Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110δ result in T cell senescence and human immunodeficiency.

The p110δ subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. Here we report fourteen patients from seven families who were heterozygous for three different germline, gain-of-function mutations in PIK3CD (which encodes p110δ). These patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and viremia due to cytomegalovirus (CMV) and/or Epstein-Barr virus (EBV). Strikingly, they had a substantial deficiency in naive T cells but an over-representation of senescent effector T cells. In vitro, T cells from patients exhibited increased phosphorylation of the kinase Akt and hyperactivation of the metabolic checkpoint kinase mTOR, enhanced glucose uptake and terminal effector differentiation. Notably, treatment with rapamycin to inhibit mTOR activity in vivo partially restored the abundance of naive T cells, largely 'rescued' the in vitro T cell defects and improved the clinical course.

Palladium-Catalyzed Electrooxidative Double C-H Arylation.

The electrochemical transition metal-catalyzed cross-dehydrogenative reaction has emerged as a promising platform to achieve a sustainable and atom-economic organic synthesis that avoids hazardous oxidants and minimizes undesired byproducts and circuitous functional group operations. However, a poor mechanistic understanding still prevents the widespread adoption of this strategy. In this regard, we herein present an electrochemical palladium-catalyzed oxidative coupling strategy to access biaryls in the absence of a stoichiometric chemical oxidant. The robust palladaelectrocatalysis considerably suppresses the occurrence of homocoupling and oxygenation, being compatible even with electron-deficient arenes. Late-stage functionalization and Boscalid precursor synthesis further highlighted the practical importance of our electrolysis. Remarkably, mechanistic studies including the evaluation of the reaction order of each component by variable time normalization analysis (VTNA) and initial rate analysis, H/D exchange experiment, kinetic isotope effect, and stoichiometric organometallic experiments provided strong support for the involvement of transmetalation between two organopalladium complexes in the turnover limiting step. Therefore, matching the concentrations or lifetimes of two distinct organopalladium intermediates is revealed to be a pivot to the success of electrooxidative catalysis. Moreover, the presence of cationic copper(II) seems to contribute to the stabilization of the palladium(0) catalyst instead of playing a role in the oxidation of the catalyst.

Development of an automated estimation of foot process width using deep learning in kidney biopsies from patients with Fabry, minimal change, and diabetic kidney diseases.

Podocyte injury plays a key role in pathogenesis of many kidney diseases with increased podocyte foot process width (FPW), an important measure of podocyte injury. Unfortunately, there is no consensus on the best way to estimate FPW and unbiased stereology, the current gold standard, is time consuming and not widely available. To address this, we developed an automated FPW estimation technique using deep learning. A U-Net architecture variant model was trained to semantically segment the podocyte-glomerular basement membrane interface and filtration slits. Additionally, we employed a post-processing computer vision approach to accurately estimate FPW. A custom segmentation utility was also created to manually classify these structures on digital electron microscopy (EM) images and to prepare a training dataset. The model was applied to EM images of kidney biopsies from 56 patients with Fabry disease, 15 with type 2 diabetes, 10 with minimal change disease, and 17 normal individuals. The results were compared with unbiased stereology measurements performed by expert technicians unaware of the clinical information. FPW measured by deep learning and by the expert technicians were highly correlated and not statistically different in any of the studied groups. A Bland-Altman plot confirmed interchangeability of the methods. FPW measurement time per biopsy was substantially reduced by deep learning. Thus, we have developed a novel validated deep learning model for FPW measurement on EM images. The model is accessible through a cloud-based application making calculation of this important biomarker more widely accessible for research and clinical applications.

Genetic Ancestry, Race, and Severity of Acutely Decompensated Cirrhosis in Latin America.

BACKGROUND & AIMS: Genetic ancestry or racial differences in health outcomes exist in diseases associated with systemic inflammation (eg, COVID-19). This study aimed to investigate the association of genetic ancestry and race with acute-on-chronic liver failure (ACLF), which is characterized by acute systemic inflammation, multi-organ failure, and high risk of short-term death. METHODS: This prospective cohort study analyzed a comprehensive set of data, including genetic ancestry and race among several others, in 1274 patients with acutely decompensated cirrhosis who were nonelectively admitted to 44 hospitals from 7 Latin American countries. RESULTS: Three hundred ninety-five patients (31.0%) had ACLF of any grade at enrollment. Patients with ACLF had a higher median percentage of Native American genetic ancestry and lower median percentage of European ancestry than patients without ACLF (22.6% vs 12.9% and 53.4% vs 59.6%, respectively). The median percentage of African genetic ancestry was low among patients with ACLF and among those without ACLF. In terms of race, a higher percentage of patients with ACLF than patients without ACLF were Native American and a lower percentage of patients with ACLF than patients without ACLF were European American or African American. In multivariable analyses that adjusted for differences in sociodemographic and clinical characteristics, the odds ratio for ACLF at enrollment was 1.08 (95% CI, 1.03-1.13) with Native American genetic ancestry and 2.57 (95% CI, 1.84-3.58) for Native American race vs European American race CONCLUSIONS: In a large cohort of Latin American patients with acutely decompensated cirrhosis, increasing percentages of Native American ancestry and Native American race were factors independently associated with ACLF at enrollment.

Sleep deprivation increases the regularity of isometric torque fluctuations.

The regularity of the fluctuations present in torque signals represent the adaptability of the motor control. While previous research showed how it is affected by neuromuscular fatigue and ageing, the underlying mechanisms remain unclear. It is currently under debate whether these changes are explained by central or peripheral neuromuscular mechanisms. Here, we experimentally manipulated the sleep of thirteen young adults through a supervised 24 h-sleep deprivation protocol. This study aimed to investigate the effect of sleep deprivation on the regularity of torque fluctuations, and other standard torque-related outcomes (Peak Torque - PT - and Rate of Torque Development - RTD). The participants were asked to perform knee extension maximal voluntary contractions (MVC) and submaximal knee extensions at 40% of MVC for 30 s. PT and RTD were calculated from the MVC and the regularity of the torque fluctuations was determined on the submaximal task through Sample Entropy (SampEn). In addition, rate of perceived effort (RPE) was collected. We found no significant changes in PT and RTD. The regularity of torque fluctuations significantly increased (i.e., a decrease in SampEn) after 24 h-sleep deprivation (PRE = 1.76 ± 0.268, POS24 = 1.71 ± 0.306; p = 0.044). Importantly, we found a negative correlation between RPE and SampEn relative changes after sleep deprivation. This study brings new insights towards the understanding of the underlying mechanisms that explain changes in torque fluctuations, demonstrating that these changes are not limited to neuromuscular processes but are also likely to be affected by other domains, such as psychological profile, which can indirectly affect the neural drive to the muscles.

Assessment of inter- and intraobserver agreement for META score in distinguishing osteoporotic from multiple myeloma vertebral fractures.

PURPOSE: To conduct an independent assessment of inter- and intraobserver agreement for the META score as a tool for differentiating osteoporotic vertebral fractures and multiple myeloma vertebral fractures. METHODS: This is a retrospective observational study. The magnetic resonance imaging analysis was made by two independent spinal surgeons. We designated a Subjective assessment, in which the surgeon should establish a diagnostic classification for each vertebral fracture based on personal experience: secondary to osteoporosis, categorized as a benign vertebral fracture (BVF), or attributed to multiple myeloma, categorized a malign vertebral fracture (MVF). After a 90-day interval, both surgeons repeated the evaluations. For the next step, the observers should establish a diagnosis between BVF and MVF according to the META score system, and both observers repeated the evaluations after a 90-day interval. The intra and interobserver reliability of the Subjective evaluation was studied using the kappa (κ) test. Then, the META evaluations were paralleled using the intraclass correlation coefficient (ICC). RESULTS: A total of 220 patients who had the potential to participate in the study were initially enrolled, but after applying the exclusion criteria, 44 patients were included. Thirty-three patients had BVF, and 12 patients presented MVF. Interobserver agreement for both Subjective evaluations moments (initial and 90-days interval) found a slight agreement for both moments (0.35 and 0.40 respectively). Kappa test for both META evaluations moments (initial and 90-days interval) found a moderate interobserver agreement for both moments (0.54 and 0.48 respectively). It was observed that the ICC calculated for the Initial evaluation using META score was 0.680 and that in the 90-days interval was 0.726, indicating regular to good agreement. Kappa test for intraobserver agreements for the Subjective evaluation presented moderate agreement for both Surgeons. On the other side, Kappa test for intraobserver agreements for the META evaluation presented substantial agreement for both Surgeons. The Intraclass Correlation Coefficient of the META score found presented an almost perfect agreement for both Surgeons. CONCLUSION: Intra and interobserver agreement for both surgeons were unsatisfactory. The lack of consistent reproducibility by the same observer discourages and disfavors the routine use of the META score in clinical decision making, when potentially cases of multiple myeloma may be present.

Ethical regulation of biomedical research in Brazil: a quality improvement initiative.

BACKGROUND: Q-CEP (Qualificação dos Comitês de Ética em Pesquisa que compõem o Sistema CEP/Conep) is a nationwide project resulting from a partnership between the Brazilian National Research Ethics Commission (Conep), the Ministry of Health and Hospital Moinhos de Vento (HMV). It was developed to consolidate policy for ethical review of research with human beings in all members of the CEP/Conep System, Brazil's national system of institutional review boards. The aim of this study was therefore to report on the experience and results of the Q-CEP project. METHODS: An observational, retrospective study includes data from the Q-CEP, obtained from visits to all the institutional research ethics committees (RECs) in the country. The actions implemented by Q-CEP were part of a two-step process: (i) training visits to each REC; (ii) development of distance learning modules on strategic topics pertaining to research ethics evaluation. The data presented herein cover step one (training visits), defined by Q-CEP as the diagnostic stage of the project. For a country with social and economics inequalities such as Brazil, this is a particularly important stage; an accurate picture of reality is needed to inform planning of quality improvement strategies. RESULTS: In 2019-2021, Q-CEP visited 832 RECs and trained 11,197 people. This sample covered almost all active RECs in the country; only 4 (0.5%) were not evaluated. Of the 94 items evaluated, 62% did not reach the target of at least 80% compliance and around 1/4 (26%) were below 50% compliance. The diagnostic stage of the process revealed inadequacies on the part of the RECs in their ethical reviews. The analysis of informed consent forms showed compliance in only 131 RECs (15.74%). The description of pending issues made by RECs in their reports was compliant in 19.33% (n = 161). Administrative and operational aspects were also considered inadequate by more than half of the RECs. CONCLUSIONS: Overall, Brazilian RECs showed poor compliance in several aspects of their operation, both in ethics evaluation and in other processes, which justifies additional training. The Q-CEP project is part of a quality improvement policy promoted by the Brazilian Ministry of Health. The data obtained in the diagnostic step of the project have contributed to the qualification and consolidation of one of the world's largest research ethics evaluation systems.

Short term creatine loading improves strength endurance even without changing maximal strength, RPE, fatigue index, blood lactate, and mode state.

Creatine is consumed by athletes to increase strength and gain muscle. The aim of this study was to evaluate the effects of creatine supplementation on maximal strength and strength endurance. Twelve strength-trained men (25.2 ± 3.4 years) supplemented with 20 g Creatina + 10g maltodextrin or placebo (20g starch + 10g maltodextrin) for five days in randomized order. Maximal strength and strength endurance (4 sets 70% 1RM until concentric failure) were determined in the bench press. In addition, blood lactate, rate of perceived effort, fatigue index, and mood state were evaluated. All measurements were performed before and after the supplementation period. There were no significant changing in maximal strength, blood lactate, RPE, fatigue index, and mood state in either treatment. However, the creatine group performed more repetitions after the supplementation (Cr: Δ = +3.4 reps, p = 0.036, g = 0.53; PLA: Δ = +0.3reps, p = 0.414, g = 0.06), and higher total work (Cr: Δ = +199.5au, p = 0.038, g = 0.52; PLA: Δ = +26.7au, p = 0.402, g = 0.07). Creatine loading for five days allowed the subjects to perform more repetitions, resulting in greater total work, but failed to change the maximum strength.

Effects of interprofessional practice on nursing workload in hospitals: A systematic review.

OBJECTIVE: To synthesise scientific evidence on interprofessional practice in hospital care and the effects on nursing workload. METHODS: Systematic mixed method review, registered in PROSPERO (CRD42021225627) and conducted in the following databases: CINAHL, Medline, Web of Science and Scopus, with no restrictions on the publication period of the studies. Primary studies were recruited on nurses' interprofessional practice (actions and interactions with other professional categories) in hospitals and the effects on one or more dimensions of nursing workload (quantitative, qualitative, physical, cognitive, emotional, time and variation). Scientific articles available in open access, in English, Spanish or Portuguese, were included. The searches were carried out in January 2021. The studies were evaluated by pairs of independent researchers to verify methodological quality, through the Mixed Method Appraisal Tool, and data extraction. To summarise the studies, thematic analysis was adopted. RESULTS: A total of 1774 publications were assessed for eligibility and 17 studies were included. Of these, two were mixed methods, four were qualitative, and 11 were quantitative, published between 2011 and 2020. The main scenarios investigated were Intensive Care Units and/or Inpatient Units. During data analysis, three thematic categories emerged: Interprofessional practice in coping with emotional overload; Time dedicated by nurses to professional communication; and Working conditions and patient care. The third category consisted of three subthemes: Conflict and flexibility in the context of practice; Working conditions and interprofessional practice; and Effects on patient care. CONCLUSIONS: The evidence points to the emotional overload of nurses in the face of uncooperative practices. Interprofessional actions, especially communicative ones, demand nurses' time and impact the care provided. The results contribute to political decisions and health work management.

The meaning in loss protocol: A clinical trial of online grief therapy.

For a minority of the bereaved, the loss of a significant other can trigger an overwhelming emotional reaction and impaired functioning across life domains, known as prolonged grief disorder (PGD). Hence, ongoing efforts have been made to refine existing treatments to increase their efficacy and to accommodate the idiosyncrasies of grief reactions. This study presents the results of an open clinical trial of the feasibility and effectiveness of the Meaning in Loss (MIL) protocol in an online format. The brief intervention of 12 to 16 sessions combines constructivist and narrative strategies to explore and work through impediments to meaning reconstruction in loss. The sample included 25 participants diagnosed with PGD who were treated by six therapists. Baseline and post-therapy comparisons showed a significant improvement in all clinical measures (grief symptomatology, depression and general distress) and an increase of meaning making regarding the loss. Meaning making was found to be a prospective mediator of symptomatic improvement in grief across the course of therapy. These findings suggest the effectiveness of the MIL protocol in decreasing grief specific and associated symptomatology and argue for the relevance of further controlled evaluations of its efficacy. Moreover, results confirm previous findings that meaning making is a relevant factor in the evolution of grief reactions, including in the context of psychotherapy.

Chagas Disease: A Silent Threat for Dogs and Humans.

Chagas disease (CD) is a vector-borne Neglected Zoonotic Disease (NZD) caused by a flagellate protozoan, Trypanosoma cruzi, that affects various mammalian species across America, including humans and domestic animals. However, due to an increase in population movements and new routes of transmission, T. cruzi infection is presently considered a worldwide health concern, no longer restricted to endemic countries. Dogs play a major role in the domestic cycle by acting very efficiently as reservoirs and allowing the perpetuation of parasite transmission in endemic areas. Despite the significant progress made in recent years, still there is no vaccine against human and animal disease, there are few drugs available for the treatment of human CD, and there is no standard protocol for the treatment of canine CD. In this review, we highlight human and canine Chagas Disease in its different dimensions and interconnections. Dogs, which are considered to be the most important peridomestic reservoir and sentinel for the transmission of T. cruzi infection in a community, develop CD that is clinically similar to human CD. Therefore, an integrative approach, based on the One Health concept, bringing together the advances in genomics, immunology, and epidemiology can lead to the effective development of vaccines, new treatments, and innovative control strategies to tackle CD.

Spirulina (Arthrospira platensis) supplementation: Impact on growth, metabolism, and antioxidant status in zebrafish.

Zebrafish (Danio rerio) is a valuable model for biomedical research because of its mammalian genetic similarities, rapid reproduction, and low maintenance costs. However, further investigation is required regarding their nutritional requirements and standardized laboratory diets. This study evaluated the metabolic and growth responses of zebrafish juveniles fed on diets supplemented with spirulina, Arthrospira platensis (SP) at different levels for 77 days. Six diets with SP inclusion levels of 0%, 2%, 4%, 6%, 8%, and 10% (SP0-SP10) were formulated. A total of 300 zebrafish juveniles with an average initial weight of 0.113 ± 0.10 g (mean ± SD) were randomly distributed across six groups, with five replicates per group, each containing 10 animals. After 77 days, the SP6 group demonstrated significantly enhanced growth performance compared with the other supplementation levels. The condition factor was markedly higher in the SP6 and SP8 groups than in the SP0 group. No significant effects on total cholesterol levels were observed, but the SP4, SP6, and SP10 diets decreased triglyceride levels. Lipase activity was higher in the SP6 and SP8 groups than in the control group, whereas amylase activity showed no significant differences between treatments. Catalase and superoxide dismutase activities were significantly higher in the SP8 and SP10 groups than in the SP0 and SP2 groups. Glutathione S-transferase activity was higher in the SP6, SP8, and SP10 groups than in the SP0 group. In addition, SP inclusion in zebrafish diets improved female gonadal development. In conclusion, this study indicates that SP supplementation has substantial potential as a growth promoter, positively influencing lipid metabolism and antioxidant enzyme activity without affecting zebrafish survival.

Astrocyte structural heterogeneity in the mouse hippocampus.

Astrocytes are integral components of brain circuits, where they sense, process, and respond to surrounding activity, maintaining homeostasis and regulating synaptic transmission, the sum of which results in behavior modulation. These interactions are possible due to their complex morphology, composed of a tree-like structure of processes to cover defined territories ramifying in a mesh-like system of fine leaflets unresolved by conventional optic microscopy. While recent reports devoted more attention to leaflets and their dynamic interactions with synapses, our knowledge about the tree-like "backbone" structure in physiological conditions is incomplete. Recent transcriptomic studies described astrocyte molecular diversity, suggesting structural heterogeneity in regions such as the hippocampus, which is crucial for cognitive and emotional behaviors. In this study, we carried out the structural analysis of astrocytes across the hippocampal subfields of Cornu Ammonis area 1 (CA1) and dentate gyrus in the dorsoventral axis. We found that astrocytes display heterogeneity across the hippocampal subfields, which is conserved along the dorsoventral axis. We further found that astrocytes appear to contribute in an exocytosis-dependent manner to a signaling loop that maintains the backbone structure. These findings reveal astrocyte heterogeneity in the hippocampus, which appears to follow layer-specific cues and depend on the neuro-glial environment.

Bi-allelic JAM2 Variants Lead to Early-Onset Recessive Primary Familial Brain Calcification.

Primary familial brain calcification (PFBC) is a rare neurodegenerative disorder characterized by a combination of neurological, psychiatric, and cognitive decline associated with calcium deposition on brain imaging. To date, mutations in five genes have been linked to PFBC. However, more than 50% of individuals affected by PFBC have no molecular diagnosis. We report four unrelated families presenting with initial learning difficulties and seizures and later psychiatric symptoms, cerebellar ataxia, extrapyramidal signs, and extensive calcifications on brain imaging. Through a combination of homozygosity mapping and exome sequencing, we mapped this phenotype to chromosome 21q21.3 and identified bi-allelic variants in JAM2. JAM2 encodes for the junctional-adhesion-molecule-2, a key tight-junction protein in blood-brain-barrier permeability. We show that JAM2 variants lead to reduction of JAM2 mRNA expression and absence of JAM2 protein in patient's fibroblasts, consistent with a loss-of-function mechanism. We show that the human phenotype is replicated in the jam2 complete knockout mouse (jam2 KO). Furthermore, neuropathology of jam2 KO mouse showed prominent vacuolation in the cerebral cortex, thalamus, and cerebellum and particularly widespread vacuolation in the midbrain with reactive astrogliosis and neuronal density reduction. The regions of the human brain affected on neuroimaging are similar to the affected brain areas in the myorg PFBC null mouse. Along with JAM3 and OCLN, JAM2 is the third tight-junction gene in which bi-allelic variants are associated with brain calcification, suggesting that defective cell-to-cell adhesion and dysfunction of the movement of solutes through the paracellular spaces in the neurovascular unit is a key mechanism in CNS calcification.

Quantitative Evaluation of Non-basic Nitrogen-Containing Compounds in Petroleum-Derived Samples by Direct Injection ESI (-) Orbitrap MS.

The quantification of non-basic nitrogen-containing compounds (NCCs) in petroleum-derived samples has become a critical issue due to the undesirable effects of these compounds on the petroleum industry. In addition, there is a lack of analytical methods that allow the direct quantification of NCCs in these matrices. This paper provides strategies for obtaining quantitative information of NCCs in petroleum-derived samples using direct flow injection electrospray ionization (ESI) (-) Orbitrap mass spectrometry without fractionation steps. Benzocarbazole (BC) quantification was performed using the standard addition method. The method was validated, and all analytical parameters demonstrated satisfactory results in the matrix-mix. Paired Student's t-test exhibited the matrix effect (95% confidence level, p < 0.05). Limits of detection ranged from 2.94 to 14.91 µg L-1, and the limits of quantification ranged from 9.81 to 49.69 µg L-1. Intraday and interday accuracy and precision were not above 15%. Quantification of non-basic NCCs was carried out based on two approaches. In approach 1, the non-basic NCCs' total content in petroleum-derived samples was determined by the BC concentration and the total abundance correction. The method presented good performance with the average error of 21, 8.3, and 28% for crude oil, gas oil, and diesel samples, respectively. Approach 2 was based on the multiple linear regression model with regression significant at a 0.05 significance level within average relative errors of 16, 7.8, and 17% for the crude oil, gas oil, and diesel samples, respectively. Then, both approaches successfully predicted the quantification of non-basic NCCs by ESI direct flow injection.

Global reach of over 20 years of experience in the patient-centered Fabry Registry: Advancement of Fabry disease expertise and dissemination of real-world evidence to the Fabry community.

Fabry disease (FD, α-galactosidase A deficiency) is a rare, progressive, complex lysosomal storage disorder affecting multiple organ systems with a diverse spectrum of clinical phenotypes, particularly among female patients. Knowledge of its clinical course was still limited in 2001 when FD-specific therapies first became available and the Fabry Registry (NCT00196742; sponsor: Sanofi) was initiated as a global observational study. The Fabry Registry has now been operational for over 20 years, overseen by expert Boards of Advisors, and has collected real-world demographic and longitudinal clinical data from more than 8000 individuals with FD. Leveraging the accumulating evidence base, multidisciplinary collaborations have resulted in the creation of 32 peer-reviewed scientific publications, which have contributed to the greatly expanded knowledge on the onset and progression of FD, its clinical management, the role of sex and genetics, the outcomes of enzyme replacement therapy with agalsidase beta, and prognostic factors. We review how the Fabry Registry has evolved from its inception to become the largest global source of real-world FD patient data, and how the generated scientific evidence has helped to better inform the medical community, individuals living with FD, patient organizations, and other stakeholders. The patient-centered Fabry Registry fosters collaborative research partnerships with the overarching goal of optimizing the clinical management of patients with FD and is well positioned to add to its past achievements.

Bridging Chemical Knowledge and Machine Learning for Performance Prediction of Organic Synthesis.

Recent years have witnessed a boom of machine learning (ML) applications in chemistry, which reveals the potential of data-driven prediction of synthesis performance. Digitalization and ML modelling are the key strategies to fully exploit the unique potential within the synergistic interplay between experimental data and the robust prediction of performance and selectivity. A series of exciting studies have demonstrated the importance of chemical knowledge implementation in ML, which improves the model's capability for making predictions that are challenging and often go beyond the abilities of human beings. This Minireview summarizes the cutting-edge embedding techniques and model designs in synthetic performance prediction, elaborating how chemical knowledge can be incorporated into machine learning until June 2022. By merging organic synthesis tactics and chemical informatics, we hope this Review can provide a guide map and intrigue chemists to revisit the digitalization and computerization of organic chemistry principles.

Pre-pandemic support for shared reading buffers adverse parenting impacts: an RCT in Brazil.

BACKGROUND: To examine whether (1) a parent-child reading program (Universidade do Bebê [UBB]), conducted in Brazil pre-pandemic can support parenting and parent-child reading 6 months into the pandemic, (2) cognitive stimulation at pandemic onset mediates effects of UBB on these outcomes, and (3) UBB pre-pandemic buffers associations between COVID-19-related distress and parenting/parent-child reading 6 months into the pandemic. METHODS: 400 women, either pregnant or with children 0-24 months, were randomized to UBB (n = 200) or control groups. UBB consisted of monthly parent workshops focusing on parent-child reading and a book-lending library. Assessments pre-pandemic (June-2019) and at pandemic onset (April-2020) included cognitive stimulation. Assessments 6 months into the pandemic (October-2020) included COVID-19 exposure/impact/distress, as well as parenting and parent-child reading. RESULTS: 133 families (n = 69 UBB) contributed data 6 months into the pandemic. Participation in UBB pre-pandemic was associated with parent-child reading but not parenting 6 months into the pandemic. Indirect effects of UBB through cognitive stimulation at pandemic onset were observed for both outcomes. Increased COVID-19-related distress was significantly associated with reduced parenting/parent-child reading 6 months into the pandemic in the control group only. CONCLUSION: Promotion of cognitive stimulation pre-pandemic may have reduced risk for effects of the pandemic on parenting/parent-child reading. CLINICAL TRIAL REGISTRATION: The trial has been registered with the Brazilian Clinical Trials Registry RBR-29RZDH on 05/28/2018. IMPACT: This is the first study showing sustained impacts of a reading aloud intervention beginning in pregnancy and early infancy implemented pre-pandemic. Findings suggest that participation in a reading-aloud intervention buffered associations between COVID-19 distress and parenting/parent-child reading 6 months into the pandemic. Novel empirical evidence suggests that promotion of cognitive stimulation prior to the pandemic may buffer its impacts on parenting and parent-child book reading following onset in low- and middle-income countries. Findings provide important new support for implementation of parent-child reading aloud programs and likely have implications for early childhood development beyond the COVID-19 pandemic for disasters generally.

Template Synthesis to Solve the Unreachable Ortho C-H Functionalization Reaction of Aryl Iodide.

This report describes the use of a simple Pd/NBE catalytic system to achieve ortho C-H oxylation and phosphonylation and other functionalizations of aryl iodide through templated conversion reactions. Dimethylamine is introduced in the ortho-site of aryl iodide through C-H amination, and aryl dimethylamine is quickly converted to methyl quaternary ammonium salt precipitation. Methyl quaternary ammonium salt avoids Hofmann elimination in subsequent functionalization. This method solves various ortho functionalization reactions of aryl iodide that have not been achieved for a long time in the field of Pd/NBE chemistry indirectly.

Challenges and recommendations to increasing the use of exome sequencing and whole genome sequencing for diagnosing rare diseases in Brazil: an expert perspective.

Early diagnosis of genetic rare diseases is an unmet need in Brazil, where an estimated 10-13 million people live with these conditions. Increased use of chromosome microarray assays, exome sequencing, and whole genome sequencing as first-tier testing techniques in suitable indications can shorten the diagnostic odyssey, eliminate unnecessary tests, procedures, and treatments, and lower healthcare expenditures. A selected panel of Brazilian experts in fields related to rare diseases was provided with a series of relevant questions to address before a multi-day conference. Within this conference, each narrative was discussed and edited through numerous rounds of discussion until agreement was achieved. The widespread adoption of exome sequencing and whole genome sequencing in Brazil is limited by various factors: cost and lack of funding, reimbursement, awareness and education, specialist shortages, and policy issues. To reduce the burden of rare diseases and increase early diagnosis, the Brazilian healthcare authorities/government must address the barriers to equitable access to early diagnostic methods for these conditions. Recommendations are provided, including broadening approved testing indications, increasing awareness and education efforts, increasing specialist training opportunities, and ensuring sufficient funding for genetic testing.