HLA-DQB1*05 subtypes and not DRB1*10:01 mediates risk in anti-IgLON5 disease.

Anti-IgLON5 disease is a rare and likely underdiagnosed subtype of autoimmune encephalitis. The disease displays a heterogeneous phenotype that includes sleep, movement, and bulbar-associated dysfunction. Presence of IgLON5-antibodies in CSF/serum, together with a strong association with HLA-DRB1*10:01∼DQB1*05:01, support an autoimmune basis. In this study, a multicentric HLA study of 87 anti-IgLON5 patients revealed a stronger association with HLA-DQ than HLA-DR. Specifically, we identified a predisposing rank-wise association with HLA-DQA1*01:05∼DQB1*05:01, HLA-DQA1*01:01∼DQB1*05:01 and HLA-DQA1*01:04∼DQB1*05:03 in 85% of patients. HLA sequences and binding cores for these three DQ heterodimers were similar, unlike those of linked DRB1 alleles, supporting a causal link to HLA-DQ. This association was further reflected in an increasingly later age of onset across each genotype group, with a delay of up to 11 years, while HLA-DQ-dosage dependent effects were also suggested by reduced risk in the presence of non-predisposing DQ1 alleles. The functional relevance of the observed HLA-DQ molecules was studied with competition binding assays. These proof-of-concept experiments revealed preferential binding of IgLON5 in a post-translationally modified, but not native, state to all three risk-associated HLA-DQ receptors. Further, a deamidated peptide from the Ig2-domain of IgLON5 activated T cells in two patients, compared to one control carrying HLA-DQA1*01:05∼DQB1*05:01. Taken together, these data support a HLA-DQ-mediated T cell response to IgLON5 as a potentially key step in the initiation of autoimmunity in this disease.

Circadian protein expression patterns in healthy young adults.

OBJECTIVES: To explore how the blood plasma proteome fluctuates across the 24-hour day and identify a subset of proteins that show endogenous circadian rhythmicity. METHODS: Plasma samples from 17 healthy adults were collected hourly under controlled conditions designed to unmask endogenous circadian rhythmicity; in a subset of 8 participants, we also collected samples across a day on a typical sleep-wake schedule. A total of 6916 proteins were analyzed from each sample using the SomaScan aptamer-based multiplexed platform. We used differential rhythmicity analysis based on a cosinor model with mixed effects to identify a subset of proteins that showed circadian rhythmicity in their abundance. RESULTS: One thousand and sixty-three (15%) proteins exhibited significant daily rhythmicity. Of those, 431 (6.2%) proteins displayed consistent endogenous circadian rhythms on both a sleep-wake schedule and under controlled conditions: it included both known and novel proteins. When models were fitted with two harmonics, an additional 259 (3.7%) proteins exhibited significant endogenous circadian rhythmicity, indicating that some rhythmic proteins cannot be solely captured by a simple sinusoidal model. Overall, we found that the largest number of proteins had their peak levels in the late afternoon/evening, with another smaller group peaking in the early morning. CONCLUSIONS: This study reveals that hundreds of plasma proteins exhibit endogenous circadian rhythmicity in humans. Future analyses will likely reveal novel physiological pathways regulated by circadian clocks and pave the way for improved diagnosis and treatment for patients with circadian disorders and other pathologies. It will also advance efforts to include knowledge about time-of-day, thereby incorporating circadian medicine into personalized medicine.

Ambulatory Detection of Isolated Rapid-Eye-Movement Sleep Behavior Disorder Combining Actigraphy and Questionnaire.

BACKGROUND: Isolated rapid-eye-movement sleep behavior disorder (iRBD) is in most cases a prodrome of neurodegenerative synucleinopathies, affecting 1% to 2% of middle-aged and older adults; however, accurate ambulatory diagnostic methods are not available. Questionnaires lack specificity in nonclinical populations. Wrist actigraphy can detect characteristic features in individuals with RBD; however, high-frequency actigraphy has been rarely used. OBJECTIVE: The aim was to develop a machine learning classifier using high-frequency (1-second resolution) actigraphy and a short patient survey for detecting iRBD with high accuracy and precision. METHODS: The method involved analysis of home actigraphy data (for seven nights and more) and a nine-item questionnaire (RBD Innsbruck inventory and three synucleinopathy prodromes of subjective hyposmia, constipation, and orthostatic dizziness) in a data set comprising 42 patients with iRBD, 21 sleep clinic patients with other sleep disorders, and 21 community controls. RESULTS: The actigraphy classifier achieved 95.2% (95% confidence interval [CI]: 88.3-98.7) sensitivity and 90.9% (95% CI: 82.1-95.8) precision. The questionnaire classifier achieved 90.6% accuracy and 92.7% precision, exceeding the performance of the Innsbruck RBD Inventory and prodromal questionnaire alone. Concordant predictions between actigraphy and questionnaire reached a specificity and precision of 100% (95% CI: 95.7-100.0) with 88.1% sensitivity (95% CI: 79.2-94.1) and outperformed any combination of actigraphy and a single question on RBD or prodromal symptoms. CONCLUSIONS: Actigraphy detected iRBD with high accuracy in a mixed clinical and community cohort. This cost-effective fully remote procedure can be used to diagnose iRBD in specialty outpatient settings and has potential for large-scale screening of iRBD in the general population. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Effects of water restriction and dirt on grooming behavior in neotropical rodents (Trinomys setosus and T. yonenagae) (Echimyidae).

Grooming in rodents presents an evolutionarily conserved behavioral pattern that may cause water loss since saliva is deposited during washing onto large body surfaces. Trinomys yonenagae and Trinomys setosus are sister species of spiny rats occurring in Brazil, the former inhabiting a paleodesert of fixed dunes in the Caatinga, the latter being found in mesic environments of the Atlantic Forest. Consequently, it is expected that both species evolved under different selective pressures related to water balance, with T. yonenagae presenting mechanisms for dealing with water deprivation not found in T. setosus. Reduction of self-cleaning expression seems to offer a possible way to save water, as previously suggested by studies of the sand-dwelling spiny rat. Therefore, we propose to investigate grooming under four conditions: 'control' (C), a regimen of 'water restriction' (WR), of 'dirt' (D), and the combination of both conflicting stimuli (WR + D), in T. setosus, T. yonenagae, and Rattus norvegicus to compare the behavioral responses of these species. The main differences are observed in the forest dweller: T. setosus expresses a low relative duration of face washing under C, whose value is intermediate between the ones found in the two other species. WR treatment does not alter this pattern, however, the addition of dirt (D, WR + D) significantly increases the relative duration of washing in relation to C. Locomotor activity is decreased both in T. setosus and Wistar rats when they are under WR, a situation that could jeopardize antipredatory performance. T. yonenagae, the sand dweller, maintains a significantly lower expression of washing under C, as previously suggested, and under WR, D and WR + D. In addition, differently from the other two species the sand dweller maintains a normal activity level during all treatments. This study suggests differences in grooming as a strategy alluding to water balance by the two spiny rats inhabiting different ecosystems. A significantly clear pattern that saves water is observed in T. yonenagae, which probably has contributed to his evolution in one of the hottest semiarid areas of the world.

IMPACTO-MR: um estudo brasileiro de plataforma nacional para avaliar infecções e multirresistência em unidades de terapia intensiva / IMPACTO-MR: a Brazilian nationwide platform study to assess infections and multidrug resistance in intensive care units

RESUMO Objetivo: Descrever o IMPACTO-MR, um estudo brasileiro de plataforma nacional em unidades de terapia intensiva focado no impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Métodos: Descrevemos a plataforma IMPACTO-MR, seu desenvolvimento, critérios para seleção das unidades de terapia intensiva, caracterização da coleta de dados, objetivos e projetos de pesquisa futuros a serem realizados na plataforma. Resultados: Os dados principais foram coletados por meio do Epimed Monitor System® e consistiram em dados demográficos, dados de comorbidades, estado funcional, escores clínicos, diagnóstico de internação e diagnósticos secundários, dados laboratoriais, clínicos e microbiológicos e suporte de órgãos durante a internação na unidade de terapia intensiva, entre outros. De outubro de 2019 a dezembro de 2020, 33.983 pacientes de 51 unidades de terapia intensiva foram incluídos no banco de dados principal. Conclusão: A plataforma IMPACTO-MR é um banco de dados clínico brasileiro de unidades de terapia intensiva focado na pesquisa do impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Essa plataforma fornece dados para o desenvolvimento e pesquisa de unidades de terapia intensiva individuais e ensaios clínicos observacionais e prospectivos multicêntricos.

ABSTRACT Objective: To describe the IMPACTO-MR, a Brazilian nationwide intensive care unit platform study focused on the impact of health care-associated infections due to multidrug-resistant bacteria. Methods: We described the IMPACTO-MR platform, its development, criteria for intensive care unit selection, characterization of core data collection, objectives, and future research projects to be held within the platform. Results: The core data were collected using the Epimed Monitor System® and consisted of demographic data, comorbidity data, functional status, clinical scores, admission diagnosis and secondary diagnoses, laboratory, clinical, and microbiological data, and organ support during intensive care unit stay, among others. From October 2019 to December 2020, 33,983 patients from 51 intensive care units were included in the core database. Conclusion: The IMPACTO-MR platform is a nationwide Brazilian intensive care unit clinical database focused on researching the impact of health care-associated infections due to multidrug-resistant bacteria. This platform provides data for individual intensive care unit development and research and multicenter observational and prospective trials.

Solidariedade pandêmica: respostas da sociedade diante da insuficiência estatal / Pandemic solidarity: society's responses to state insufficiency

Resumo A pandemia de COVID-19 chegou ao Brasil em um contexto de crises política e econômica que aprofundaram desigualdades e vulnerabilidades já existentes. Ações de apoio ao outro foram empreendidas por pessoas e organizações no sentido de mitigar os efeitos da pandemia. Foram realizadas 34 entrevistas entre outubro e novembro de 2020 com a finalidade de identificar as ações de apoio efetivadas para ajudar o outro, analisando-as em termos de solidariedade (pandêmica). Solidariedade e individualismo apareceram com frequência nas entrevistas como qualificadores das ações. Além disso, foram identificados três núcleos em que essas ações foram operadas: a família, o condomínio e a comunidade. A família foi citada como forma de suporte mútuo fundamentado pelo parentesco. Já as ações do condomínio se subdividiram entre as ações para dentro dos muros (de suporte mútuo entre semelhantes) e para fora dos muros (que revelam a diferenciação entre o condomínio e locais mais pobres). A comunidade se mostra como uma forma mais potente de ação, com experiências de autogestão, apoio mútuo e vulnerabilidade compartilhada. Nesse sentido, os resultados nos animam a compreender a solidariedade como método transformador da sociedade, independentemente da presença do Estado.

Abstract The COVID-19 pandemic reached Brazil in a context of political and economic crises that have exacerbated existing inequalities and vulnerabilities. Individuals and organizations undertook actions to support others to mitigate the pandemic effects. Thirty-four interviews were conducted from October to November 2020 to identify the supportive actions to help others, analyzing them concerning (pandemic) solidarity. Solidarity and individualism frequently appeared in the interviews as qualifiers of such actions. Furthermore, we identified three cores in which these actions were staged: the family, the condominium, and the community. The family was mentioned as mutual support based on kinship. On the other hand, condominium actions were subdivided into intramural (mutual support actions among similar people) and extramural actions (which reveal the differentiation between the condominium and more impoverished places). The community emerges as a more powerful type of action, with self-management, mutual support, and shared vulnerability experiences. In this sense, the results encourage us to understand solidarity as a way of transforming society, regardless of the State's presence.

Pandemic solidarity: society's responses to state insufficiency. / Solidariedade pandêmica: respostas da sociedade diante da insuficiência estatal.

The COVID-19 pandemic reached Brazil in a context of political and economic crises that have exacerbated existing inequalities and vulnerabilities. Individuals and organizations undertook actions to support others to mitigate the pandemic effects. Thirty-four interviews were conducted from October to November 2020 to identify the supportive actions to help others, analyzing them concerning (pandemic) solidarity. Solidarity and individualism frequently appeared in the interviews as qualifiers of such actions. Furthermore, we identified three cores in which these actions were staged: the family, the condominium, and the community. The family was mentioned as mutual support based on kinship. On the other hand, condominium actions were subdivided into intramural (mutual support actions among similar people) and extramural actions (which reveal the differentiation between the condominium and more impoverished places). The community emerges as a more powerful type of action, with self-management, mutual support, and shared vulnerability experiences. In this sense, the results encourage us to understand solidarity as a way of transforming society, regardless of the State's presence.

A pandemia de COVID-19 chegou ao Brasil em um contexto de crises política e econômica que aprofundaram desigualdades e vulnerabilidades já existentes. Ações de apoio ao outro foram empreendidas por pessoas e organizações no sentido de mitigar os efeitos da pandemia. Foram realizadas 34 entrevistas entre outubro e novembro de 2020 com a finalidade de identificar as ações de apoio efetivadas para ajudar o outro, analisando-as em termos de solidariedade (pandêmica). Solidariedade e individualismo apareceram com frequência nas entrevistas como qualificadores das ações. Além disso, foram identificados três núcleos em que essas ações foram operadas: a família, o condomínio e a comunidade. A família foi citada como forma de suporte mútuo fundamentado pelo parentesco. Já as ações do condomínio se subdividiram entre as ações para dentro dos muros (de suporte mútuo entre semelhantes) e para fora dos muros (que revelam a diferenciação entre o condomínio e locais mais pobres). A comunidade se mostra como uma forma mais potente de ação, com experiências de autogestão, apoio mútuo e vulnerabilidade compartilhada. Nesse sentido, os resultados nos animam a compreender a solidariedade como método transformador da sociedade, independentemente da presença do Estado.

IMPACTO-MR: a Brazilian nationwide platform study to assess infections and multidrug resistance in intensive care units. / IMPACTO-MR: um estudo brasileiro de plataforma nacional para avaliar infecções e multirresistência em unidades de terapia intensiva.

OBJECTIVE: To describe the IMPACTO-MR, a Brazilian nationwide intensive care unit platform study focused on the impact of health care-associated infections due to multidrug-resistant bacteria. METHODS: We described the IMPACTO-MR platform, its development, criteria for intensive care unit selection, characterization of core data collection, objectives, and future research projects to be held within the platform. RESULTS: The core data were collected using the Epimed Monitor System® and consisted of demographic data, comorbidity data, functional status, clinical scores, admission diagnosis and secondary diagnoses, laboratory, clinical, and microbiological data, and organ support during intensive care unit stay, among others. From October 2019 to December 2020, 33,983 patients from 51 intensive care units were included in the core database. CONCLUSION: The IMPACTO-MR platform is a nationwide Brazilian intensive care unit clinical database focused on researching the impact of health care-associated infections due to multidrug-resistant bacteria. This platform provides data for individual intensive care unit development and research and multicenter observational and prospective trials.

OBJETIVO: Descrever o IMPACTO-MR, um estudo brasileiro de plataforma nacional em unidades de terapia intensiva focado no impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. MÉTODOS: Descrevemos a plataforma IMPACTO-MR, seu desenvolvimento, critérios para seleção das unidades de terapia intensiva, caracterização da coleta de dados, objetivos e projetos de pesquisa futuros a serem realizados na plataforma. RESULTADOS: Os dados principais foram coletados por meio do Epimed Monitor System® e consistiram em dados demográficos, dados de comorbidades, estado funcional, escores clínicos, diagnóstico de internação e diagnósticos secundários, dados laboratoriais, clínicos e microbiológicos e suporte de órgãos durante a internação na unidade de terapia intensiva, entre outros. De outubro de 2019 a dezembro de 2020, 33.983 pacientes de 51 unidades de terapia intensiva foram incluídos no banco de dados principal. CONCLUSÃO: A plataforma IMPACTO-MR é um banco de dados clínico brasileiro de unidades de terapia intensiva focado na pesquisa do impacto das infecções por bactérias multirresistentes relacionadas à assistência à saúde. Essa plataforma fornece dados para o desenvolvimento e pesquisa de unidades de terapia intensiva individuais e ensaios clínicos observacionais e prospectivos multicêntricos.

Evaluation of the efficacy and safety of icatibant and C1 esterase/kallikrein inhibitor in severe COVID-19: study protocol for a three-armed randomized controlled trial.

BACKGROUND: SARS-CoV-2, the virus that causes COVID-19, enters the cells through a mechanism dependent on its binding to angiotensin-converting enzyme 2 (ACE2), a protein highly expressed in the lungs. The putative viral-induced inhibition of ACE2 could result in the defective degradation of bradykinin, a potent inflammatory substance. We hypothesize that increased bradykinin in the lungs is an important mechanism driving the development of pneumonia and respiratory failure in COVID-19. METHODS: This is a phase II, single-center, three-armed parallel-group, open-label, active control superiority randomized clinical trial. One hundred eighty eligible patients will be randomly assigned in a 1:1:1 ratio to receive either the inhibitor of C1e/kallikrein 20 U/kg intravenously on day 1 and day 4 plus standard care; or icatibant 30 mg subcutaneously, three doses/day for 4 days plus standard care; or standard care alone, as recommended in the clinical trials published to date, which includes supplemental oxygen, non-invasive and invasive ventilation, antibiotic agents, anti-inflammatory agents, prophylactic antithrombotic therapy, vasopressor support, and renal replacement therapy. DISCUSSION: Accumulation of bradykinin in the lungs is a common side effect of ACE inhibitors leading to cough. In animal models, the inactivation of ACE2 leads to severe acute pneumonitis in response to lipopolysaccharide (LPS), and the inhibition of bradykinin almost completely restores the lung structure. We believe that inhibition of bradykinin in severe COVID-19 patients could reduce the lung inflammatory response, impacting positively on the severity of disease and mortality rates. TRIAL REGISTRATION: Brazilian Clinical Trials Registry Universal Trial Number (UTN) U1111-1250-1843. Registered on May/5/2020.

COVID-19 en América Latina y Caribe: determinación de prioridadesen investigación y llamado a la acción / COVID-19 in Latin America and Caribbean: a determination of research priorities and call to action

Antecedentes: La Red de Salud Global estableció, en enero 2020, una comunidad de práctica para abordar la investigación en COVID-19 en países de ingresos bajos/medios. Objetivo: Identificar prioridades en investigación sobre COVID-19 que requieren atención urgente en América Latina y el Caribe (LAC) y establecer una comunidad de práctica abierta local para apoyar su implementación. Métodos: Estudio exploratorio mixto. Se analizaron los resultados específicos para LAC de una encuesta en línea (enfoque cuantitativo) que evaluó si la agenda prioritaria de investigación para COVID-19 de la OMS sigue siendo pertinente solicitando a los participantes que clasificaran sus tres principales prioridades a corto y largo plazo. Asimismo, se organizó un taller virtual abierto (enfoque cualitativo) el cual fue grabado. Se realizó un análisis temático pragmático a partir de las presentaciones de los panelistas y de las preguntas y comentarios de la audiencia. Se generó un marco de codificación mediante enfoques inductivo y luego deductivo siguiendo la agenda OMS. Resultados: Se contó con 223 participantes de 22 países. Se identificó un consenso sobre los temas de investigación e innovación prioritarios para LAC, dentro y fuera del marco de la agenda OMS, siendo una gran prioridad la necesidad de estudios de ciencias sociales para ayudar a los científicos biomédicos. Discusión: Dado que los casos siguen aumentando en LAC, consideramos que nuestros hallazgos son útiles para orientar tanto a las redes de investigación en la planificación de estudios como a los financiadores en sus decisiones para la asignación de recursos para investigación e innovación...(AU)

COVID-19-associated ARDS treated with DEXamethasone (CoDEX): study design and rationale for a randomized trial. / Síndrome do desconforto respiratório agudo associada à COVID-19 tratada com DEXametasona (CoDEX): delineamento e justificativa de um estudo randomizado.

OBJECTIVE: The infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads worldwide and is considered a pandemic. The most common manifestation of SARS-CoV-2 infection (coronavirus disease 2019 - COVID-19) is viral pneumonia with varying degrees of respiratory compromise and up to 40% of hospitalized patients might develop acute respiratory distress syndrome. Several clinical trials evaluated the role of corticosteroids in non-COVID-19 acute respiratory distress syndrome with conflicting results. We designed a trial to evaluate the effectiveness of early intravenous dexamethasone administration on the number of days alive and free of mechanical ventilation within 28 days after randomization in adult patients with moderate or severe acute respiratory distress syndrome due to confirmed or probable COVID-19. METHODS: This is a pragmatic, prospective, randomized, stratified, multicenter, open-label, controlled trial including 350 patients with early-onset (less than 48 hours before randomization) moderate or severe acute respiratory distress syndrome, defined by the Berlin criteria, due to COVID-19. Eligible patients will be randomly allocated to either standard treatment plus dexamethasone (Intervention Group) or standard treatment without dexamethasone (Control Group). Patients in the intervention group will receive dexamethasone 20mg intravenous once daily for 5 days, followed by dexamethasone 10mg IV once daily for additional 5 days or until intensive care unit discharge, whichever occurs first. The primary outcome is ventilator-free days within 28 days after randomization, defined as days alive and free from invasive mechanical ventilation. Secondary outcomes are all-cause mortality rates at day 28, evaluation of the clinical status at day 15 assessed with a 6-level ordinal scale, mechanical ventilation duration from randomization to day 28, Sequential Organ Failure Assessment Score evaluation at 48 hours, 72 hours and 7 days and intensive care unit -free days within 28.

OBJETIVO: A infecção causada pelo coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2) disseminou-se por todo o mundo e foi categorizada como pandemia. As manifestações mais comuns da infecção pelo SARS-CoV-2 (doença pelo coronavírus 2019 - COVID-19) se referem a uma pneumonia viral com graus variáveis de comprometimento respiratório e até 40% dos pacientes hospitalizados, que podem desenvolver uma síndrome do desconforto respiratório agudo. Diferentes ensaios clínicos avaliaram o papel dos corticosteroides na síndrome do desconforto respiratório agudo não relacionada com COVID-19, obtendo resultados conflitantes. Delineamos o presente estudo para avaliar a eficácia da administração endovenosa precoce de dexametasona no número de dias vivo e sem ventilação mecânica nos 28 dias após a randomização, em pacientes adultos com quadro moderado ou grave de síndrome do desconforto respiratório agudo causada por COVID-19 provável ou confirmada. MÉTODOS: Este é um ensaio pragmático, prospectivo, randomizado, estratificado, multicêntrico, aberto e controlado que incluirá 350 pacientes com quadro inicial (menos de 48 horas antes da randomização) de síndrome do desconforto respiratório agudo moderada ou grave, definida segundo os critérios de Berlim, causada por COVID-19. Os pacientes elegíveis serão alocados de forma aleatória para tratamento padrão mais dexametasona (Grupo Intervenção) ou tratamento padrão sem dexametasona (Grupo Controle). Os pacientes no Grupo Intervenção receberão dexametasona 20mg por via endovenosa uma vez ao dia, por 5 dias, e, a seguir, dexametasona por via endovenosa 10mg ao dia por mais 5 dias, ou até receber alta da unidade de terapia intensiva, o que ocorrer antes. O desfecho primário será o número de dias livres de ventilação mecânica nos 28 dias após a randomização, definido como o número de dias vivo e livres de ventilação mecânica invasiva. Os desfechos secundários serão a taxa de mortalidade por todas as causas no dia 28, a condição clínica no dia 15 avaliada com utilização de uma escala ordinal de seis níveis, a duração da ventilação mecânica desde a randomização até o dia 28, a avaliação com o Sequential Organ Failure Assessment Score após 48 horas, 72 horas e 7 dias, e o número de dias fora da unidade de terapia intensiva nos 28 dias após a randomização.

Effect of Dexamethasone on Days Alive and Ventilator-Free in Patients With Moderate or Severe Acute Respiratory Distress Syndrome and COVID-19: The CoDEX Randomized Clinical Trial.

Importance: Acute respiratory distress syndrome (ARDS) due to coronavirus disease 2019 (COVID-19) is associated with substantial mortality and use of health care resources. Dexamethasone use might attenuate lung injury in these patients. Objective: To determine whether intravenous dexamethasone increases the number of ventilator-free days among patients with COVID-19-associated ARDS. Design, Setting, and Participants: Multicenter, randomized, open-label, clinical trial conducted in 41 intensive care units (ICUs) in Brazil. Patients with COVID-19 and moderate to severe ARDS, according to the Berlin definition, were enrolled from April 17 to June 23, 2020. Final follow-up was completed on July 21, 2020. The trial was stopped early following publication of a related study before reaching the planned sample size of 350 patients. Interventions: Twenty mg of dexamethasone intravenously daily for 5 days, 10 mg of dexamethasone daily for 5 days or until ICU discharge, plus standard care (n =151) or standard care alone (n = 148). Main Outcomes and Measures: The primary outcome was ventilator-free days during the first 28 days, defined as being alive and free from mechanical ventilation. Secondary outcomes were all-cause mortality at 28 days, clinical status of patients at day 15 using a 6-point ordinal scale (ranging from 1, not hospitalized to 6, death), ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, and Sequential Organ Failure Assessment (SOFA) scores (range, 0-24, with higher scores indicating greater organ dysfunction) at 48 hours, 72 hours, and 7 days. Results: A total of 299 patients (mean [SD] age, 61 [14] years; 37% women) were enrolled and all completed follow-up. Patients randomized to the dexamethasone group had a mean 6.6 ventilator-free days (95% CI, 5.0-8.2) during the first 28 days vs 4.0 ventilator-free days (95% CI, 2.9-5.4) in the standard care group (difference, 2.26; 95% CI, 0.2-4.38; P = .04). At 7 days, patients in the dexamethasone group had a mean SOFA score of 6.1 (95% CI, 5.5-6.7) vs 7.5 (95% CI, 6.9-8.1) in the standard care group (difference, -1.16; 95% CI, -1.94 to -0.38; P = .004). There was no significant difference in the prespecified secondary outcomes of all-cause mortality at 28 days, ICU-free days during the first 28 days, mechanical ventilation duration at 28 days, or the 6-point ordinal scale at 15 days. Thirty-three patients (21.9%) in the dexamethasone group vs 43 (29.1%) in the standard care group experienced secondary infections, 47 (31.1%) vs 42 (28.3%) needed insulin for glucose control, and 5 (3.3%) vs 9 (6.1%) experienced other serious adverse events. Conclusions and Relevance: Among patients with COVID-19 and moderate or severe ARDS, use of intravenous dexamethasone plus standard care compared with standard care alone resulted in a statistically significant increase in the number of ventilator-free days (days alive and free of mechanical ventilation) over 28 days. Trial Registration: ClinicalTrials.gov Identifier: NCT04327401.

Síndrome do desconforto respiratório agudo associada à COVID-19 tratada com DEXametasona (CoDEX): delineamento e justificativa de um estudo randomizado / COVID-19-associated ARDS treated with DEXamethasone (CoDEX): study design and rationale for a randomized trial

RESUMO Objetivo: A infecção causada pelo coronavírus da síndrome respiratória aguda grave 2 (SARS-CoV-2) disseminou-se por todo o mundo e foi categorizada como pandemia. As manifestações mais comuns da infecção pelo SARS-CoV-2 (doença pelo coronavírus 2019 - COVID-19) se referem a uma pneumonia viral com graus variáveis de comprometimento respiratório e até 40% dos pacientes hospitalizados, que podem desenvolver uma síndrome do desconforto respiratório agudo. Diferentes ensaios clínicos avaliaram o papel dos corticosteroides na síndrome do desconforto respiratório agudo não relacionada com COVID-19, obtendo resultados conflitantes. Delineamos o presente estudo para avaliar a eficácia da administração endovenosa precoce de dexametasona no número de dias vivo e sem ventilação mecânica nos 28 dias após a randomização, em pacientes adultos com quadro moderado ou grave de síndrome do desconforto respiratório agudo causada por COVID-19 provável ou confirmada. Métodos: Este é um ensaio pragmático, prospectivo, randomizado, estratificado, multicêntrico, aberto e controlado que incluirá 350 pacientes com quadro inicial (menos de 48 horas antes da randomização) de síndrome do desconforto respiratório agudo moderada ou grave, definida segundo os critérios de Berlim, causada por COVID-19. Os pacientes elegíveis serão alocados de forma aleatória para tratamento padrão mais dexametasona (Grupo Intervenção) ou tratamento padrão sem dexametasona (Grupo Controle). Os pacientes no Grupo Intervenção receberão dexametasona 20mg por via endovenosa uma vez ao dia, por 5 dias, e, a seguir, dexametasona por via endovenosa 10mg ao dia por mais 5 dias, ou até receber alta da unidade de terapia intensiva, o que ocorrer antes. O desfecho primário será o número de dias livres de ventilação mecânica nos 28 dias após a randomização, definido como o número de dias vivo e livres de ventilação mecânica invasiva. Os desfechos secundários serão a taxa de mortalidade por todas as causas no dia 28, a condição clínica no dia 15 avaliada com utilização de uma escala ordinal de seis níveis, a duração da ventilação mecânica desde a randomização até o dia 28, a avaliação com o Sequential Organ Failure Assessment Score após 48 horas, 72 horas e 7 dias, e o número de dias fora da unidade de terapia intensiva nos 28 dias após a randomização.

Abstract Objective: The infection caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spreads worldwide and is considered a pandemic. The most common manifestation of SARS-CoV-2 infection (coronavirus disease 2019 - COVID-19) is viral pneumonia with varying degrees of respiratory compromise and up to 40% of hospitalized patients might develop acute respiratory distress syndrome. Several clinical trials evaluated the role of corticosteroids in non-COVID-19 acute respiratory distress syndrome with conflicting results. We designed a trial to evaluate the effectiveness of early intravenous dexamethasone administration on the number of days alive and free of mechanical ventilation within 28 days after randomization in adult patients with moderate or severe acute respiratory distress syndrome due to confirmed or probable COVID-19. Methods: This is a pragmatic, prospective, randomized, stratified, multicenter, open-label, controlled trial including 350 patients with early-onset (less than 48 hours before randomization) moderate or severe acute respiratory distress syndrome, defined by the Berlin criteria, due to COVID-19. Eligible patients will be randomly allocated to either standard treatment plus dexamethasone (Intervention Group) or standard treatment without dexamethasone (Control Group). Patients in the intervention group will receive dexamethasone 20mg intravenous once daily for 5 days, followed by dexamethasone 10mg IV once daily for additional 5 days or until intensive care unit discharge, whichever occurs first. The primary outcome is ventilator-free days within 28 days after randomization, defined as days alive and free from invasive mechanical ventilation. Secondary outcomes are all-cause mortality rates at day 28, evaluation of the clinical status at day 15 assessed with a 6-level ordinal scale, mechanical ventilation duration from randomization to day 28, Sequential Organ Failure Assessment Score evaluation at 48 hours, 72 hours and 7 days and intensive care unit -free days within 28.

Class 3 Obesity in a Multidisciplinary Metabolic Weight Management Program: The Effect of Preexisting Type 2 Diabetes on 6-Month Weight Loss.

INTRODUCTION: Class 3 obesity (BMI ≥ 40 kg/m2) is a growing health problem worldwide associated with considerable comorbidity including Type 2 diabetes mellitus (T2DM). The multidisciplinary medical management of obesity can be difficult in T2DM due to potential weight gain from medications including sulphonylureas and insulin. However, newer weight-neutral/losing diabetes medications can aid additional weight loss. The aim of this study was to compare weight loss outcomes of patients with and without T2DM, and in patients with T2DM, to compare diabetes outcomes and change in medications at 6 months. METHODS: All patients entering a multidisciplinary weight management metabolic program in a publicly funded hospital clinic in Sydney between March 2018 and March 2019, with BMI ≥ 40 kg/m2 and aged ≥18 years were included. Data was collected from patient clinical and electronic notes at baseline and 6 months. RESULTS: Of the 180 patients who entered the program, 53.3% had T2DM at baseline. There was no difference in percentage weight loss in those with or without T2DM (4.2 ± 4.9% vs. 3.6 ± 4.7%, p = 0.35). Additionally, T2DM patients benefited from a 0.47% reduction in HbA1c (p < 0.01) and a reduction in the number of medications from baseline to 6 months (1.8 ± 1.0/patient vs. 1.0 ± 1.2/patient, p < 0.001). T2DM patients who started on weigh-neutral/losing medications in the program lost more weight than those started on weight-gaining medications (7.7 ± 5.3% vs. 2.4 ± 3.8%, p = 0.015). CONCLUSIONS: Patients with class 3 obesity had significant weight loss at 6 months in this program. Patients with T2DM at baseline had comparable weight loss at 6 months, a significant improvement in glycaemic control, and a reduction in diabetes medication load. Additionally, patients with T2DM who were started on weight-neutral/losing medications lost significantly more weight than those started on weight-gaining medications, and these medications should be preferentially used in class 3 obesity and comorbid T2DM.

Saúde global e integração regional: a resposta sul-americana à emergência da síndrome congênita do vírus Zika / Global health and regional integration: the South American response to the emergency of the congenital Zika syndrom

Em 2015, um aumento incomum do número de bebês nascidos com problemas neurológicos foi detectado no Nordeste do Brasil, suscitando a suspeita de um vínculo entre a infecção pelo vírus Zika em mulheres grávidas e as malformações em seus bebês. O Brasil declarou Emergência Nacional em novembro de 2015 e os dados foram reportados à Organização Pan-Americana da Saúde (OPAS), de acordo com o Regulamento Sanitário Internacional (RSI). Em fevereiro de 2016, a Organização Mundial de Saúde declarou uma Emergência de Saúde Pública de Interesse Internacional (ESPII), apesar de muitos atores da comunidade internacional ainda não estarem convencidos do vínculo entre o vírus Zika e as malformações. Naquele momento de grande turbulência política no Brasil, que desaguou no impeachment da Presidente Dilma Rousseff, assuntos internacionais não eram uma prioridade e a América do Sul perdia paulatinamente a sua centralidade, o que contribuiu para uma crise sem precedentes da integração regional. Como todos os países da região relataram casos de Zika, esperava-se que organizações regionais, como OPAS, União Sul-americana de Nações (Unasul) e Mercado Comum do Sul (Mercosul), colocassem em prática seus planos de resposta a emergências. O objetivo desta tese é avaliar se houve circulação internacional de políticas públicas na resposta à ESPII em nível regional; e se havia um sistema regional de vigilância e resposta, identificando os principais fatores que influenciaram a resposta regional. A metodologia qualitativa foi empregada por meio de levantamento bibliográfico, análise de documentos e entrevistas com os atores-chave do governo brasileiro e das organizações em foco. Concluiu-se que a OPAS destacou-se em relação às outras organizações regionais por ser a mais antiga, por ter grande permeabilidade nos países e por oferecer apoio técnico, facilitando suas ações mesmo em meio a crises políticas. Já a resposta da Unasul e do Mercosul foi prejudicada pela crise política. Nesse contexto, dois processos diferentes foram identificados na resposta regional à ESPII. O primeiro foi a difusão da tese brasileira de que havia um vínculo entre a infecção de gestantes pelo vírus Zika e as malformações congênitas em bebês. O segundo processo foi a circulação do arcabouço normativo do RSI. Estas descobertas comprovam que havia um mecanismo regional de resposta a emergências que operou no caso do Zika na América do Sul. A OPAS, como guardiã do RSI na região, atuou com destaque no reconhecimento de emergências e na ativação de seus mecanismos. Não foi confirmada a hipótese de que um equipamento regional foi operado pela UNASUL.

In 2015, an uncommon increase in the number of babies born with neurological problems was detected in Northeast Brazil, raising suspicious there was a link between infection by the Zika virus in pregnant women and their babies´ malformations. Brazil declared a National Emergency in November 2015, and data was reported to the Pan-American Health Organization (PAHO), according to the International Health Regulations (IHR). In February 2016, the World Health Organization declared the situation a Public Health Emergency of International Concern (PHEIC), even though many actors of the international community were still not convinced that the Zika virus was the agent behind the malformations. At that moment of great political turmoil in Brazil, which lead to the impeachment of President Dilma Rousseff, international affairs were not a priority and the central role of South America was lost progressively, resulting in an unprecedented crisis of the regional integration process. As all countries in the region reported Zika cases, it was expected regional organizations, such as PAHO, the Union of South American Nations (Unasur) and the Common Market of the South (Mercosur) to put in practice their emergency response plans. The aim of this thesis is to assess whether there was international circulation of public policies in the response to the PHEIC at the regional level and whether there was a regional health surveillance and response system in place, identifying the main factors that influenced the regional response. Qualitative methodology was conducted through bibliographic survey, document analysis and interviews with key actors from the Brazilian government and the organizations focused in this thesis. The following conclusions were reach: on the one hand, PAHO stood out in relation to the other regional organizations for being the oldest, having great permeability in the countries and offering countries technical support, facilitating its actions, even during a political crisis. On the other, Unasur and Mercosur had a poor performance in responding due to the political crisis. In this context, two different processes were identified as operating in the regional response to the PHEIC. The first one was the diffusion of the Brazilian thesis of the link between the infection of pregnant women by the Zika virus and the congenital malformations in babies. The second, was the circulation of the IHR normative framework. The above findings show that there was a regional emergency response mechanism that operated in the Zika case in South America. PAHO, being the body that enforces the application of the IHR in the region, acted prominently in both emergency recognition and the activation of its mechanisms. The hypothesis of a regional gear operated by Unasur was not confirmed.

Zika e Aedes aegypti: antigos e novos desafios / Zika and Aedes aegypti: new and old challenges

Resumo: A infecção por zika teve grande impacto não somente nas grávidas e nos recém-nascidos, mas também na saúde pública, nas ideias populares sobre o Aedes aegypti e no respeito dos direitos sociais das mulheres. O objetivo deste texto é identificar esse impacto e as mudanças históricas, sociais e sanitárias da doença e o legado do vírus zika. As intervenções de pesquisadores de diferentes disciplinas propiciam condições para investigações mais abrangentes sobre futuras ameaças epidêmicas no Brasil e na América Latina. Este diálogo ocorreu após o seminário "Aedes aegypti: antigas e novas emergências sanitárias", organizado pela Casa de Oswaldo Cruz, quando conversamos com alguns palestrantes e outros destacados pesquisadores sobre a história e os desafios do Aedes aegypti e do zika.

Abstract: Infection with the zika virus had a great impact not only on pregnant women and newborns, but also on public health, on popular ideas about Aedes aegypti and with respect to women's social rights. The objective of this paper is to identify this impact and the historical, social and health changes of the disease and the legacy of the zika virus. Interventions by researchers from different specialties foster conditions for more comprehensive investigations into future epidemic threats in Brazil and Latin America. This dialogue took place after the seminar "Aedes aegypti: past and future health emergencies," organized by the Casa de Oswaldo Cruz, when we talked with some speakers and other leading researchers about the history and challenges of Aedes aegypti and zika.

Health surveillance and response on a regional scale: a preliminary study of the Zika virus fever case. / Vigilância e resposta em saúde no plano regional: um estudo preliminar do caso da febre do Zika vírus.

Although awareness of the Zika virus has existed since the 1950s, only recently has it attracted the interest of the international community. In 2015 and 2016, the virus spread throughout Brazil and suspicions on the possible relation between parallel increases in neurological disorders and the infection arose. By November 2015, this concern had developed into a National Public Health Emergency. On February 1, 2016, WHO formally declared its suspicion that this was a Public Health Emergency of International Concern (PHEIC), and sent a response in accordance with International Health Regulations (2005). Zika is present in almost all South American countries, and PAHO/WHO, Unasur, and Mercosur are developing responsive actions to the epidemic. The aim of this article is to present a critical analysis of the regional South American and Brazilian responses of February through September 2016, in respect of this PHEIC announcement, utilizing qualitative methodologies via bibliographical examination and document analysis. In this context, the PAHO/WHO played a prominent role as compared with the other organizations. Moreover, the political environment of the region also played a major role in the instability of both Mercosur and Unasur, which could impact the capacity and effectiveness of the response.

Zika and Aedes aegypti: new and old challenges. / Zika e Aedes aegypti: antigos e novos desafios.

Infection with the zika virus had a great impact not only on pregnant women and newborns, but also on public health, on popular ideas about Aedes aegypti and with respect to women's social rights. The objective of this paper is to identify this impact and the historical, social and health changes of the disease and the legacy of the zika virus. Interventions by researchers from different specialties foster conditions for more comprehensive investigations into future epidemic threats in Brazil and Latin America. This dialogue took place after the seminar "Aedes aegypti: past and future health emergencies," organized by the Casa de Oswaldo Cruz, when we talked with some speakers and other leading researchers about the history and challenges of Aedes aegypti and zika.

A infecção por zika teve grande impacto não somente nas grávidas e nos recém-nascidos, mas também na saúde pública, nas ideias populares sobre o Aedes aegypti e no respeito dos direitos sociais das mulheres. O objetivo deste texto é identificar esse impacto e as mudanças históricas, sociais e sanitárias da doença e o legado do vírus zika. As intervenções de pesquisadores de diferentes disciplinas propiciam condições para investigações mais abrangentes sobre futuras ameaças epidêmicas no Brasil e na América Latina. Este diálogo ocorreu após o seminário "Aedes aegypti: antigas e novas emergências sanitárias", organizado pela Casa de Oswaldo Cruz, quando conversamos com alguns palestrantes e outros destacados pesquisadores sobre a história e os desafios do Aedes aegypti e do zika.

Vigilância e resposta em saúde no plano regional: um estudo preliminar do caso da febre do Zika vírus / Health surveillance and response on a regional scale: a preliminary study of the Zika virus fever case

Apesar de ser conhecido desde os anos 50, o Zika vírus não havia despertado interesse da comunidade internacional. Entre 2015 e 2016, o vírus se alastrou pelo Brasil com a suspeita de que o aumento de casos de distúrbios neurológicos poderia ter vínculos com a infecção, configurando uma Emergência Nacional de Saúde Pública em novembro de 2015. Em 1º de fevereiro de 2016, a OMS declarou esta suspeita como uma Emergência de Saúde Pública de Importância Internacional (ESPII), deflagrando resposta conforme o Regulamento Sanitário Internacional (2005). O Zika está presente também em quase todos os países da América do Sul. Nesse sentido, organizações internacionais como a OPAS/OMS, Unasul e Mercosul estão desenvolvendo ações de resposta à epidemia. O objetivo deste artigo é analisar criticamente as respostas regional sul-americana e brasileira de fevereiro a setembro de 2016 com relação à esta declaração de ESPII, utilizando metodologia qualitativa, por meio do levantamento bibliográfico e análise documental. Nesse contexto, a OPAS/OMS teve atuação destacada em relação às demais organizações. Além disso, a conjuntura política da região parece ter papel importante na instabilidade do Mercosul e da Unasul, o que pode afetar sua capacidade e efetividade de resposta.

Determinantes sociales de la salud y convergencias en agendas de salud de organismos regionales de América del Sur / Social determinants of health and convergence in health agendas of regional agencies in South America

Objetivo. Caracterizar áreas de cooperación interinstitucional y agendas con-vergentes de salud de la Organización Panamericana de la Salud/Organización Mundial de la Salud (OPS/OMS), del Consejo de Salud de la Unión de Naciones Suramericanas (UNASUR) y de la Organización del Tratado de Cooperación Amazónica (OTCA) en América del Sur a partir de los determinantes sociales de la salud. Métodos. Estudio cualitativo basado en fuentes documentales oficiales de las tres organizaciones. El abordaje metodológico desarrolló un análisis comparativo sobre las agendas de salud de esos organismos y la Declaración de Río (2011). La sistematización de la información se realizó por medio de una matriz analítica que identifica convergencias en las respectivas agendas. Resultados. La formulación de las agendas de salud de estos organismos recibe influencias de diversas fuerzas internacionales tales como la política externa de los Estados Miembros, estrategias y modelos de cooperación internacional y lineamientos político-estratégicos de las instituciones. Estas agendas revelan esfuerzos por fortalecer bloques, mecanismos de cooperación y acciones programáticas articuladas. Conclusiones. Las agendas de la OPS/OMS, del Consejo de Salud de la UNASUR y de la OTCA apuntan posibilidades de convergencias en diversas áreas programáticas, con énfasis en los determinantes sociales de la salud. A partir de los acuerdos globales de la Declaración de Río como un marco analítico que establece recomendaciones en cinco esferas decisorias, es posible desarrollar acciones de cooperación estructurante en los países de la región, mediadas en conjunto por estos organismos.

Objective. Characterize areas of interinstitutional cooperation and converging health agendas of the Pan American Health Organization/World Health Organization (PAHO/WHO), the Health Council of the Union of South American Nations (UNASUR), and the Amazon Cooperation Treaty Organization (ACTO) in South America based on social determinants of health. Methods. A qualitative study based on official documentary sources from the three organizations, using a comparative analysis of the health agendas of these agencies and the Rio Political Declaration on Social Determinants of Health (2011). Information was systematized using an analytical matrix that identifies convergences in the respective agendas. Results. Development of the health agendas of these agencies is influenced by various international forces such as Member States’ foreign policy, international cooperation strategies and models, and the institutions’ political and strategic guidelines. These agendas reveal efforts to strengthen blocs, cooperation mechanisms, and coordinated programmatic actions. Conclusions. The agendas of PAHO/WHO, the UNASUR Health Council, and ACTO point towards opportunities for convergence in various programmatic areas, emphasizing social determinants of health. Based on the overall agreements of the Rio Declaration as an analytical framework with recommendations in five decisionmaking spheres, structural cooperation actions can be carried out in the region’s countries, jointly mediated by these agencies.