Longitudinal decline of plasma neurofilament light levels after antiretroviral initiation in people living with HIV.

BACKGROUND: This retrospective follow-up study aims to investigate the dynamic longitudinal change of plasma neurofilament light (NfL) levels after antiretroviral therapy (ART) initiation in a cohort of people living with human immunodeficiency virus (HIV) (PWH). METHODS: We tested a convenience sample of 116 patients from the NORTHIV study. Plasma NfL levels-measured using Single molecule array (Simoa) technology-as well as other laboratory parameters were collected at baseline, weeks 4, 48, 96, and 144. Linear mixed-effects models were estimated to evaluate longitudinal change over time. Baseline CD4+ T-cell levels, CDC classification, and HIV RNA levels were considered. Models were adjusted by age, sex, treatment regimen, and baseline serum creatinine levels. RESULTS: Plasma NfL levels were higher at baseline and also declined faster during the follow-up for participants with CD4+ count <100 cells/µl compared with >100 cells/µl. No significant difference was found between the CD4+ strata 100-199 and 200-499/µl. Participants with CDC classification stages B and C had higher levels of plasma NfL at baseline, as well as faster decline compared with participants with stage A. No significant main effects or change over time was found in baseline HIV RNA levels, treatment regimen, or sex. CONCLUSION: Plasma NfL is a sensitive biomarker to assess ongoing central nervous system injury in PWH. Plasma NfL concentrations decline relatively fast following ART initiation and then stabilize after 48 weeks. Plasma NfL concentrations are associated with CD4+ count and stage of HIV disease. No correlations were seen with different ART regimens.

Beyond p < .05: a critical review of new Bayesian proposals for assessing the p-value.

This paper reviews recent contributions from a Bayesian-oriented perspective, after the ASA statement on p-values (2016). We classify proposals that (i) supplement the p-value; (ii) modify the p-value itself. In the first group, we review the Bayes factor, the False Positive risk, the rejection odds and the analysis of credibility from both Matthews' and Held's point of view. We also put forth and discuss a new index of credibility, about which we conduct a delimited simulation study. In the second group, we discuss Gannon's modification of the p-value based on the Bayes factor and the second-generation p-value. The theory is illustrated with two case studies on pharmacotherapy in infectious diseases. Contemporary authors still refer to the p-value as a statistical indicator but have abandoned the perspective of evaluating p-values with fixed thresholds. Statistical societies worldwide should target new strategies to disseminate the debate on p-values in all applied fields of knowledge, as well as they may promote the use of different statistical procedures to supplement p-values.

Clinical and genetic correlations of scoliosis in Rett syndrome.

AIM: To identify the clinical features correlating with the presence and severity of scoliosis in girls with Rett syndrome (RTT). METHOD: Seventy-five girls with a clinical and genetically determined diagnosis of RTT participated in this cross-sectional study. Clinical scales administered included the Rett assessment rating scale, the modified Ashworth scale, the Rett syndrome motor evaluation scale, the PainAD, and the scale of evaluation of purposeful hand function. Multivariable analyses, such as ordinal logistic regression and ANCOVA, were used to assess the correlation between these scales and a clinical score of scoliosis. RESULTS: About 60% of patients had scoliosis, in general mild or moderate. The severity of scoliosis correlated with age and important neurological factors such as muscular hypertonus and hyperreflexia, standing, walking (level walking and on stairs), and postural transitions. No association was found with global disease severity, hand function, pain, or type of genetic mutation. INTERPRETATION: Scoliosis is a relevant problem in RTT. It should be carefully monitored along the life span, especially in conjunction with (loco-)motor impairment in these patients.

Best uses of p-values and complementary measures in medical research: Recent developments in the frequentist and Bayesian frameworks.

The p-value is a classical proposal of statistical inference, dating back to the seminal contributions by Fisher, Neyman and E. Pearson. However, p-values have been frequently misunderstood and misused in practice, and medical research is not an exception. In recent years, in several statistical and applied journals, a debate erupted about the need of clear guidelines in reporting p-values, which culminated with the publication of the ASA statement in 2016. In this paper, we assess strengths and limitations of p-values and we assert that in applied research the p-value should be supplemented by other measures, such as the Bayes factor, the Bayes false discovery rate and the local Bayes false discovery rate. We also review a recent proposal by Bayarri et al. from a Bayesian perspective that has the advantage of introducing an indicator, the rejection odds, which keeps into account both pre- and post-experimental information, and could also have a straightforward frequentist interpretation. We conduct a delimited numerical study that investigates on the relation of the Bayes factor with its maximum, and of the local Bayes false discovery rate with its minimum under different distributional assumptions and parameter choices. We illustrate the concepts expressed in theory with an example in clinical oncology, namely a randomized trial on the effectiveness of a new chemotherapy for patients with AIDS and Kaposi's sarcoma.

Parenting girls with Rett syndrome: An investigation on self-perceived levels of stress.

BACKGROUND: Although lives of parents of girls with Rett syndrome (RTT) are centred on the process of care, in the current literature their perceived levels of stress have been rarely investigated. METHODS: We analysed levels of stress in a sample of 79 fathers and mothers parenting girls with RTT, who were required to compile the Parenting Stress Index (PSI) questionnaire. RESULTS: We found clinical levels of stress in about 39% of fathers, as compared with 44% of the mothers. Severity of RTT, but not other factors such as the genetic domain, presence of epilepsy or scoliosis, predicted Total Stress scores in both fathers' subsample and mothers' subsample. A cumulative effect of caring, that is association of higher levels of stress with longer process of care, did also emerge from estimation of smoothing splines. CONCLUSIONS: Fathers' resources should be taken more into account, especially in the rehabilitation and socialization process of adults with RTT.

Motor function in Rett syndrome: comparing clinical and parental assessments.

AIM: To describe a new clinical tool, the Rett Syndrome Motor Evaluation Scale (RESMES) and to assess (loco-)motor function in people with Rett syndrome (RTT). METHOD: Formal assessment provided by physicians was followed by parents' direct observation at home using the RESMES. Sixty females (mean [SD] age 12y 5mo [8y 9mo], range 3-40y) with a clinical diagnosis and genetically determined RTT participated in the study. Spearman's/Pearson's coefficients assessed the correlation between the clinicians' and caregivers' evaluations, as well as the correlation of RESMES scores with other scales, namely the Pain Assessment in Advanced Dementia, the Rett Assessment Rating Scale, the Modified Ashworth Scale, and hand function (assessed with a scale of evaluation of purposeful hand function). Scores provided by parents and clinicians were tested statistically by Mann-Whitney U test. RESULTS: Approximately 88% of patients had moderate to severe RTT symptoms and, on average, moderate motor impairment based on the RESMES. RESMES total scores provided by clinicians and caregivers were highly correlated (r=0.91), as were the subscale scores. Postural transition was a critical area of the RESMES, where parents systematically provided lower scores than clinicians, indicating milder degrees of disability. Severity of scoliosis and mutation type emerged as significant predictors of motor function. INTERPRETATION: The RESMES characterized the (loco-)motor impairments of the patients with RTT well. It also showed a close correlation between the evaluations of clinicians and caregivers, with the possible exception of postural transition tasks, which should be carefully addressed in a clinical setting. The type of mutation and presence of scoliosis should be evaluated, as they predicted the ability to walk. WHAT THIS PAPER ADDS: Caregivers at home can reliably assess motor function in Rett syndrome using the Rett Syndrome Motor Evaluation Scale (RESMES). RESMES scores provided by clinicians and parents were highly correlated. The severity of scoliosis and the genetic mutation predicted standing and walking abilities.

FUNCIÓN MOTORA EN EL SÍNDROME DE RETT: COMPARACIÓN DE EVALUACIONES CLÍNICAS Y PARENTALES: OBJETIVO: Describir una nueva herramienta clínica, la Escala de Evaluación Motora del Síndrome de Rett (RESMES) y evaluar la función motora (locomotora) en personas con síndrome. de Rett (RTT). METODO: La evaluación formal proporcionada por los médicos fue seguida por la observación directa de los padres en el hogar utilizando los RESMES. Sesenta mujeres (edad media 12 años 5 meses[DS =8 años 9 meses], rango 3-40 años) con diagnóstico clínico y genético de RTT participaron en el estudio. Los coeficientes de Spearman / Pearson evaluaron la correlación entre las evaluaciones de los médicos y los cuidadores, así como la correlación de las puntuaciones de RESMES con otras escalas, como la Evaluación del Dolor en la Demencia Avanzada (Pain Assessment in Advanced Dementia), la Escala de Calificación de la Evaluación de Rett (Rett Assessment Rating Scale), la Escala de Ashworth modificada y la función de la mano (evaluado con una escala de evaluación de la función voluntaria de la mano). Las puntuaciones proporcionadas por los padres y los clínicos se evaluaron estadísticamente mediante la prueba U de Mann-Whitney. RESULTADOS: Aproximadamente el 88% de los pacientes tenían síntomas de RTT de moderados a severos y, en promedio, una discapacidad motora moderada basada en los puntajes de RESMES. Se encontró una correlación muy alta (r = 0,91) entre los puntajes totales de RESMES proporcionados por los médicos y cuidadores, al igual que los puntajes con las otras escalas. La transición postural fue un área crítica de RESMES, donde los padres proporcionaron sistemáticamente puntuaciones más bajas que los clínicos, lo que indica grados más leves de discapacidad. La gravedad de la escoliosis y el tipo de mutación fueron factores significativamente predictivos de la función motora. INTERPRETACIÓN: Los puntajes de RESMES caracterizaron bien las alteraciones motoras de las pacientes con RTT. Se encontró una estrecha correlación entre las evaluaciones de los médicos y los cuidadores, con la posible excepción de los cambios postural, que deben evaluarse con cuidado en un entorno clínico. Se debe considerar el tipo de mutación y la presencia de escoliosis, ya que predijeron la capacidad de caminar.

FUNÇÃO MOTORA NA SÍNDROME DE RETT: COMPARANDO AVALIAÇÕES CLÍNICAS E DOS PAIS: OBJETIVO: Descrever uma nova ferramenta clínica, a Escala de avaliação motora da síndrome de Rett (RESMES) e avaliar a função (loco)motora em pessoas com síndrome de Rett (RTT). MÉTODO: A avaliação formal por médicos foi seguida por observação direta dos pais em casa usando a RESMES. Sessenta meninas (média [DP] idade 12a 5m [8a 9m], variação 3-40a) com diagnóstico clínico e RTT determinada geneticamente participaram no estudo. Coeficientes de Spearman/Pearson avaliaram a correlação entre avaliações dos clínicos e cuidadores, assim como as correlações dos escores na RESMES com outras escalas: Avaliação da Dor na Demência avançada (Pain Assessment in Advanced Dementia), Escala de Classificação de Rett (Rett Assessment Rating Scale), a Escala de Ashworth Modificada, e função manual (avaliada com uma escala de avaliação da função manual voluntária). Os escores fornecidos pelos pais e clínicos foram testados estatisticamente com o teste de Mann-Whitney U. RESULTADOS: Aproximadamente 88% dos pacientes tinham sintomas de RTT de moderados a severos e, em média, comprometimento motor moderado na RESMES. Os escores totais da RESMES dados pelos clínicos e cuidadores foram altamente correlacionados (r=0,91), assim como os escores das subescalas. Transição postural foi uma área crítica da RESMES, em que pais sistematicamente ponturam mais baixo que os clínicos, indicando graus mais leves de incapacidade. A severidade da escoliose e tipo de mutação emergiram como preditores significativos da função motora. INTERPRETAÇÃO: A RESMES caracterizou bem as deficiências (loco) motoras de pacientes com RTT. Também mostrou correlação próxima entre as avaliações de clínicos e cuidadores, com a possível exceção das tarefas de transição postural, as quais devem ser cuidadosamente abordadas no contexto clínico. O tipo de mutação e presença de escoliose devem ser avaliados, pois predizem a capacidade de andar.

Parents' perception of health care services for girls with Rett syndrome.

BACKGROUND: Rett syndrome (RTT) is a severe neurodevelopmental disorder, implying impairment and disability across several domains. METHOD: We investigated parents' perception of the caregiving process in a sample of 55 mothers and fathers of girls with RTT using the MPOC-20 questionnaire. The association of parents' satisfaction with clinical variables has also been explored. RESULTS: We obtained intermediate levels of satisfaction on the MPOC-20 Coordinated and Comprehensive Care and Respectful and Supportive Care scales. The performance was lower on the scales Providing General Information and Providing Specific Information. Mothers' assessment was not associated with clinical variables such as walking disability, presence of scoliosis, or epilepsy. For children with greater degree of walking impairment, fathers expressed the need of having more information available. CONCLUSIONS: Although parents seemed satisfied of the caregiving process, clinicians should put more emphasis on their need of receiving general and specific information on RTT along the entire rehabilitation program.

Tests for noninferiority trials with binomial endpoints: A guide to modern and quasi-exact methods for biomedical researchers.

Applied statisticians and pharmaceutical researchers are frequently involved in the design and analysis of clinical trials where at least one of the outcomes is binary. Treatments are judged by the probability of a positive binary response. A typical example is the noninferiority trial, where it is tested whether a new experimental treatment is practically not inferior to an active comparator with a prespecified margin δ. Except for the special case of δ = 0, no exact conditional test is available although approximate conditional methods (also called second-order methods) can be applied. However, in some situations, the approximation can be poor and the logical argument for approximate conditioning is not compelling. The alternative is to consider an unconditional approach. Standard methods like the pooled z-test are already unconditional although approximate. In this article, we review and illustrate unconditional methods with a heavy emphasis on modern methods that can deliver exact, or near exact, results. For noninferiority trials based on either rate difference or rate ratio, our recommendation is to use the so-called E-procedure, based on either the score or likelihood ratio statistic. This test is effectively exact, computationally efficient, and respects monotonicity constraints in practice. We support our assertions with a numerical study, and we illustrate the concepts developed in theory with a clinical example in pulmonary oncology; R code to conduct all these analyses is available from the authors.

HLA-G coding region polymorphism is skewed in autistic spectrum disorders.

Different isoforms of HLA-G protein are endowed with a differential ability to induce allogenic tolerance during pregnancy. As prenatal immune activation is suggested to play a role in the onset of autistic spectrum disorders (ASD), we evaluated HLA G*01:01-*01:06 allelic polymorphism in a cohort of Italian children affected by ASD (N=111) their mothers (N=81), and their healthy siblings (N=39). DNA sequencing analysis of HLA-G exon 2, 3 and 4 was used to obtain HLA-G allelic frequencies; alleles distribution was compared with that of two control groups of Caucasoid couples of multiparous women and their partners from Brazil and Denmark. HLA-G distribution was significantly different in ASD children compared to both control groups (Brazilian pc=1×10-4; Danish pc=1×10-3). Since HLA-G distribution was similar in the two control groups, their data were pooled. Results indicated that HLA-G*01:01 was significantly less frequent (pc=1×10-4; OR:0.5, 95%CI: 0.3-0.7) whereas HLA-G*01:05N was significantly more frequent (pc=2×10-3; OR:7.3, 95%CI: 2.4-26.6) in ASD children compared to combined controls. Finally, no clear pattern emerged when HLA-G allelic distribution was analyzed in healthy sibs. Notably, HLA-G allelic distribution found in ASD mothers was similar to that observed in the control subgroup of women with recurrent miscarriages, whilst it was significantly different compared to women without miscarriages (pc=6×10-4 df=12). Since HLA-G*01:01 is associated with the elicitation of KIR-mediated tolerogenic responses and HLA-G*01:05N correlates with NK cells activation, results herein indicate that an immune activating milieu during pregnancy is more likely observed in association with the development of ASD, similarly to what occurs in women with recurrent miscarriages.

Word and pseudoword superiority effects in a shallow orthography language: the role of hemispheric lateralization.

The word superiority effect (WSE) has made it possible to demonstrate the automatic activation of lexical-orthographic entries in reading. The observation of this effect is important since it led to experimental support of the main cognitive reading models. These models were mostly developed on English data, hence the verification in different orthography systems is relevant. The present study tested WSE in Italian, a language in which this effect was predicted to be less constant given the highly consistent correspondence between orthography and phonology. Moreover, the presentation of the items in a lateralized visual field condition allowed testing of assumptions about the roles of the right and left hemispheres in written word recognition and, in particular, on the hemispheric lateralization of lexical processing. Two experiments were conducted with undergraduate students who had to recognize a target letter within a word, pseudoword, or nonword. In Experiment 1, prime and probe letters were in the same letter case, while in Experiment 2 they were in different letter cases. Error rates and reaction times were analyzed with mixed models. The results showed a superiority of pseudowords (pseudoword superiority effect; PSE) over illegal strings with no evidence of a clear superiority of words over pseudowords for both left and right visual field presentations. This suggests that in Italian, the sub-lexical route could play a major role in reading and that this route relies on a visual-perceptual orthographic coding concerning familiarity of letter combinations, which is also available to the right hemisphere.

A semi-standardized music therapy intervention for girls with Rett syndrome: A descriptive essay.

Rett syndrome (RTT) is a severe neurodevelopmental disorder resulting in a wide range of functional impairments and therefore greatly impacts the lives of both patients and their families. While genetic and medical aspects have been studied for several decades, rehabilitation intervention research is still in its infancy. In this study, the investigating researchers have presented a rehabilitative framework by using music therapy for girls with RTT. This model is founded upon the use of music therapy in light of Stern's proposal of subjective experience and affect attunement; it also refers to Rosenbaum's family-centered rehabilitation medicine perspective. This study both describes the theory behind this intervention and presents a newly developed outcome measure. This novel tool may have future clinical and research applications. Music therapy for patients with RTT has not been well researched yet, and, as a result, is not universally recommended. However this study's findings suggest that music therapy is an important component of multidisciplinary therapy. Further collaborative research should be encouraged in order to study and implement the use of music therapy in the treatment of severe disabilities. Projects such as the Enablin+ program with the support from the European Commission constitute fundamental tools in promoting integrative medical research and international networks.

A comprehensive open-source library for exact required sample size in binary clinical trials.

We describe how we are creating a new and comprehensive R library solving the problem of exact sample size determination of RCTs. A crucial prerequisite for the trial protocol is a priori sample sizes that bound the test size below a target (often 5%) and the test power above a target (often 80%). Approximate formulas are available for binary trials but the target test size and power are often violated by standard methods for even quite large sample sizes. Moreover, adjusting standard tests to take account of their size bias can reduce power substantially. This has been well known for several decades. Exact and quasi-exact tests are now available and can be computed in a few seconds for a single data set. However, calculating the exact power and size of such tests requires computing them for all possible outcomes. Searching for minimum samples sizes that achieve a given target requires doing this for a wide range of sample sizes. This becomes computationally infeasible very quickly; to compute required sample sizes for a target size of 5% and power of 80% would, on a standard computer, take several months. Computation time increases as the size and clinically relevant difference decreases. After having presented the main operative challenges to creating this library, mainly due to the need of summarizing a very large amount of information, we put forward our innovative solutions to deal with this complex problem from a statistical viewpoint. The described library will be released in open source.

Living With Chronic HIV Disease in the Antiretroviral Era: The Impact of Neurocognitive Impairment on Everyday Life Functions.

Although there is extensive literature around the biologic correlations of neurocognitive function in HIV/AIDS, less is known about the impact in everyday living. We conducted a systematic review of the association of neurocognitive impairment with everyday life functions in people with HIV on antiretroviral therapy. We specifically focused on attention, executive function, processing speed, and the central executive component of the working memory. We considered 3 domains of everyday functions: (1) autonomy, (2) decision making and adherence to treatment, and (3) quality of life and psychologic wellbeing. The relationship between neurocognitive impairment and mental health was examined, given its correlation with everyday life functions. Results indicate that people with HIV do experience problems with autonomy of daily living (especially if aged older than 50 years) and with decision making, and neurocognitive impairment plays a role in this regard. Psychologic wellbeing is associated with executive function and processing speed. These patients may also have a reduced quality of life, but the relationship between quality of life and cognition is uncertain or could be mediated by other factors. Neurocognitive impairment correlates with depression and anxiety; however, the relationship of cognitive performance with apathy is still controversial.

The Association Between Injurious Falls and Older Adults' Cognitive Function: The Role of Depressive Mood and Physical Performance.

BACKGROUND: The impact of falls on cognitive function is unclear. We explored whether injurious falls are associated with cognitive decline in older adults, and evaluated the role of changes in psychological and physical health as mediators of such association. METHODS: This prospective study involved 2267 community-dwelling participants in the Swedish National study on Aging and Care in Kungsholmen (≥60 years). Data on injurious falls (ie, falls requiring medical attention) during each 3-year time interval of follow-up were obtained from national registers. Assessment of cognitive function (Mini-Mental State Examination), depressive mood (Montgomery-Åsberg Depression Rating Scale), and physical performance (walking speed) were carried out every 3 or 6 years over a 12-year follow-up. The association between falls and cognition was estimated through linear mixed-effects models, and the mediating role of changes in depressive mood and physical performance was tested using mediation analysis. RESULTS: After adjusting for potential confounders, individuals who experienced injurious falls had a greater annual decline in Mini-Mental State Examination in the subsequent time interval (ß = -1.49, 95% CI: -1.84; -1.13), than those who did not. The association increased with the occurrence of ≥2 falls (ß = -2.13, 95% CI: -2.70; -1.56). Worsening of walking speed and depressive mood explained around 26% and 8%, respectively, of the association between falls and cognitive decline. CONCLUSIONS: Injurious falls are associated with greater cognitive decline, and this association is partly mediated by worsening of physical performance and, in a lesser extent, of depressive mood. These findings suggest that physical deficits and low mood are potential therapeutic targets for mitigating the association between falls and cognitive decline.

The Syntaxin-1A gene single nucleotide polymorphism rs4717806 associates with the risk of ischemic heart disease.

Ischemic heart disease (IHD) has a genetic predisposition and a number of cardiovascular risk factors are known to be affected by genetic factors. Development of metabolic syndrome and insulin resistance, strongly influenced by lifestyle and environmental factors, frequently occur in subjects with a genetic susceptibility. The definition of genetic factors influencing disease susceptibility would allow to identify individuals at higher risk and thus needing to be closely monitored.To this end, we focused on a complex of soluble-N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), playing an important role in metabolic syndrome and insulin resistance, involved in endothelial dysfunction and heart disease. We assessed if genetic variants of the SNARE genes are associated with IHD.SNAP25 rs363050, Stx-1A rs4717806, rs2293489, and VAMP2 26bp ins/del genetic polymorphisms were analyzed in a cohort of 100 participants who underwent heart surgery; 56 of them were affected by IHD, while 44 were not. A statistical association of plasma glycemia and insulin resistance, calculated as Triglyceride glucose (TyG) index, was observed in IHD (P < .001 and P = .03, respectively) after binomial logistic stepwise regression analysis, adjusted by age, gender, diabetes positivity, waist circumference, and cholesterol plasma level. Among genetic polymorphisms, rs4717806(A) and rs2293489(T), as well as the rs4717806 - rs2293489 (A-T) haplotype were associated with higher risk for IHD (Pc = .02; Pc = .02; P = .04, respectively). Finally, a statistical association of rs4717806(AA) genotype with higher TyG index in IHD patients (P = .03) was highlighted by multiple regression analysis considering log-transformed biochemical parameters as dependent variable and presence of coronary artery disease, age, gender, waist circumference, presence of diabetes as predictors. These results point to a role of the Stx-1A rs4717806 SNP in IHD, possibly due to its influence on Stx-1A expression and, as a consequence, on insulin secretion and glucose metabolism.

A New Scale to Evaluate Motor Function in Rett Syndrome: Validation and Psychometric Properties.

BACKGROUND: We aim to describe and psychometrically validate the Rett Syndrome Motor Evaluation Scale, a 25-item ordinal scale examining (loco-)motor function across six sections: standing, sitting, transitions, walking, running, and walking up or downstairs. METHODS: We illustrate the process of item construction and validation, report findings and normative data obtained on a standardization sample of 60 patients with Rett syndrome. We investigate the validity and reliability of the scale and illustrate its psychometric properties using modern multivariate techniques of data analysis. RESULTS: Sixty patients with Rett syndrome were included (all female; mean age 12.45 (S.D. 8.75) years). The multidimensional latent structure of the scale was supported by the results of the confirmatory factor analysis. Rett Syndrome Motor Evaluation Scale showed strong internal consistency reliability as well as excellent inter-rater agreement. The Rett Syndrome Motor Evaluation Scale scores were not predicted by age, but were associated with disease severity, degree of spasticity, and hand dysfunction. We also identified three latent classes with different degrees of impairment. CONCLUSIONS: Rett Syndrome Motor Evaluation Scale is a new, valid, and reliable scale that can be introduced in clinical practice when assessing (loco-)motor function in Rett syndrome.

Stavudine Reduces NLRP3 Inflammasome Activation and Modulates Amyloid-ß Autophagy.

BACKGROUND: Alzheimer's disease (AD) is associated with the accumulation of amyloid-ß (Aß) within senile plaques in the brain and neuroinflammation, possibly driven by the activation of the NLRP3 inflammasome. Nucleoside reverse transcriptase inhibitors (NRTI) hamper the NLRP3 inflammasome assembly. OBJECTIVE: We utilized an in vitro model reproducing the Aß-driven inflammation seen in AD to analyze whether stavudine (D4T), a prototypical NRTI, modulates Aß-mediated inflammasome activation and the ability of macrophages to eliminate Aß via phagocytosis and autophagy. METHODS: THP-1-derived macrophages were stimulated in vitro with Aß42 or with Aß42 after LPS-priming in the presence/absence of D4T. NLRP3 and TREM2 expression was analyzed by RT-PCR; phagocytosis, as well as ASC-Speck formation, was analyzed by Amnis FlowSight Imaging; NLRP3-produced cytokines were quantified by ELISA and, finally, autophagy was analyzed by measuring p-ERK1/2, p-AKT, beclin, p70-S6Kinase, and Lamp by ELISA and western blot. RESULTS: IL-1ß, IL-18, and caspase-1 were increased whereas Aß phagocytosis and TREM2 were reduced in LPS+Aß42-stimulated cells. D4T reduced NLRP3 assembly as well as IL-18 and caspase-1 production, but did not affect IL-1ß production and TREM2 expression. Notably, whereas D4T reduced Aß phagocytosis, Aß autophagy by macrophages was stimulated by D4T, as witnessed by the down-modulation of ERK1/2 and AKT phosphorylation and the upregulation of beclin, LAMP, and p70-S6K, their downstream targets. CONCLUSION: In this in vitro model of AD, D4T reduces NLRP3 inflammasome-associated inflammation and stimulates Aß autophagy by macrophages. It will be interesting to verify the possibly beneficial effects of D4T in the clinical scenario.

Word and pseudoword superiority effects: Evidence from a shallow orthography language.

The word superiority effect (WSE) denotes better recognition of a letter embedded in a word rather than in a pseudoword. Along with WSE, also a pseudoword superiority effect (PSE) has been described: It is easier to recognise a letter in a legal pseudoword than in an unpronounceable nonword. At the current state of the art, both WSE and PSE have been mainly tested with English speakers. This study uses the Reicher-Wheeler paradigm with native speakers of Italian (a shallow orthography language). Different from English and French, we found WSE for reaction times (RTs) only, whereas PSE was significant for both accuracy and RTs. This finding indicates that in the Reicher-Wheeler task, readers of a shallow orthography language can effectively rely on both the lexical and the sublexical routes. As to the effect of letter position, a clear advantage for the first-letter position emerged, a finding suggesting a fine-grained processing of the letter strings with coding of letter position and indicating the role of visual acuity and crowding factors.