >90% seizure reduction. The mean ketogenic ratio was 1.1:1 (fat:carbohydrates and protein) for those who provided a MAD food record at follow-up. Over the study period, the median number of e-mails sent by the participants was 6 (range 1-19). The most frequent side effect was weight loss. SIGNIFICANCE: E-mail administration of the MAD to adults with refractory epilepsy appears to be feasible and effective. Therefore, when dietitian or physician support is limited for adult patients with epilepsy, remote access via telemedicine could provide an alternative.

Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity.

Interleukin-23 (IL-23) plays an essential role in driving intestinal pathology in experimental models of both T-cell-dependent and innate colitis. Furthermore, genome-wide association studies have identified several single-nucleotide polymorphisms in the IL-23 receptor (IL-23R) gene that are associated with either susceptibility or resistance to inflammatory bowel disease in humans. Although initially found to support the expansion and maintenance of CD4(+) T helper 17 (Th17) cells, IL-23 is now recognized as having multiple effects on the immune response, including restraining Foxp3(+) regulatory T-cell activity and inducing the expression of Th17-type cytokines from non-T-cell sources. Here we focus on Th17 cells and their associated cytokines IL-17A, IL-17F, IL-21 and IL-22. We review studies performed in mouse models of colitis where these effector cytokines have been shown to have either a pathogenic or a tissue-protective function. We also discuss the heterogeneity found within the Th17 population and the phenomenon of plasticity of Th17 cells, in particular the ability of these lymphocytes to extinguish IL-17 expression and turn on interferon-γ production to become Th1-like 'ex-Th17' cells. Interleukin-23 has been identified as a key driver in this process, and this may be an additional mechanism by which IL-23 promotes pathology in the intestinal tract. These 'ex-Th17' cells may contribute to disease pathogenesis through their secretion of pro-inflammatory mediators.

And then there were four: Anatomical observations on the pollical palmar interosseous muscle in humans.

Although anatomists generally agree upon the presence of four interosseous muscles in the human hand, the number and identity of the palmar interosseous muscles remains contentious. Recent studies suggest that a majority of human hands possess four palmar interossei, yet most contemporary texts suggest the presence of only three. The pollical palmar interosseous muscle (PPIM), associated with the first digit, has been alternatively interpreted as a distinct muscle, part of another hand muscle, or nonexistent. We examined 45 hands from 23 human cadavers to investigate the prevalence of this muscle and found it to occur in varying degrees of expression in 91% of specimens. We also tested the hypothesis that the PPIM forms the smaller part of a "parallel muscle combination" and is therefore ideally suited to act as a proprioceptive organ. Results do not show a significantly higher density of muscle spindles in the PPIM relative to the adjacent adductor pollicis, provisionally refuting this hypothesis. The presence of the PPIM, observed in the majority of hands from several populations, indicates that it should be regularly included in mainstream anatomy texts and atlases.