Neurofilament Light Chain as a Biomarker of Neuronal Damage in Children With Malaria.

Malaria can cause brain injury. Neurofilament light chain (NfL) is a biomarker of neuronal damage. Here we examined longitudinal plasma NfL levels in children aged 1-12 years with uncomplicated and severe malaria from Mozambique. NfL levels were similar in all malaria cases at hospital admission. However, levels increased over time and the increment was significantly higher in severe malaria cases with neurological manifestations (ie, coma, impaired consciousness, or repeated seizures). NfL may be useful to identify and quantify brain injury in malaria.

In-person validation of the Ichthyosis Scoring System.

BACKGROUND: Ichthyoses are a heterogeneous group of skin disorders characterized by scaling and erythema. Recognizing the variability of scale and erythema by region and ichthyosis subtype, we developed the Ichthyosis Scoring System (ISS) to quantify severity. We previously found ISS to have high inter- and intrarater reliability in evaluating photographic images. To confirm ISS clinical utility, we examined its performance at the 2022 Foundation for Ichthyosis and Related Skin Types conference. METHODS: Sixty-five participants were evaluated by 3 of 9 medical professionals trained to score ichthyosis scale and erythema using ISS. Intrarater and interrater intraclass correlation coefficients (ICC) were analyzed using one-way and two-way random effects models, respectively. RESULTS: Intrarater reliability was excellent (ICC = 0.931, 95% CI, 0.921-0.940) for scale and good (ICC = 0.876, 95% CI, 0.853-0.899) for erythema scoring. Compared to photo validation with excellent intrarater reliability ratings for both scale (ICC = 0.956, 95% CI, 0.925-0.974) and erythema (ICC = 0.913, 95% CI, 0.855-0.949), ISS demonstrated equivalent reliability for live use. Overall interrater reliability for 10 body sites showed excellent (ICC >0.9) and good (ICC >0.75) agreement and consistency for both scale and erythema. Palms were an exception, demonstrating moderate (ICC >0.5) interrater agreement and consistency for erythema evaluation. CONCLUSIONS: ISS is a reliable measure of global and regional ichthyosis severity during in-person evaluations. Ease-of-use, accessibility, and content validity in both live and photographic evaluation endorse ISS as a standard for ichthyosis severity analysis.

Apolipoprotein E4 Reduction with Antisense Oligonucleotides Decreases Neurodegeneration in a Tauopathy Model.

OBJECTIVE: Apolipoprotein E (ApoE) genotype is the strongest genetic risk factor for late-onset Alzheimer's disease, with the ε4 allele increasing risk in a dose-dependent fashion. In addition to ApoE4 playing a crucial role in amyloid-ß deposition, recent evidence suggests that it also plays an important role in tau pathology and tau-mediated neurodegeneration. It is not known, however, whether therapeutic reduction of ApoE4 would exert protective effects on tau-mediated neurodegeneration. METHODS: Herein, we used antisense oligonucleotides (ASOs) against human APOE to reduce ApoE4 levels in the P301S/ApoE4 mouse model of tauopathy. We treated P301S/ApoE4 mice with ApoE or control ASOs via intracerebroventricular injection at 6 and 7.5 months of age and performed brain pathological assessments at 9 months of age. RESULTS: Our results indicate that treatment with ApoE ASOs reduced ApoE4 protein levels by ~50%, significantly protected against tau pathology and associated neurodegeneration, decreased neuroinflammation, and preserved synaptic density. These data were also corroborated by a significant reduction in levels of neurofilament light chain (NfL) protein in plasma of ASO-treated mice. INTERPRETATION: We conclude that reducing ApoE4 levels should be explored further as a therapeutic approach for APOE4 carriers with tauopathy including Alzheimer's disease. ANN NEUROL 2021;89:952-966.

Heparin-Binding Protein Stratifies Mortality Risk Among Ugandan Children Hospitalized With Respiratory Distress.

Background: Current prognostic tools do not reliably and objectively identify children with pneumonia at risk of a severe or life-threatening episode. Heparin-binding protein (HBP) is a host immune protein that is released in response to infection. We hypothesized that measuring HBP concentrations at hospital admission could help risk-stratify children with pneumonia and identify those at higher risk of an adverse prognosis. Methods: We evaluated the prognostic accuracy of HBP for predicting in-hospital mortality among children with respiratory distress, and whether HBP could improve the accuracy of validated composite clinical severity scores. Results: Of 778 Ugandan children under 5 years of age and presenting with clinically defined pneumonia, 60 (7.7%) died during hospital admission. HBP concentrations at presentation were significantly higher in children with fatal outcomes (median, 76 ng/mL [interquartile range {IQR}, 41-150]) compared to children who survived (median, 31 ng/mL [IQR, 18-57]) (P < .001). Children with HBP >41 ng/mL on admission had an elevated risk of death (hazard ratio, 5.3 [95% confidence interval {CI}, 2.9-9.5]; P < .0001). In receiver operating characteristic (ROC) curve analysis, HBP concentrations distinguished between fatal and nonfatal outcomes (area under the ROC curve, 0.75 [95% CI, .66-.84]) and significantly improved the prediction provided by the Respiratory Index of Severity in Children, a composite clinical severity score (P = .0026). Conclusions: Measuring HBP at presentation could help identify children at risk of severe and fatal pneumonia. Adding HBP to clinical scores could improve the recognition and triage of children with pneumonia at risk of death.

How Home Delivery of Antiretroviral Drugs Ensured Uninterrupted HIV Treatment During COVID-19: Experiences From Indonesia, Laos, Nepal, and Nigeria.

INTRODUCTION: Faced with the coronavirus disease (COVID-19) pandemic, governments worldwide instituted lockdowns to curtail virus spread. Health facility closures and travel restrictions disrupted access to antiretroviral (ARV) therapy for people living with HIV. This report describes how HIV programs in Indonesia, Laos, Nepal, and Nigeria supported treatment continuation by introducing home delivery of ARVs. METHODS: Staff supporting the programs provided accounts of when and how decisions were taken to support ARV home delivery. They captured programmatic information about home delivery implementation using an intervention documentation tool. The 4 country experiences revealed lessons learned about factors favoring successful expansion of ARV home delivery. RESULTS: Three of the countries relied on existing networks of community health workers for ARV delivery; the fourth country, Indonesia, relied on a private sector courier service. Across the 4 countries, between 19% and 51% of eligible clients were served by home delivery. The experiences showed that ARV home delivery is feasible and acceptable to health service providers, clients, and other stakeholders. Essential to success was rapid mobilization of stakeholders who led the design of the home delivery mechanisms and provided leadership support of the service innovations. Timely service adaptation was made possible by pre-existing differentiated models of care supportive of community-based ARV provision by outreach workers. Home delivery models prioritized protection of client confidentiality and prevention measures for COVID-19. Sustainability of the innovation depends on reinforcement of the commodity management infrastructure and investment in financing mechanisms. CONCLUSION: Home delivery of ARVs is a feasible client-centered approach to be included among the options for decentralized drug distribution. It serves as a measure for expanding access to care both when access to health services is disrupted and under routine circumstances.

Effects of packaging design on sensory liking and willingness to purchase: A study using novel chocolate packaging.

Packaging is the first impression consumers have of food products which determines likelihood of purchasing. Therefore, the objective of this study was to evaluate the effect of chocolate packaging design on sensory liking and willingness to purchase (WTP) of consumers (n = 75) under three conditions:(1) blind [product], (2) packaging, and (3) informed [product and packaging]. The same chocolate tasted in (1) was wrapped in six different packaging concepts (bold, fun, every day, special, healthy, premium) developed based on TNS NeedScope™ model for (3). There were significant differences in liking towards taste based on packaging. Liking scores for (3) reduced when expectations created by packaging were not met. Regression analysis explained, taste had strongest association (r = 0.73) towards WTP. Cochran's Q and McNemar tests showed significant differences in frequencies of emotion-based terms between packaging and informed conditions. These findings can be used in product design to evaluate product attributes by enhancing emotional attachment towards chocolate.

Consumer Acceptability, Eye Fixation, and Physiological Responses: A Study of Novel and Familiar Chocolate Packaging Designs Using Eye-Tracking Devices.

Eye fixations on packaging elements are not necessarily correlated to consumer attention or positive emotions towards those elements. This study aimed to assess links between the emotional responses of consumers and the eye fixations on areas of interest (AOI) of different chocolate packaging designs using eye trackers. Sixty participants were exposed to six novel and six familiar (commercial) chocolate packaging concepts on tablet PC screens. Analysis of variance (ANOVA) and multivariate analysis were performed on eye tracking, facial expressions, and self-reported responses. The results showed that there were significant positive correlations between liking and familiarity in commercially available concepts (r = 0.88), whereas, with novel concepts, there were no significant correlations. Overall, the total number of fixations on the familiar packaging was positively correlated (r = 0.78) with positive emotions elicited in people using the FaceReader™ (Happy), while they were not correlated with any emotion for the novel packaging. Fixations on a specific AOI were not linked to positive emotions, since, in some cases, they were related to negative emotions elicited in people or not even associated with any emotion. These findings can be used by package designers to better understand the link between the emotional responses of consumers and their eye fixation patterns for specific AOI.

Lack of hepatic apoE does not influence early Aß deposition: observations from a new APOE knock-in model.

BACKGROUND: The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease (AD). ApoE is produced by both astrocytes and microglia in the brain, whereas hepatocytes produce the majority of apoE found in the periphery. Studies using APOE knock-in and transgenic mice have demonstrated a strong isoform-dependent effect of apoE on the accumulation of amyloid-ß (Aß) deposition in the brain in the form of both Aß-containing amyloid plaques and cerebral amyloid angiopathy. However, the specific contributions of different apoE pools to AD pathogenesis remain unknown. METHODS: We have begun to address these questions by generating new lines of APOE knock-in (APOE-KI) mice (ε2/ε2, ε3/ε3, and ε4/ε4) where the exons in the coding region of APOE are flanked by loxP sites, allowing for cell type-specific manipulation of gene expression. We assessed these mice both alone and after crossing them with mice with amyloid deposition in the brain. Using biochemical and histological methods. We also investigated how removal of APOE expression from hepatocytes affected cerebral amyloid deposition. RESULTS: As in other APOE knock-in mice, apoE protein was present predominantly in astrocytes in the brain under basal conditions and was also detected in reactive microglia surrounding amyloid plaques. Primary cultured astrocytes and microglia from the APOE-KI mice secreted apoE in lipoprotein particles of distinct size distribution upon native gel analysis with microglial particles being substantially smaller than the HDL-like particles secreted by astrocytes. Crossing of APP/PS1 transgenic mice to the different APOE-KI mice recapitulated the previously described isoform-specific effect (ε4 > ε3) on amyloid plaque and Aß accumulation. Deletion of APOE in hepatocytes did not alter brain apoE levels but did lead to a marked decrease in plasma apoE levels and changes in plasma lipid profile. Despite these changes in peripheral apoE and on plasma lipids, cerebral accumulation of amyloid plaques in APP/PS1 mice was not affected. CONCLUSIONS: Altogether, these new knock-in strains offer a novel and dynamic tool to study the role of APOE in AD pathogenesis in a spatially and temporally controlled manner.

Age-Dependent Effects of apoE Reduction Using Antisense Oligonucleotides in a Model of ß-amyloidosis.

The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer disease. Previous studies suggest that reduction of apoE levels through genetic manipulation can reduce Aß pathology. However, it is not clear how reduction of apoE levels after birth would affect amyloid deposition. We utilize an antisense oligonucleotide (ASO) to reduce apoE expression in the brains of APP/PS1-21 mice homozygous for the APOE-ε4 or APOE-ε3 allele. ASO treatment starting after birth led to a significant decrease in Aß pathology when assessed at 4 months. Interestingly, ASO treatment starting at the onset of amyloid deposition led to an increase in Aß plaque size and a reduction in plaque-associated neuritic dystrophy with no change in overall plaque load. These results suggest that lowering apoE levels prior to plaque deposition can strongly affect the initiation of Aß pathology while lowering apoE after Aß seeding modulates plaque size and toxicity.