Striatal Dopamine Contributions to Skilled Motor Learning.

Coordinated multijoint limb and digit movements-"manual dexterity"-underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that corticostriatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release in both male and female mice as they learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In the dorsolateral striatum, dopamine dynamics are faster than in the dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of the striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

Impact of the COVID-19 pandemic on excess maternal deaths in Brazil: A two-year assessment.

BACKGROUND: Accurate estimates of the COVID-19 pandemic's indirect impacts are crucial, especially in low- and middle-income countries. This study aims to update estimates of excess maternal deaths in Brazil during the first two years of the COVID-19 pandemic. METHODS: This was an exploratory mixed ecological study using the counterfactual approach. The observed maternal deaths were gathered from the Mortality Information System (SIM) for the period between March 2015 and February 2022. Expected deaths from March 2020 to February 2022 were estimated using quasipoisson generalized additive models, considering quadrimester, age group, and their interaction as predictor variables. Analyses were performed in R version 4.1.2, RStudio, version 2023.03.1+446 and carried out with support from the "mgcv" and "plot_model" libraries. RESULTS: A total of 5,040 maternal deaths were reported, with varying excess mortality across regions and age groups, resulting in 69% excess maternal mortality throughout Brazil during the first two years of the pandemic. The Southeast region had 50% excess mortality throughout the first two years and 76% excess in the second year. The North region had 69% excess mortality, increasing in the second year, particularly among women aged 20-34. The Northeast region showed 80% excess mortality, with a significant increase in the second year, especially among women aged 35-49. The Central-West region had 75% excess mortality, higher in the second year and statistically significant among women aged 35-49. The South region showed 117% excess mortality, reaching 203% in the second year among women aged 20-34, but no excess mortality in the 10-19 age category. CONCLUSIONS: Over two years, Brazil saw a significant impact on maternal excess deaths, regardless of region and pandemic year. The highest peak occurred between March and June 2021, emphasizing the importance of timely and effective epidemic responses to prevent avoidable deaths and prepare for new crises.

Striatal dopamine contributions to skilled motor learning.

Coordinated multi-joint limb and digit movements - "manual dexterity" - underlie both specialized skills (e.g., playing the piano) and more mundane tasks (e.g., tying shoelaces). Impairments in dexterous skill cause significant disability, as occurs with motor cortical injury, Parkinson's Disease, and a range of other pathologies. Clinical observations, as well as basic investigations, suggest that cortico-striatal circuits play a critical role in learning and performing dexterous skills. Furthermore, dopaminergic signaling in these regions is implicated in synaptic plasticity and motor learning. Nonetheless, the role of striatal dopamine signaling in skilled motor learning remains poorly understood. Here, we use fiber photometry paired with a genetically encoded dopamine sensor to investigate striatal dopamine release as mice learn and perform a skilled reaching task. Dopamine rapidly increases during a skilled reach and peaks near pellet consumption. In dorsolateral striatum, dopamine dynamics are faster than in dorsomedial and ventral striatum. Across training, as reaching performance improves, dopamine signaling shifts from pellet consumption to cues that predict pellet availability, particularly in medial and ventral areas of striatum. Furthermore, performance prediction errors are present across the striatum, with reduced dopamine release after an unsuccessful reach. These findings show that dopamine dynamics during skilled motor behaviors change with learning and are differentially regulated across striatal subregions.

Sudden Unexpected Death in Epilepsy and Respiratory Defects in a Mouse Model of DEPDC5-Related Epilepsy.

OBJECTIVES: DEPDC5 is a common causative gene in familial focal epilepsy with or without malformations of cortical development. Its pathogenic variants also confer a significantly higher risk for sudden unexpected death in epilepsy (SUDEP), providing opportunities to investigate the pathophysiology intersecting neurodevelopment, epilepsy, and cardiorespiratory function. There is an urgent need to gain a mechanistic understanding of DEPDC5-related epilepsy and SUDEP, identify biomarkers for patients at high risk, and develop preventive interventions. METHODS: Depdc5 was specifically deleted in excitatory or inhibitory neurons in the mouse brain to determine neuronal subtypes that drive epileptogenesis and SUDEP. Electroencephalogram (EEG), cardiac, and respiratory recordings were performed to determine cardiorespiratory phenotypes associated with SUDEP. Baseline respiratory function and the response to hypoxia challenge were also studied in these mice. RESULTS: Depdc5 deletion in excitatory neurons in cortical layer 5 and dentate gyrus caused frequent generalized tonic-clonic seizures and SUDEP in young adult mice, but Depdc5 deletion in cortical interneurons did not. EEG suppression immediately following ictal offset was observed in fatal and non-fatal seizures, but low amplitude rhythmic theta frequency activity was lost only in fatal seizures. In addition, these mice developed baseline respiratory dysfunction prior to SUDEP, during which ictal apnea occurred long before terminal cardiac asystole. INTERPRETATION: Depdc5 deletion in excitatory neurons is sufficient to cause DEPDC5-related epilepsy and SUDEP. Ictal apnea and respiratory dysregulation play critical roles in SUDEP. Our study also provides a novel mouse model to investigate the underlying mechanisms of DEPDC5-related epilepsy and SUDEP. ANN NEUROL 2023;94:812-824.

Antibodies as drugs-a Keystone Symposia report.

Therapeutic antibodies have broad indications across diverse disease states, such as oncology, autoimmune diseases, and infectious diseases. New research continues to identify antibodies with therapeutic potential as well as methods to improve upon endogenous antibodies and to design antibodies de novo. On April 27-30, 2022, experts in antibody research across academia and industry met for the Keystone symposium "Antibodies as Drugs" to present the state-of-the-art in antibody therapeutics, repertoires and deep learning, bispecific antibodies, and engineering.

Protein re-surfacing of E. coli L-Asparaginase to evade pre-existing anti-drug antibodies and hypersensitivity responses.

The optimal use of many biotherapeutics is restricted by Anti-drug antibodies (ADAs) and hypersensitivity responses which can affect potency and ability to administer a treatment. Here we demonstrate that Re-surfacing can be utilized as a generalizable approach to engineer proteins with extensive surface residue modifications in order to avoid binding by pre-existing ADAs. This technique was applied to E. coli Asparaginase (ASN) to produce functional mutants with up to 58 substitutions resulting in direct modification of 35% of surface residues. Re-surfaced ASNs exhibited significantly reduced binding to murine, rabbit and human polyclonal ADAs, with a negative correlation observed between binding and mutational distance from the native protein. Reductions in ADA binding correlated with diminished hypersensitivity responses in an in vivo mouse model. By using computational design approaches to traverse extended distances in mutational space while maintaining function, protein Re-surfacing may provide a means to generate novel or second line therapies for life-saving drugs with limited therapeutic alternatives.

Risk factors for intensive care unit admission and death from COVID-19 in fully vaccinated patients hospitalized for severe COVID-19, Brazil, 2021-2022.

Objectives: To assess factors associated with admission to an intensive care unit (ICU) and death from coronavirus disease 2019 (COVID-19) in fully vaccinated patients with severe COVID-19 in Brazil and the association between ICU admission and death from COVID-19. Methods: This was retrospective study of patients hospitalized for COVID-19 from February 12, 2021 to January 10, 2022 across Brazil who were fully vaccinated against COVID-19 before hospitalization. Outcomes were admission in an ICU for COVID-19 and death from COVID-19. Variables evaluated were: sex; age; self-reported skin color; macroregion; comorbidities; time between full vaccination and onset of symptoms; and time between onset of symptoms and hospitalization. A Poisson regression model was used to estimate crude and adjusted risk ratios. Results: Of 74 991 patients hospitalized for severe COVID-19, 67.28% were ≥ 70 years and 68.32% had at least one comorbidity. Men, patients aged 60-69 years, and patients aged 18-39 years with obesity had the greatest risk of ICU admission. Patients aged 18-39 years with obesity, diabetes, or renal diseases had the highest risk of death from COVID-19. When age and time between onset of symptoms and hospitalization were considered effect modifiers, patients admitted to an ICU 9-13 days after symptom onset in each age category had the greatest risk of death from COVID-19. Conclusion: Although older patients were at greatest risk of ICU admission and death from COVID-19, the difference in the risk of dying from COVID-19 between patients admitted to an ICU and those not admitted was greatest for young adults.

Risk factors for intensive care unit admission and death from COVID-19 in fully vaccinated patients hospitalized for severe COVID-19, Brazil, 2021–2022

[ABSTRACT]. Objectives. To assess factors associated with admission to an intensive care unit (ICU) and death from corona- virus disease 2019 (COVID-19) in fully vaccinated patients with severe COVID-19 in Brazil and the association between ICU admission and death from COVID-19. Methods. This was retrospective study of patients hospitalized for COVID-19 from February 12, 2021 to Jan- uary 10, 2022 across Brazil who were fully vaccinated against COVID-19 before hospitalization. Outcomes were admission in an ICU for COVID-19 and death from COVID-19. Variables evaluated were: sex; age; self-re- ported skin color; macroregion; comorbidities; time between full vaccination and onset of symptoms; and time between onset of symptoms and hospitalization. A Poisson regression model was used to estimate crude and adjusted risk ratios. Results. Of 74 991 patients hospitalized for severe COVID-19, 67.28% were ≥ 70 years and 68.32% had at least one comorbidity. Men, patients aged 60–69 years, and patients aged 18–39 years with obesity had the greatest risk of ICU admission. Patients aged 18–39 years with obesity, diabetes, or renal diseases had the highest risk of death from COVID-19. When age and time between onset of symptoms and hospitalization were considered effect modifiers, patients admitted to an ICU 9–13 days after symptom onset in each age category had the greatest risk of death from COVID-19. Conclusion. Although older patients were at greatest risk of ICU admission and death from COVID-19, the difference in the risk of dying from COVID-19 between patients admitted to an ICU and those not admitted was greatest for young adults.

[RESUMEN]. Objetivos. Evaluar los factores asociados con el ingreso en la unidad de cuidados intensivos (UCI) y la muerte por la enfermedad del coronavirus del 2019 (COVID-19) en pacientes con el esquema completo de vacunación que presentan un cuadro grave de COVID-19, así como la relación entre el ingreso en la UCI y la muerte por esta enfermedad en Brasil. Métodos. Se realizó en Brasil un estudio retrospectivo de pacientes hospitalizados con COVID-19 del 12 de febrero del 2021 al 10 de enero del 2022 que habían recibido el esquema completo de vacunación contra la COVID-19 antes de ser hospitalizados. Los resultados fueron el ingreso en la UCI debido a la COVID-19 y la muerte por esta enfermedad. Las variables evaluadas fueron sexo, edad, color de piel autonotificado, mac- rorregión, comorbilidades, período entre el esquema completo de vacunación y la aparición de los síntomas y período entre el inicio de los síntomas y la hospitalización. Se utilizó un modelo de regresión de Poisson para estimar los cocientes de riesgo crudo y ajustado. Resultados. De los 74 991 pacientes hospitalizados con un cuadro grave de COVID-19, 67,28% tenía 70 años o más y 68,32% tenía al menos una comorbilidad. Los varones, los pacientes de 60 a 69 años y los paci- entes de 18 a 39 años con obesidad presentaron el mayor riesgo de ingreso en la UCI. Los pacientes de 18 a 39 años con obesidad, diabetes o enfermedades renales presentaban el mayor riesgo de muerte por esta enfermedad. Cuando la edad y el período entre el inicio de los síntomas y la hospitalización se consideraron modificadores del efecto, los pacientes ingresados en la UCI entre 9 y 13 días después del inicio de los sín- tomas en cada categoría de edad presentaron el mayor riesgo de muerte debido a la COVID-19. Conclusión. Aunque los pacientes de mayor edad presentaron el mayor riesgo de ingreso en la UCI y muerte debido a la COVID-19, la diferencia en el riesgo de morir por esta enfermedad entre pacientes ingresados en la UCI y pacientes no ingresados fue más elevada en adultos jóvenes.

[RESUMO]. Objetivos. Avaliar fatores associados à admissão em unidade de tratamento intensivo (UTI) e óbito por doença do coronavírus 2019 em pacientes com COVID-19 grave, totalmente vacinados, no Brasil, bem como a relação entre a entrada na UTI e a morte por COVID-19. Métodos. Estudo retrospectivo de pacientes hospitalizados com COVID-19, de 12 de fevereiro de 2021 a 10 de janeiro de 2022, em todo o Brasil, que tinham o esquema vacinal completo contra a COVID-19 antes da hospitalização. Os desfechos foram a admissão em UTI devido à COVID-19 e a morte em decorrência da doença. As variáveis avaliadas foram sexo, idade, cor da pele autodeclarada, macrorregião, comorbidades, tempo entre a vacinação completa e o início dos sintomas, e tempo entre o início dos sintomas e a internação. Para estimar os coeficientes de risco bruto e ajustado foi usado um modelo de regressão de Poisson. Resultados. Dos 74.991 pacientes internados com quadro de COVID-19 grave, 67,28% tinham ≥ 70 anos e 68,32% apresentavam pelo menos uma comorbidade. Os homens, pacientes entre 60-69 anos e pacientes entre 18-39 anos com obesidade tinham o maior risco de internação na UTI. Os pacientes de 18-39 anos de idade com obesidade, diabetes ou doenças renais apresentavam o maior risco de morte por COVID-19. Quando a idade e o intervalo entre o início dos sintomas e a hospitalização foram considerados modificadores de efeito, os pacientes admitidos em UTI entre 9 e 13 dias após o início dos sintomas em cada categoria de idade tinham o maior risco de morte devido à COVID-19. Conclusão. Embora os pacientes mais velhos tivessem maior risco de admissão na UTI e morte por COVID- 19, a diferença no risco de óbito pelo coronavírus entre os pacientes admitidos em uma UTI e aqueles não admitidos foi maior para os adultos jovens.

Excess maternal mortality in Brazil: Regional inequalities and trajectories during the COVID-19 epidemic.

BACKGROUND: The COVID-19 pandemic has exceeded 6 million known disease-related deaths and there is evidence of an increase in maternal deaths, especially in low- and middle-income countries. We aimed to estimate excess maternal deaths in Brazil and its macroregions as well as their trajectories in the first 15 months of the COVID-19 epidemic. METHODS: This study evaluated maternal deaths from the Mortality Information System of the Ministry of Health, with excess deaths being assessed between March 2020 and May 2021 by quasi-Poisson generalized additive models adjusted for overdispersion. Observed deaths were compared to deaths expected without the pandemic, accompanied by 95% confidence intervals according to region, age group, and trimester of occurrence. Analyses were conducted in R version 3.6.1 and RStudio version 1.2.1335. RESULTS: There were 3,291 notified maternal deaths during the study period, resulting in a 70% excess of deaths regardless of region, while in the North, Northeast, South and Southeast regions, excess deaths occurred regardless of age group. Excess deaths occurred in the March-May 2021 trimester regardless of region and age group. Excess deaths were observed in the Southeast region for the 25-36-year-old age group regardless of the trimester assessed, and in the North, Central-West and South regions, the only period in which excess deaths were not observed was September-November 2020. Excess deaths regardless of trimester were observed in the 37-49-year-old age group in the North region, and the South region displayed explosive behavior from March-May 2021, with a 375% excess of deaths. CONCLUSIONS: Excess maternal deaths, with geographically heterogenous trajectories and consistently high patterns at the time of the epidemic's greatest impact, reflect not only the previous effect of socioeconomic inequalities and of limited access to maternal health services, but most of all the precarious management of Brazil's health crisis.

Obesity and COVID-19 in-hospital fatality in southern Brazil: impact by age and skin color.

OBJECTIVES: To estimate the relative risk (RR) of death associated with obesity, the attributable fraction in the exposed/with obesity (AFo), and the hospitalized population attributable risk (hospitalized PAR) associated with obesity of death among all adults and among Black and non-Black adults hospitalized for severe COVID-19 in the state of Rio Grande do Sul, Brazil. METHODS: This retrospective cohort study of prognostic factors analyzed all cases of adults hospitalized for severe COVID-19 in the state of Rio Grande do Sul, Brazil. The occurrence of obesity was measured using secondary data from hospital teams' surveillance records. The outcome assessed was hospital deaths caused by severe COVID-19. Poisson regression was used to estimate RRs and 95% confidence intervals (95%CI). RESULTS: The study sample consisted of 100,099 patients hospitalized for severe COVID-19, most of whom were White (84.7%) and male (54.7%). The effect of obesity was strongly modified by age, being higher in younger age groups. For the 18-39-year-old age group, RR = 2.54 (95%CI: 2.33-2.77), and in individuals 70 years and above, RR = 1.09 (95%CI: 1.05-1.13). For the 18-39-year-old age range, AFo = 60.6% and AFo = 42.5% in individuals 40-59 years old. For all hospitalizations, Hospitalized PAR measuring obesity for individuals 18-39 years old was 25.3%, while in the 40-59-year-old range, the hospitalized PAR = 11.2%. The hospitalized PAR was 31.7% in the Black population aged 18-39 years and 24.8% in non-Blacks. The hospitalized PAR was also larger in Blacks aged 40-59 years. CONCLUSIONS: Obesity largely impacted in-hospital case-fatality rates among young adults and Black people contaminated by COVID-19. These data highlight the extent of the risk concerning obesity, a highly prevalent chronic condition.

A dystonia mouse model with motor and sequencing deficits paralleling human disease.

The dystonias are a group of movement disorders characterized by involuntary twisting movements and postures. A lack of well characterized behavioral models of dystonia has impeded identification of circuit abnormalities giving rise to the disease. Most mouse behavioral assays are implemented independently of cortex, but cortical dysfunction is implicated in human dystonia. It is therefore important to identify dystonia models in which motor cortex-dependent behaviors are altered in ways relevant to human disease. The goal of this study was to characterize a cortically-dependent behavior in the recently-developed Dlx-CKO mouse model of DYT1 dystonia. Mice performed two tasks: skilled reaching and water-elicited grooming. These tests assess motor learning, dexterous skill, and innate motor sequencing. Furthermore, skilled reaching depends strongly on motor cortex, while dorsal striatum is critical for normal grooming. Dlx-CKO mice exhibited significantly lower success rates and pellet contacts compared to control mice during skilled reaching. Despite the skilled reaching impairments, Dlx-CKO mice adapt their reaching strategies. With training, they more consistently contacted the target. Grooming patterns of Dlx-CKO mice are more disorganized than in control mice, as evidenced by a higher proportion of non-chain grooming. However, when Dlx-CKO mice engage in syntactic chains, they execute them similarly to control mice. These abnormalities may provide targets for preclinical intervention trials, as well as facilitate determination of the physiologic path from torsinA dysfunction to motor phenotype.

Dopamine neuron stimulation induces context-dependent abnormal involuntary movements in healthy rats.

With continued levodopa treatment, most patients with Parkinson disease (PD) develop levodopa-induced dyskinesias (LIDs)-abnormal involuntary movements (AIMs) characterized primarily by chorea. Clinically, LIDs depend on nigrostriatal degeneration and sensitization to repeated levodopa doses. However, the degree of dopamine denervation is correlated with levodopa-induced changes in striatal dopamine. Therefore, pulsatile dopamine release may induce AIMs independently of nigrostriatal degeneration. We optogenetically stimulated dopamine neurons in healthy rats as they engaged in skilled reaching. Repeated stimulation induced progressive AIMs whose severity was modified by behavioral context. AIMs were milder with stimulation during reaches, and more severe if stimulation occurred between reaches. Despite gradual induction, AIMs recurred immediately with subsequent dopamine neuron stimulation. Thus, nigrostriatal denervation is not necessary for fluctuating striatal dopamine to induce AIMs, and behavioral context modulates AIM expression. Furthermore, pulsatile dopamine release induces persistent changes in motor circuits that are revealed by subsequent dopamine neuron activation in appropriate contexts.

Stress-related genetic components in attention-deficit/hyperactivity disorder (ADHD): Effects of the SERPINA6 and SERPINA1 genetic markers in a family-based brazilian sample.

SERPINA6 and SERPINA1 were recently identified as the main genes associated with plasma cortisol concentration in humans. Although dysregulation in the Hypothalamus-Pituitary-Adrenal (HPA) axis has been observed in Attention Deficit/Hyperactivity Disorder (ADHD), the molecular mechanisms underlying this relationship are still unclear. Evaluation of the SERPINA6/SERPINA1 gene cluster in ADHD may provide relevant information to uncover them. We tested the association between the SERPINA6/SERPINA1 locus, including 95 single nucleotide polymorphisms (SNPs), and ADHD, using data from a Brazilian clinical sample of 259 ADHD probands and their parents. The single SNP association was tested using binary logistic regression, and we performed Classification and Regression Tree (CART) analysis to evaluate genotype combinations' effects on ADHD susceptibility. We assessed SNPs' regulatory effects through the Genotype-Tissue Expression (GTEx) v8 tool, and performed a complementary look-up analysis in the largest ADHD GWAS to date. There was a suggestive association between ADHD and eight variants located in the SERPINA6 region and one in the intergenic region between SERPINA6 and SERPINA1 after correction for multiple tests (p < 0.032). CART analysis showed that the combined effects of genotype GG in rs2144833 and CC in rs10129500 were associated with ADHD (OR = 1.78; CI95% = 1.24-2.55). The GTEx assigned the SNPs as eQTLs for genes in different tissues, including SERPINA6, and the look-up analysis revealed two SNPs associated with ADHD. These results suggest a shared genetic component between cortisol levels and ADHD. HPA dysregulation/altered stress response in ADHD might be mediated by upregulation of corticosteroid binding globulin (CBG, encoded by SERPINA6) expression.

Obesity and COVID-19 in-hospital fatality in southern Brazil: impact by age and skin color

ABSTRACT OBJECTIVES To estimate the relative risk (RR) of death associated with obesity, the attributable fraction in the exposed/with obesity (AFo), and the hospitalized population attributable risk (hospitalized PAR) associated with obesity of death among all adults and among Black and non-Black adults hospitalized for severe COVID-19 in the state of Rio Grande do Sul, Brazil. METHODS This retrospective cohort study of prognostic factors analyzed all cases of adults hospitalized for severe COVID-19 in the state of Rio Grande do Sul, Brazil. The occurrence of obesity was measured using secondary data from hospital teams' surveillance records. The outcome assessed was hospital deaths caused by severe COVID-19. Poisson regression was used to estimate RRs and 95% confidence intervals (95%CI). RESULTS The study sample consisted of 100,099 patients hospitalized for severe COVID-19, most of whom were White (84.7%) and male (54.7%). The effect of obesity was strongly modified by age, being higher in younger age groups. For the 18-39-year-old age group, RR = 2.54 (95%CI: 2.33-2.77), and in individuals 70 years and above, RR = 1.09 (95%CI: 1.05-1.13). For the 18-39-year-old age range, AFo = 60.6% and AFo = 42.5% in individuals 40-59 years old. For all hospitalizations, Hospitalized PAR measuring obesity for individuals 18-39 years old was 25.3%, while in the 40-59-year-old range, the hospitalized PAR = 11.2%. The hospitalized PAR was 31.7% in the Black population aged 18-39 years and 24.8% in non-Blacks. The hospitalized PAR was also larger in Blacks aged 40-59 years. CONCLUSIONS Obesity largely impacted in-hospital case-fatality rates among young adults and Black people contaminated by COVID-19. These data highlight the extent of the risk concerning obesity, a highly prevalent chronic condition.

Risk factors for intensive care unit admission and death from COVID-19 in fully vaccinated patients hospitalized for severe COVID-19, Brazil, 2021-2022 / Factores de riesgo para el ingreso en la unidad de cuidados intensivos y la muerte debido a la COVID-19 en pacientes con el esquema completo de vacunación hospitalizados por COVID-19 grave en Brasil, 2021-2022 / Fatores de risco para admissão em unidade de terapia intensiva e óbito pelo coronavírus em pacientes totalmente vacinados, internados por COVID-19 grave no Brasil, 2021-2022

ABSTRACT Objectives. To assess factors associated with admission to an intensive care unit (ICU) and death from coronavirus disease 2019 (COVID-19) in fully vaccinated patients with severe COVID-19 in Brazil and the association between ICU admission and death from COVID-19. Methods. This was retrospective study of patients hospitalized for COVID-19 from February 12, 2021 to January 10, 2022 across Brazil who were fully vaccinated against COVID-19 before hospitalization. Outcomes were admission in an ICU for COVID-19 and death from COVID-19. Variables evaluated were: sex; age; self-reported skin color; macroregion; comorbidities; time between full vaccination and onset of symptoms; and time between onset of symptoms and hospitalization. A Poisson regression model was used to estimate crude and adjusted risk ratios. Results. Of 74 991 patients hospitalized for severe COVID-19, 67.28% were ≥ 70 years and 68.32% had at least one comorbidity. Men, patients aged 60-69 years, and patients aged 18-39 years with obesity had the greatest risk of ICU admission. Patients aged 18-39 years with obesity, diabetes, or renal diseases had the highest risk of death from COVID-19. When age and time between onset of symptoms and hospitalization were considered effect modifiers, patients admitted to an ICU 9-13 days after symptom onset in each age category had the greatest risk of death from COVID-19. Conclusion. Although older patients were at greatest risk of ICU admission and death from COVID-19, the difference in the risk of dying from COVID-19 between patients admitted to an ICU and those not admitted was greatest for young adults.

RESUMEN Objetivos. Evaluar los factores asociados con el ingreso en la unidad de cuidados intensivos (UCI) y la muerte por la enfermedad del coronavirus del 2019 (COVID-19) en pacientes con el esquema completo de vacunación que presentan un cuadro grave de COVID-19, así como la relación entre el ingreso en la UCI y la muerte por esta enfermedad en Brasil. Métodos. Se realizó en Brasil un estudio retrospectivo de pacientes hospitalizados con COVID-19 del 12 de febrero del 2021 al 10 de enero del 2022 que habían recibido el esquema completo de vacunación contra la COVID-19 antes de ser hospitalizados. Los resultados fueron el ingreso en la UCI debido a la COVID-19 y la muerte por esta enfermedad. Las variables evaluadas fueron sexo, edad, color de piel autonotificado, macrorregión, comorbilidades, período entre el esquema completo de vacunación y la aparición de los síntomas y período entre el inicio de los síntomas y la hospitalización. Se utilizó un modelo de regresión de Poisson para estimar los cocientes de riesgo crudo y ajustado. Resultados. De los 74 991 pacientes hospitalizados con un cuadro grave de COVID-19, 67,28% tenía 70 años o más y 68,32% tenía al menos una comorbilidad. Los varones, los pacientes de 60 a 69 años y los pacientes de 18 a 39 años con obesidad presentaron el mayor riesgo de ingreso en la UCI. Los pacientes de 18 a 39 años con obesidad, diabetes o enfermedades renales presentaban el mayor riesgo de muerte por esta enfermedad. Cuando la edad y el período entre el inicio de los síntomas y la hospitalización se consideraron modificadores del efecto, los pacientes ingresados en la UCI entre 9 y 13 días después del inicio de los síntomas en cada categoría de edad presentaron el mayor riesgo de muerte debido a la COVID-19. Conclusión. Aunque los pacientes de mayor edad presentaron el mayor riesgo de ingreso en la UCI y muerte debido a la COVID-19, la diferencia en el riesgo de morir por esta enfermedad entre pacientes ingresados en la UCI y pacientes no ingresados fue más elevada en adultos jóvenes.

RESUMO Objetivos. Avaliar fatores associados à admissão em unidade de tratamento intensivo (UTI) e óbito por doença do coronavírus 2019 em pacientes com COVID-19 grave, totalmente vacinados, no Brasil, bem como a relação entre a entrada na UTI e a morte por COVID-19. Métodos. Estudo retrospectivo de pacientes hospitalizados com COVID-19, de 12 de fevereiro de 2021 a 10 de janeiro de 2022, em todo o Brasil, que tinham o esquema vacinal completo contra a COVID-19 antes da hospitalização. Os desfechos foram a admissão em UTI devido à COVID-19 e a morte em decorrência da doença. As variáveis avaliadas foram sexo, idade, cor da pele autodeclarada, macrorregião, comorbidades, tempo entre a vacinação completa e o início dos sintomas, e tempo entre o início dos sintomas e a internação. Para estimar os coeficientes de risco bruto e ajustado foi usado um modelo de regressão de Poisson. Resultados. Dos 74.991 pacientes internados com quadro de COVID-19 grave, 67,28% tinham ≥ 70 anos e 68,32% apresentavam pelo menos uma comorbidade. Os homens, pacientes entre 60-69 anos e pacientes entre 18-39 anos com obesidade tinham o maior risco de internação na UTI. Os pacientes de 18-39 anos de idade com obesidade, diabetes ou doenças renais apresentavam o maior risco de morte por COVID-19. Quando a idade e o intervalo entre o início dos sintomas e a hospitalização foram considerados modificadores de efeito, os pacientes admitidos em UTI entre 9 e 13 dias após o início dos sintomas em cada categoria de idade tinham o maior risco de morte devido à COVID-19. Conclusão. Embora os pacientes mais velhos tivessem maior risco de admissão na UTI e morte por COVID-19, a diferença no risco de óbito pelo coronavírus entre os pacientes admitidos em uma UTI e aqueles não admitidos foi maior para os adultos jovens.

Evolution of Gross Forelimb and Fine Digit Kinematics during Skilled Reaching Acquisition in Rats.

The ability to learn dexterous motor skills is a fundamental aspect of human behavior. However, the underlying neural circuit mechanisms for dexterous skill learning are unclear. Advancing our understanding of motor skill learning requires the integration of modern neuroscientific techniques with a rigorously characterized dexterous task. The development of automated rodent skilled reaching with paw tracking allows detailed analysis of how reach-to-grasp kinematics evolve during learning. We assessed how both "gross" forelimb and "fine" digit kinematics changed as rats learned skilled reaching. Rats whose success rates increased (learners) consistently reduced the variability in their reach trajectories. Refinement of fine digit control generally continued after consistency in gross hand transport to the pellet plateaued. Interestingly, most rats whose success rates did not increase (non-learners) also converged on consistent reach kinematics. Some non-learners, however, maintained substantial variability in hand and digit trajectories throughout training. These results suggest that gross and fine motor components of dexterous skill are, on average, learned over different timescales. Nonetheless, there is significant intersubject variability in learning rates as assessed by both reaching success and consistency of reach kinematics.

Metabolic modulation of tumours with engineered bacteria for immunotherapy.

The availability of L-arginine in tumours is a key determinant of an efficient anti-tumour T cell response1-4. Consequently, increases of typically low L-arginine concentrations within the tumour may greatly potentiate the anti-tumour responses of immune checkpoint inhibitors, such as programmed death-ligand 1 (PD-L1)-blocking antibodies5. However, currently no means are available to locally increase intratumoural L-arginine levels. Here we used a synthetic biology approach to develop an engineered probiotic Escherichia coli Nissle 1917 strain that colonizes tumours and continuously converts ammonia, a metabolic waste product that accumulates in tumours6, to L-arginine. Colonization of tumours with these bacteria increased intratumoural L-arginine concentrations, increased the number of tumour-infiltrating T cells and had marked synergistic effects with PD-L1 blocking antibodies in the clearance of tumours. The anti-tumour effect of these bacteria was mediated by L-arginine and was dependent on T cells. These results show that engineered microbial therapies enable metabolic modulation of the tumour microenvironment leading to enhanced efficacy of immunotherapies.

[Maternal and child health inequalities among migrants: the case of Haiti and the Dominican RepublicDesigualdades na saúde materno-infantil entre migrantes: o caso do Haiti e da República Dominicana]. / Desigualdades en la salud maternoinfantil de los migrantes: el caso de Haití y la República Dominicana.

OBJECTIVE: To assess coverage and inequalities in maternal and child health interventions among Haitians, Haitian migrants in the Dominican Republic and Dominicans. METHODS: Cross-sectional study using data from nationally representative surveys carried out in Haiti in 2012 and in the Dominican Republic in 2014. Nine indicators were compared: demand for family planning satisfied with modern methods, antenatal care, delivery care (skilled birth attendance), child vaccination (BCG, measles and DPT3), child case management (oral rehydration salts for diarrhea and careseeking for suspected pneumonia), and the composite coverage index. Wealth was measured through an asset-based index, divided into tertiles, and place of residence (urban or rural) was established according to the country definition. RESULTS: Haitians showed the lowest coverage for demand for family planning satisfied with modern methods (44.2%), antenatal care (65.3%), skilled birth attendance (39.5%) and careseeking for suspected pneumonia (37.9%), and the highest for oral rehydration salts for diarrhea (52.9%), whereas Haitian migrants had the lowest coverage in DPT3 (44.1%) and oral rehydration salts for diarrhea (38%) and the highest in careseeking for suspected pneumonia (80.7%). Dominicans presented the highest coverage for most indicators, except oral rehydration salts for diarrhea and careseeking for suspected pneumonia. The composite coverage index was 79.2% for Dominicans, 69.0% for Haitian migrants, and 52.6% for Haitians. Socioeconomic inequalities generally had pro-rich and pro-urban pattern in all analyzed groups. CONCLUSION: Haitian migrants presented higher coverage than Haitians, but lower than Dominicans. Both countries should plan actions and policies to increase coverage and address inequalities of maternal health interventions.

OBJETIVO: Avaliar cobertura e desigualdades nas intervenções em saúde materno-infantil entre os haitianos, migrantes haitianos na República Dominicana e dominicanos. MÉTODOS: Estudo transversal utilizando dados de pesquisas representativas nacionalmente realizadas no Haiti em 2012, e na República Dominicana em 2014. Nove indicadores foram comparados: demanda por planejamento familiar atendida com métodos modernos, atendimento pré-natal, atendimento ao parto (presença de profissional qualificado no parto), vacinação de crianças (BCG, sarampo e DPT3), atendimento de crianças (sais de reidratação oral para diarreia e demanda por assistência por suspeita de pneumonia) e índice composto de cobertura. A riqueza foi medida por meio de índice baseado em recursos, dividido em tercis, e o local de residência (urbano ou rural) foi estabelecido segundo a definição dos países. RESULTADOS: Os haitianos apresentaram a menor cobertura de demanda por planejamento familiar atendida com métodos modernos (44,2%), atendimento pré-natal (65,3%), presença de profissional qualificado no parto (39,5%) e de atendimento por suspeita de pneumonia (37,9%), e a mais alta para sais de reidratação oral na diarreia (52,9%), enquanto os migrantes haitianos tiveram a menor cobertura de DPT3 (44,1%) e sais de reidratação oral para diarreia (38%), e a mais alta na assistência por suspeita de pneumonia (80,7%). Os dominicanos apresentaram a cobertura mais alta para a maioria dos indicadores, exceto para sais de reidratação oral para diarreia e demanda por assistência por suspeita de pneumonia. O índice composto de cobertura foi 79,2% para dominicanos, 69,0% para migrantes haitianos e 52,6% para os haitianos. De forma geral, as desigualdades socioeconômicas apresentaram padrão pró-riqueza e pró-urbano em todos os grupos analisados. CONCLUSÕES: Os migrantes haitianos apresentaram maior cobertura que os haitianos, mas coberturas inferiores aos dominicanos. Ambos os países devem planejar ações e políticas para aumentar a cobertura e abordar as desigualdades nas intervenções em saúde materna.

Revisiting the "Paradox of Stereotaxic Surgery": Insights Into Basal Ganglia-Thalamic Interactions.

Basal ganglia dysfunction is implicated in movement disorders including Parkinson Disease, dystonia, and choreiform disorders. Contradicting standard "rate models" of basal ganglia-thalamic interactions, internal pallidotomy improves both hypo- and hyper-kinetic movement disorders. This "paradox of stereotaxic surgery" was recognized shortly after rate models were developed, and is underscored by the outcomes of deep brain stimulation (DBS) for movement disorders. Despite strong evidence that DBS activates local axons, the clinical effects of lesions and DBS are nearly identical. These observations argue against standard models in which GABAergic basal ganglia output gates thalamic activity, and raise the question of how lesions and stimulation can have similar effects. These paradoxes may be resolved by considering thalamocortical loops as primary drivers of motor output. Rather than suppressing or releasing cortex via motor thalamus, the basal ganglia may modulate the timing of thalamic perturbations to cortical activity. Motor cortex exhibits rotational dynamics during movement, allowing the same thalamocortical perturbation to affect motor output differently depending on its timing with respect to the rotational cycle. We review classic and recent studies of basal ganglia, thalamic, and cortical physiology to propose a revised model of basal ganglia-thalamocortical function with implications for basic physiology and neuromodulation.