HDAC-6 inhibition ameliorates the early neuropathology in a mouse model of Krabbe disease.

Introduction: In Krabbe disease (KD), mutations in ß-galactosylceramidase (GALC), a lysosomal enzyme responsible for the catabolism of galactolipids, leads to the accumulation of its substrates galactocerebroside and psychosine. This neurologic condition is characterized by a severe and progressive demyelination together with neuron-autonomous defects and degeneration. Twitcher mice mimic the infantile form of KD, which is the most common form of the human disease. The Twitcher CNS and PNS present demyelination, axonal loss and neuronal defects including decreased levels of acetylated tubulin, decreased microtubule stability and impaired axonal transport. Methods: We tested whether inhibiting the α-tubulin deacetylase HDAC6 with a specific inhibitor, ACY-738, was able to counteract the early neuropathology and neuronal defects of Twitcher mice. Results: Our data show that delivery of ACY-738 corrects the low levels of acetylated tubulin in the Twitcher nervous system. Furthermore, it reverts the loss myelinated axons in the sciatic nerve and in the optic nerve when administered from birth to postnatal day 9, suggesting that the drug holds neuroprotective properties. The extended delivery of ACY-738 to Twitcher mice delayed axonal degeneration in the CNS and ameliorated the general presentation of the disease. ACY-738 was effective in rescuing neuronal defects of Twitcher neurons, stabilizing microtubule dynamics and increasing the axonal transport of mitochondria. Discussion: Overall, our results support that ACY-738 has a neuroprotective effect in KD and should be considered as an add-on therapy combined with strategies targeting metabolic correction.

Presentation and outcomes of chronic kidney disease patients with COVID-19 / Apresentação e desfechos de pacientes com doença renal crônica com COVID-19

Abstract Introduction: COVID-19 is currently a global health issue and an important cause of mortality. Chronic kidney disease (CKD) is one of the risk factors for infection, morbidity and mortality by SARS-CoV-2. In our study, we aimed to evaluate the clinical presentation and outcomes of CKD patients with COVID-19, as well as identify predictors of mortality. Methods: This was a retrospective study of CKD patients admitted in a tertiary-care Portuguese hospital between March and August of 2020. Variables were submitted to univariate and multivariate analysis to determine factors predictive of in-hospital mortality. Results: 130 CKD patients were analyzed (median age 73.9 years, male 60.0%). Hypertension (81.5%), cardiovascular disease (36.2%), and diabetes (54.6%) were frequent conditions. Cough, dyspnea, fever and respiratory failure were also common. Almost 60% had anemia, 50% hypoalbuminemia, 13.8% hyperlactacidemia and 17% acidemia. Mean serum ferritin was 1531 µg/L, mean CRP 8.3 mg/dL and mean LDH 336.9 U/L. Most patients were treated with lopinavir/ritonavir, hydroxychloroquine or corticosteroids and only 2 with remdesivir. Eighty percent had acute kidney injury and 16.2% required intensive care unit admission. The 34 patients who died were older and more likely to have heart failure. They had higher neutrophils/lymphocytes ratio, ferritin, lactate, and LDH levels. Multivariate analysis identified an association between older age [OR 1.1 (CI 1.01-1.24), p=0.027], higher ferritin [OR 1.0 (CI 1.00-1.00), p=0.009] and higher LDH levels [OR 1.0 (CI 1.00-1.01), p=0.014] and mortality. Conclusion: In our cohort of CKD patients with COVID-19, older age, higher ferritin, and higher LDH levels were independent risk factors for mortality.

Resumo Introdução: COVID-19 é atualmente um problema de saúde global e uma causa importante de mortalidade. Doença renal crônica (DRC) é um dos fatores de risco para infecção, morbilidade e mortalidade por SARS-CoV-2. Neste estudo, objetivamos avaliar a apresentação clínica e os outcomes de doentes com DRC com COVID-19, bem como identificar preditores de mortalidade. Métodos: Estudo retrospetivo de doentes com DRC internados num hospital terciário português entre Março-Agosto/2020. As variáveis foram submetidas a análise univariada e multivariada para determinar fatores preditivos de mortalidade hospitalar. Resultados: analisámos 130 pacientes com DRC (média de idades 73,9 anos; 60,0% homens). Hipertensão (81,5%), doença cardiovascular (36,2%) e diabetes (54,6%) foram comorbilidades frequentes. Tosse, dispneia, febre e insuficiência respiratória também foram comuns. Quase 60% apresentavam anemia, 50% hipoalbuminemia e 13,8% hiperlactacidemia, 17% acidemia. A ferritina sérica média foi 1531 µg/L, PCR média 8,3 mg/dL, LDH médio 336,9 U/L. A maioria foi tratada com lopinavir/ritonavir, hidroxicloroquina ou corticosteroides e apenas 2 com remdesivir. Oitenta por cento tiveram lesão renal aguda; 16,2% necessitaram de internamento na unidade de cuidados intensivos. Os 34 pacientes que faleceram eram mais velhos e mais propensos a ter insuficiência cardíaca. Estes apresentaram razão neutrófilos/linfócitos e níveis de ferritina, lactato e LDH mais elevados. A análise multivariada identificou uma associação entre idade avançada [OR 1,1 (IC 1,01-1,24), p=0,027], níveis de ferritina [OR 1,0 (IC 1,00-1,00), p=0,009] e LDH mais elevados [OR 1,0 (IC 1,00-1,01), p=0,014] e mortalidade. Conclusão: Na nossa coorte de doentes com DRC com COVID-19, a idade avançada e níveis mais elevados de ferritina e LDH foram fatores de risco independentes para mortalidade.

The impact of transient and persistent acute kidney injury in hospital mortality in COVID-19 patients / O impacto da lesão renal aguda transitória e persistente na mortalidade hospitalar em pacientes com COVID-19

Abstract Introduction: Acute kidney injury (AKI) has been described in Coronavirus Disease 2019 (COVID-19) patients and is considered a marker of disease severity and a negative prognostic factor for survival. In this study, the authors aimed to study the impact of transient and persistent acute kidney injury (pAKI) on in-hospital mortality in COVID-19 patients. Methods: This was a retrospective observational study of patients hospitalized with COVID-19 in the Department of Medicine of the Centro Hospitalar Universitario Lisboa Norte, Lisbon, Portugal, between March 2020 and August 2020. A multivariate analysis was performed to predict AKI development and in-hospital mortality. Results: Of 544 patients with COVID-19, 330 developed AKI: 166 persistent AKI (pAKI), 164 with transient AKI. AKI patients were older, had more previous comorbidities, had higher need to be medicated with RAAS inhibitors, had higher baseline serum creatine (SCr) (1.60 mg/dL vs 0.87 mg/dL), higher NL ratio, and more severe acidemia on hospital admission, and more frequently required admission in intensive care unit, mechanical ventilation, and vasopressor use. Patients with persistent AKI had higher SCr level (1.71 mg/dL vs 1.25 mg/dL) on hospital admission. In-hospital mortality was 14.0% and it was higher in AKI patients (18.5% vs 7.0%). CKD and serum ferritin were independent predictors of AKI. AKI did not predict mortality, but pAKI was an independent predictor of mortality, as was age and lactate level. Conclusion: pAKI was independently associated with in-hospital mortality in COVID-19 patients but its impact on long-term follow-up remains to be determined.

Resumo Introdução: A lesão renal aguda (LRA) foi descrita em pacientes com doença do Coronavírus 2019 (COVID-19) e é considerada um marcador de gravidade da doença e fator prognóstico negativo para sobrevivência. Neste estudo, os autores visaram estudar o impacto da lesão renal aguda transitória e persistente (LRAp) na mortalidade hospitalar em pacientes com COVID-19. Métodos: Estudo observacional retrospectivo de pacientes internados com COVID-19 no Departamento de Medicina do Centro Hospitalar Universitário Lisboa Norte, Lisboa, Portugal, entre Março-Agosto de 2020. Realizou-se análise multivariada para prever desenvolvimento de LRA e mortalidade hospitalar. Resultados: De 544 pacientes com COVID-19, 330 desenvolveram LRA: 166 LRA persistente (LRAp), 164, LRA transitória. Pacientes com LRA eram mais velhos, apresentaram mais comorbidades prévias, maior necessidade de serem medicados com inibidores do SRAA, apresentaram creatina sérica basal mais elevada (CrS) (1,60 mg/dL vs 0,87 mg/dL), maior razão NL, e acidemia mais grave na admissão hospitalar, e necessitaram mais frequentemente de internação na UTI, ventilação mecânica, e uso de vasopressores. Pacientes com LRA persistente apresentaram maior nível de CrS (1,71 mg/dL vs 1,25 mg/dL) na admissão hospitalar. A mortalidade hospitalar foi de 14,0% e foi maior em pacientes com LRA (18,5% vs 7,0%). A DRC e ferritina sérica foram preditores independentes de LRA. A LRA não previu mortalidade, mas a LRAp foi um preditor independente de mortalidade, assim como idade e nível de lactato. Conclusão: A LRAp foi associada independentemente à mortalidade hospitalar em pacientes com COVID-19, mas seu impacto no acompanhamento de longo prazo ainda precisa ser determinado.

Myotonic dystrophy RNA toxicity alters morphology, adhesion and migration of mouse and human astrocytes.

Brain dysfunction in myotonic dystrophy type 1 (DM1), the prototype of toxic RNA disorders, has been mainly attributed to neuronal RNA misprocessing, while little attention has been given to non-neuronal brain cells. Here, using a transgenic mouse model of DM1 that expresses mutant RNA in various brain cell types (neurons, astroglia, and oligodendroglia), we demonstrate that astrocytes exhibit impaired ramification and polarization in vivo and defects in adhesion, spreading, and migration. RNA-dependent toxicity and phenotypes are also found in human transfected glial cells. In line with the cell phenotypes, molecular analyses reveal extensive expression and accumulation of toxic RNA in astrocytes, which result in RNA spliceopathy that is more severe than in neurons. Astrocyte missplicing affects primarily transcripts that regulate cell adhesion, cytoskeleton, and morphogenesis, and it is confirmed in human brain tissue. Our findings demonstrate that DM1 impacts astrocyte cell biology, possibly compromising their support and regulation of synaptic function.

Establishment and characterization of human pluripotent stem cells-derived brain organoids to model cerebellar diseases.

The establishment of robust human brain organoids to model cerebellar diseases is essential to study new therapeutic strategies for cerebellum-associated disorders. Machado-Joseph disease (MJD) is a cerebellar hereditary neurodegenerative disease, without therapeutic options able to prevent the disease progression. In the present work, control and MJD induced-pluripotent stem cells were used to establish human brain organoids. These organoids were characterized regarding brain development, cell type composition, and MJD-associated neuropathology markers, to evaluate their value for cerebellar diseases modeling. Our data indicate that the organoids recapitulated, to some extent, aspects of brain development, such as astroglia emerging after neurons and the presence of ventricular-like zones surrounded by glia and neurons that are found only in primate brains. Moreover, the brain organoids presented markers of neural progenitors proliferation, neuronal differentiation, inhibitory and excitatory synapses, and firing neurons. The established brain organoids also exhibited markers of cerebellar neurons progenitors and mature cerebellar neurons. Finally, MJD brain organoids showed higher ventricular-like zone numbers, an indication of lower maturation, and an increased number of ataxin-3-positive aggregates, compared with control organoids. Altogether, our data indicate that the established organoids recapitulate important characteristics of human brain development and exhibit cerebellar features, constituting a resourceful tool for testing therapeutic approaches for cerebellar diseases.

Estimation Model for Healthcare Costs and Intensive Care Units Access for Covid-19 Patients and Evaluation of the Effects of Remdesivir in the Portuguese Context: Hypothetical Study.

BACKGROUND AND OBJECTIVES: In March 2020, the World Health Organization announced a state of emergency due to the appearance of a pandemic caused by the Coronavirus 2 (SARS-CoV-2), a severe acute respiratory syndrome, known as Covid-19. Most governments chose to implement precautionary measures, e.g., physical distancing and use of protective devices, which can in part limit the transmission of the virus. However, the healthcare system experienced numerous structural problems in managing the Covid-19 patients given the limited human and technical resources in critical areas, such as the intensive care units (ICUs). Different therapeutic solutions should therefore be assessed, which can potentially minimize the negative impact of the disease on patients, favoring their recovery and optimizing healthcare resources. The objective of this study is to simulate the impact of remdesivir treatment on the pandemic course in the long term. METHODS: A forecasting model is designed to estimate how remdesivir would impact the ICU capacity and the healthcare costs from the hospital perspective when managing COVID-19 patients. This model is applied in the Portuguese context with a 20-week projection starting on May 1st and concluding on September 18th, 2021. The data inputs were carefully collected by consulting different sources, such as published global literature, official governmental reports, and available infectious diseases databases, i.e., Our World in Data, Portuguese Ministry of Health, and experts' opinions. RESULTS: The model showed that the introduction of remdesivir-based treatment in patients with Covid-19 pneumonia requiring supplemental oxygen therapy generates a significant reduction in both the number of ICU admissions and deaths, which would produce more than €23 million in cost savings and avoid more than 261 ICUs admissions and 166 deaths. CONCLUSION: It is demonstrated that alternative treatments such as remdesivir can reduce both the health burden for healthcare facilities, optimize their management, and improve patients' clinical conditions. However, the model is centered on Rt values, which cannot be generalized to the entire country; hence, the results of this research should be considered as a "hypothetical study".

Presentation and outcomes of chronic kidney disease patients with COVID-19.

INTRODUCTION: COVID-19 is currently a global health issue and an important cause of mortality. Chronic kidney disease (CKD) is one of the risk factors for infection, morbidity and mortality by SARS-CoV-2. In our study, we aimed to evaluate the clinical presentation and outcomes of CKD patients with COVID-19, as well as identify predictors of mortality. METHODS: This was a retrospective study of CKD patients admitted in a tertiary-care Portuguese hospital between March and August of 2020. Variables were submitted to univariate and multivariate analysis to determine factors predictive of in-hospital mortality. RESULTS: 130 CKD patients were analyzed (median age 73.9 years, male 60.0%). Hypertension (81.5%), cardiovascular disease (36.2%), and diabetes (54.6%) were frequent conditions. Cough, dyspnea, fever and respiratory failure were also common. Almost 60% had anemia, 50% hypoalbuminemia, 13.8% hyperlactacidemia and 17% acidemia. Mean serum ferritin was 1531 µg/L, mean CRP 8.3 mg/dL and mean LDH 336.9 U/L. Most patients were treated with lopinavir/ritonavir, hydroxychloroquine or corticosteroids and only 2 with remdesivir. Eighty percent had acute kidney injury and 16.2% required intensive care unit admission. The 34 patients who died were older and more likely to have heart failure. They had higher neutrophils/lymphocytes ratio, ferritin, lactate, and LDH levels. Multivariate analysis identified an association between older age [OR 1.1 (CI 1.01-1.24), p=0.027], higher ferritin [OR 1.0 (CI 1.00-1.00), p=0.009] and higher LDH levels [OR 1.0 (CI 1.00-1.01), p=0.014] and mortality. CONCLUSION: In our cohort of CKD patients with COVID-19, older age, higher ferritin, and higher LDH levels were independent risk factors for mortality.

The impact of transient and persistent acute kidney injury in hospital mortality in COVID-19 patients.

INTRODUCTION: Acute kidney injury (AKI) has been described in Coronavirus Disease 2019 (COVID-19) patients and is considered a marker of disease severity and a negative prognostic factor for survival. In this study, the authors aimed to study the impact of transient and persistent acute kidney injury (pAKI) on in-hospital mortality in COVID-19 patients. METHODS: This was a retrospective observational study of patients hospitalized with COVID-19 in the Department of Medicine of the Centro Hospitalar Universitario Lisboa Norte, Lisbon, Portugal, between March 2020 and August 2020. A multivariate analysis was performed to predict AKI development and in-hospital mortality. RESULTS: Of 544 patients with COVID-19, 330 developed AKI: 166 persistent AKI (pAKI), 164 with transient AKI. AKI patients were older, had more previous comorbidities, had higher need to be medicated with RAAS inhibitors, had higher baseline serum creatine (SCr) (1.60 mg/dL vs 0.87 mg/dL), higher NL ratio, and more severe acidemia on hospital admission, and more frequently required admission in intensive care unit, mechanical ventilation, and vasopressor use. Patients with persistent AKI had higher SCr level (1.71 mg/dL vs 1.25 mg/dL) on hospital admission. In-hospital mortality was 14.0% and it was higher in AKI patients (18.5% vs 7.0%). CKD and serum ferritin were independent predictors of AKI. AKI did not predict mortality, but pAKI was an independent predictor of mortality, as was age and lactate level. CONCLUSION: pAKI was independently associated with in-hospital mortality in COVID-19 patients but its impact on long-term follow-up remains to be determined.

Acute kidney injury in hospitalized patients with COVID-19: A Portuguese cohort / Lesión renal aguda en pacientes hospitalizados con COVID-19: una cohorte portuguesa

Introduction: The incidence of acute kidney injury (AKI) in coronavirus disease 2019 (COVID-19) patients ranges from 0.5% to 35% and has been associated with worse prognosis. The purpose of this study was to evaluate the incidence, severity, duration, risk factors and prognosis of AKI in hospitalized patients with COVID-19. Methods: We conducted a retrospective single-center analysis of 192 hospitalized COVID-19 patients from March to May of 2020. AKI was diagnosed using the Kidney Disease Improving Global Outcome (KDIGO) classification based on serum creatinine (SCr) criteria. Persistent and transient AKI were defined according to the Acute Disease Quality Initiative (ADQI) workgroup definitions. Results: In this cohort of COVID-19 patients, 55.2% developed AKI (n=106). The majority of AKI patients had persistent AKI (n=64, 60.4%). Overall, in-hospital mortality was 18.2% (n=35) and was higher in AKI patients (28.3% vs. 5.9%, p<0.001, unadjusted OR 6.03 (2.22–16.37), p<0.001). In this multivariate analysis, older age (adjusted OR 1.07 (95% CI 1.02–1.11), p=0.004), lower Hb level (adjusted OR 0.78 (95% CI 0.60–0.98), p=0.035), duration of AKI (adjusted OR 7.34 for persistent AKI (95% CI 2.37–22.72), p=0.001) and severity of AKI (adjusted OR 2.65 per increase in KDIGO stage (95% CI 1.32–5.33), p=0.006) were independent predictors of mortality. Conclusion: AKI was frequent in hospitalized patients with COVID-19. Persistent AKI and higher severity of AKI were independent predictors of in-hospital mortality. (AU)

Introducción: La incidencia de lesión renal aguda (LRA) en pacientes con enfermedad por coronavirus 2019 (COVID-19) oscila entre el 0,5 y el 35% y se ha asociado a peor pronóstico. El propósito de este estudio fue evaluar la incidencia, gravedad, duración, factores de riesgo y pronóstico de la LRA en pacientes hospitalizados con COVID-19. Métodos: Realizamos un análisis retrospectivo de un solo centro de 192 pacientes con COVID-19 hospitalizados de marzo a mayo de 2020. La LRA se diagnosticó utilizando la clasificación Kidney Disease Improving Global Outcome (KDIGO) basada en criterios de creatinina sérica (SCr). La LRA persistente y la transitoria se definieron de acuerdo con las definiciones del grupo de trabajo de la Iniciativa de Calidad de Enfermedades Agudas (ADQI). Resultados: En esta cohorte de pacientes con COVID-19, el 55,2% desarrolló LRA (n=106). La mayoría de los pacientes tenían LRA persistente (n=64; 60,4%). En general, la mortalidad hospitalaria fue del 18,2% (n=35) y fue mayor en los pacientes con LRA (28,3% frente a 5,9%; p<0,001), (OR no ajustada 6,03; IC 95%: 2,22-16,37; p<0,001). En este análisis multivariado, mayor edad (OR ajustada 1,07; IC 95%: 1,02-1,11; p=0,004), menor nivel de Hb (OR ajustada 0,78; IC 95%: 0,60-0,98; p=0,035), duración de la LRA (OR ajustada 7,34 para LRA persistente; IC 95%: 2,37-22,72; p=0,001) y la gravedad de LRA (OR ajustada 2,65 por aumento en el estadio KDIGO; IC 95%: 1,32-5,33; p=0,006) fueron predictores independientes de mortalidad. Conclusión: La LRA fue frecuente en pacientes hospitalizados con COVID-19. La LRA persistente y su mayor gravedad fueron predictores independientes de mortalidad hospitalaria. (AU)

Vitamin D-related polymorphisms and vitamin D levels as risk biomarkers of COVID-19 disease severity.

Vitamin D is a fundamental regulator of host defences by activating genes related to innate and adaptive immunity. Previous research shows a correlation between the levels of vitamin D in patients infected with SARS-CoV-2 and the degree of disease severity. This work investigates the impact of the genetic background related to vitamin D pathways on COVID-19 severity. For the first time, the Portuguese population was characterized regarding the prevalence of high impact variants in genes associated with the vitamin D pathways. This study enrolled 517 patients admitted to two tertiary Portuguese hospitals. The serum concentration of 25 (OH)D, was measured in the hospital at the time of patient admission. Genetic variants, 18 variants, in the genes AMDHD1, CYP2R1, CYP24A1, DHCR7, GC, SEC23A, and VDR were analysed. The results show that polymorphisms in the vitamin D binding protein encoded by the GC gene are related to the infection severity (p = 0.005). There is an association between vitamin D polygenic risk score and the serum concentration of 25 (OH)D (p = 0.04). There is an association between 25 (OH)D levels and the survival and fatal outcomes (p = 1.5e-4). The Portuguese population has a higher prevalence of the DHCR7 RS12785878 variant when compared with its prevalence in the European population (19% versus 10%). This study shows a genetic susceptibility for vitamin D deficiency that might explain higher severity degrees in COVID-19 patients. These results reinforce the relevance of personalized strategies in the context of viral diseases.Trial registration: NCT04370808.

Acute Kidney Disease and Mortality in Acute Kidney Injury Patients with COVID-19.

BACKGROUND: The incidence of AKI in coronavirus disease 2019 (COVID-19) patients is variable and has been associated with worse prognosis. A significant number of patients develop persistent kidney damage defined as Acute Kidney Disease (AKD). There is a lack of evidence on the real impact of AKD on COVID-19 patients. We aim to identify risk factors for the development of AKD and its impact on mortality in COVID-19 patients. METHODS: Retrospective analysis of COVID-19 patients with AKI admitted at the Centro Hospitalar Universitário Lisboa Norte between March and August of 2020. The Kidney Disease Improving Global Outcomes (KDIGO) classification was used to define AKI. AKD was defined by presenting at least KDIGO Stage 1 criteria for >7 days after an AKI initiating event. RESULTS: In 339 COVID-19 patients with AKI, 25.7% patients developed AKD (n = 87). The mean age was 71.7 ± 17.0 years, baseline SCr was 1.03 ± 0.44 mg/dL, and the majority of patients were classified as KDIGO stage 3 AKI (54.3%). The in-hospital mortality was 18.0% (n = 61). Presence of hypertension (p = 0.006), CKD (p < 0.001), lower hemoglobin (p = 0.034) and lower CRP (p = 0.004) at the hospital admission and nephrotoxin exposure (p < 0.001) were independent risk factors for the development of AKD. Older age (p = 0.003), higher serum ferritin at admission (p = 0.008) and development of AKD (p = 0.029) were independent predictors of in-hospital mortality in COVID-19-AKI patients. CONCLUSIONS: AKD was significantly associated with in-hospital mortality in this population of COVID-19-AKI patients. Considering the significant risk of mortality in AKI patients, it is of paramount importance to identify the subset of higher risk patients.

Impact of Chronic RAAS Use in Elderly COVID-19 Patients: A Retrospective Analysis.

Corona Virus Disease-19 (COVID-19) recently emerged as a global pandemic. Advanced age is the most important risk factor for increased virus susceptibility and worse outcomes. Many older adults are currently treated with renin-angiotensin-aldosterone system (RAAS) inhibitors and there is concern that these medications might increase the risk of mortality by COVID-19. This is a retrospective cohort of 346 patients older than 65 years with COVID-19, at the Department of Medicine of the Centro Hospitalar Universitário Lisboa Norte, in Portugal, hospitalized between March 2020 and August 2020. Mean age was 80.9 ± 8.7 years old. Most patients had arterial hypertension (n = 279, 80.6%), almost half (n = 161, 46.5%) had cardiovascular disease and approximately one-third of patients had heart failure (n = 127, 36.7%) or diabetes Mellitus (n = 113, 32.7%). Ninety-eight patients (28.3%) had chronic kidney disease and almost half of the patients (49.4%) were chronically under renin-angiotensin-aldosterone system (RAAS) inhibitors. Twenty percent of patients died during hospitalization. In a multivariate analysis, older age (OR 1.11, 95% CI 1.04, 1.18, p = 0.002), absence of baseline medication with RAAS inhibitors (OR 0.27, 95% CI 0.10, 0.75, p = 0.011), higher serum ferritin (OR 1.00, 95% CI 1.00, 1.00, p = 0.003) and higher lactate levels (OR 1.08, 95% CI 1.02, 1.14, p = 0.006) were independent predictors of mortality. Older age, higher serum ferritin and lactate levels at admission were found to be independent predictors of mortality and might act as early predictors of worsening disease in clinical practice. Chronic treatment with RAAS inhibitors appeared to be protective, supporting guidelines in not discontinuing such drugs.

Acute kidney injury in hospitalized patients with COVID-19: A Portuguese cohort.

INTRODUCTION: The incidence of acute kidney injury (AKI) in coronavirus disease 2019 (COVID-19) patients ranges from 0.5% to 35% and has been associated with worse prognosis. The purpose of this study was to evaluate the incidence, severity, duration, risk factors and prognosis of AKI in hospitalized patients with COVID-19. METHODS: We conducted a retrospective single-center analysis of 192 hospitalized COVID-19 patients from March to May of 2020. AKI was diagnosed using the Kidney Disease Improving Global Outcome (KDIGO) classification based on serum creatinine (SCr) criteria. Persistent and transient AKI were defined according to the Acute Disease Quality Initiative (ADQI) workgroup definitions. RESULTS: In this cohort of COVID-19 patients, 55.2% developed AKI (n=106). The majority of AKI patients had persistent AKI (n=64, 60.4%). Overall, in-hospital mortality was 18.2% (n=35) and was higher in AKI patients (28.3% vs. 5.9%, p<0.001, unadjusted OR 6.03 (2.22-16.37), p<0.001). In this multivariate analysis, older age (adjusted OR 1.07 (95% CI 1.02-1.11), p=0.004), lower Hb level (adjusted OR 0.78 (95% CI 0.60-0.98), p=0.035), duration of AKI (adjusted OR 7.34 for persistent AKI (95% CI 2.37-22.72), p=0.001) and severity of AKI (adjusted OR 2.65 per increase in KDIGO stage (95% CI 1.32-5.33), p=0.006) were independent predictors of mortality. CONCLUSION: AKI was frequent in hospitalized patients with COVID-19. Persistent AKI and higher severity of AKI were independent predictors of in-hospital mortality.

Gastric Adenocarcinoma Presenting as a Rheumatoid Factor and Anti-cyclic Citrullinated Protein Antibody-Positive Polyarthritis: A Case Report and Review of Literature.

A 64-year-old male presented with a 6-month history of symmetric polyarthritis involving proximal interphalangeal joints and metacarpophalangeal joints of the hands, wrists, and ankles. Associated symptoms included vomiting, progressive fatigue, and weight loss. Laboratory results showed microcytic anemia, leukocytosis, thrombocytosis, elevated C-reactive protein and erythrocyte sedimentation rate, and rheumatoid factor (RF) and anti-cyclic citrullinated protein (ACPA) antibody positivity. Joints radiographs were normal, without erosions. Upper endoscopy and gastric endoscopic ultrasonography showed a gastric adenocarcinoma with lymphatic involvement. Intraoperatively, peritoneal carcinomatosis was documented, and the patient started palliative chemotherapy. A paraneoplastic seropositive arthritis was assumed, and treatment with low-dose prednisolone and hydroxychloroquine was started. Arthritis remission was achieved and sustained up to 18 months of follow-up, although gastric cancer progression was documented. We describe a unique phenotype of paraneoplastic arthritis (PA) presenting as a seropositive (RF and ACPA positivity) rheumatoid arthritis (RA) with a good response to both low dose corticosteroids and hydroxychloroquine therapy. We also review the literature of PA, mostly the RA-like pattern, and the association between PA and ACPA positivity. This case highlights the importance of considering underlying cancer in elderly male patients, presenting with polyarthritis and systemic symptoms, even in those with ACPA-positive RA-like arthritis.

Integrative Cell Type-Specific Multi-Omics Approaches Reveal Impaired Programs of Glial Cell Differentiation in Mouse Culture Models of DM1.

Myotonic dystrophy type 1 (DM1) is a neuromuscular disorder caused by a non-coding CTG repeat expansion in the DMPK gene. This mutation generates a toxic CUG RNA that interferes with the RNA processing of target genes in multiple tissues. Despite debilitating neurological impairment, the pathophysiological cascade of molecular and cellular events in the central nervous system (CNS) has been less extensively characterized than the molecular pathogenesis of muscle/cardiac dysfunction. Particularly, the contribution of different cell types to DM1 brain disease is not clearly understood. We first used transcriptomics to compare the impact of expanded CUG RNA on the transcriptome of primary neurons, astrocytes and oligodendrocytes derived from DMSXL mice, a transgenic model of DM1. RNA sequencing revealed more frequent expression and splicing changes in glia than neuronal cells. In particular, primary DMSXL oligodendrocytes showed the highest number of transcripts differentially expressed, while DMSXL astrocytes displayed the most severe splicing dysregulation. Interestingly, the expression and splicing defects of DMSXL glia recreated molecular signatures suggestive of impaired cell differentiation: while DMSXL oligodendrocytes failed to upregulate a subset of genes that are naturally activated during the oligodendroglia differentiation, a significant proportion of missplicing events in DMSXL oligodendrocytes and astrocytes increased the expression of RNA isoforms typical of precursor cell stages. Together these data suggest that expanded CUG RNA in glial cells affects preferentially differentiation-regulated molecular events. This hypothesis was corroborated by gene ontology (GO) analyses, which revealed an enrichment for biological processes and cellular components with critical roles during cell differentiation. Finally, we combined exon ontology with phosphoproteomics and cell imaging to explore the functional impact of CUG-associated spliceopathy on downstream protein metabolism. Changes in phosphorylation, protein isoform expression and intracellular localization in DMSXL astrocytes demonstrate the far-reaching impact of the DM1 repeat expansion on cell metabolism. Our multi-omics approaches provide insight into the mechanisms of CUG RNA toxicity in the CNS with cell type resolution, and support the priority for future research on non-neuronal mechanisms and proteomic changes in DM1 brain disease.

Acute kidney injury in hospitalized patients with COVID-19: A Portuguese cohort.

INTRODUCTION: The incidence of acute kidney injury (AKI) in coronavirus disease 2019 (COVID-19) patients ranges from 0.5% to 35% and has been associated with worse prognosis. The purpose of this study was to evaluate the incidence, severity, duration, risk factors and prognosis of AKI in hospitalized patients with COVID-19. METHODS: We conducted a retrospective single-center analysis of 192 hospitalized COVID-19 patients from March to May of 2020. AKI was diagnosed using the Kidney Disease Improving Global Outcome (KDIGO) classification based on serum creatinine (SCr) criteria. Persistent and transient AKI were defined according to the Acute Disease Quality Initiative (ADQI) workgroup definitions. RESULTS: In this cohort of COVID-19 patients, 55.2% developed AKI (n = 106). The majority of AKI patients had persistent AKI (n = 64, 60.4%). Overall, in-hospital mortality was 18.2% (n = 35) and was higher in AKI patients (28.3% vs. 5.9%, p < 0.001, unadjusted OR 6.03 (2.22-16.37), p < 0.001). In this multivariate analysis, older age (adjusted OR 1.07 (95% CI 1.02-1.11), p = 0.004), lower Hb level (adjusted OR 0.78 (95% CI 0.60-0.98), p = 0.035), duration of AKI (adjusted OR 7.34 for persistent AKI (95% CI 2.37-22.72), p = 0.001) and severity of AKI (adjusted OR 2.65 per increase in KDIGO stage (95% CI 1.32-5.33), p = 0.006) were independent predictors of mortality. CONCLUSION: AKI was frequent in hospitalized patients with COVID-19. Persistent AKI and higher severity of AKI were independent predictors of in-hospital mortality.

INTRODUCCIÓN: La incidencia de lesión renal aguda (LRA) en pacientes con enfermedad por coronavirus 2019 (COVID-19) oscila entre el 0,5 y el 35% y se ha asociado a peor pronóstico. El propósito de este estudio fue evaluar la incidencia, gravedad, duración, factores de riesgo y pronóstico de la LRA en pacientes hospitalizados con COVID-19. MÉTODOS: Realizamos un análisis retrospectivo de un solo centro de 192 pacientes con COVID-19 hospitalizados de marzo a mayo de 2020. La LRA se diagnosticó utilizando la clasificación Kidney Disease Improving Global Outcome (KDIGO) basada en criterios de creatinina sérica (SCr). La LRA persistente y la transitoria se definieron de acuerdo con las definiciones del grupo de trabajo de la Iniciativa de Calidad de Enfermedades Agudas (ADQI). RESULTADOS: En esta cohorte de pacientes con COVID-19, el 55,2% desarrolló LRA (n = 106). La mayoría de los pacientes tenían LRA persistente (n = 64; 60,4%). En general, la mortalidad hospitalaria fue del 18,2% (n = 35) y fue mayor en los pacientes con LRA (28,3% frente a 5,9%; p < 0,001), (OR no ajustada 6,03; IC 95%: 2,22-16,37; p < 0,001). En este análisis multivariado, mayor edad (OR ajustada 1,07; IC 95%: 1,02-1,11; p = 0,004), menor nivel de Hb (OR ajustada 0,78; IC 95%: 0,60-0,98; p = 0,035), duración de la LRA (OR ajustada 7,34 para LRA persistente; IC 95%: 2,37-22,72; p = 0,001) y la gravedad de LRA (OR ajustada 2,65 por aumento en el estadio KDIGO; IC 95%: 1,32-5,33; p = 0,006) fueron predictores independientes de mortalidad. CONCLUSIÓN: La LRA fue frecuente en pacientes hospitalizados con COVID-19. La LRA persistente y su mayor gravedad fueron predictores independientes de mortalidad hospitalaria.

A Case of Severe Acute Respiratory Syndrome Coronavirus 2 Treatment With Remdesivir in a Hepatitis C-Coinfected Patient Resulting in Temporary Viral Control and Posttreatment Flare.

We report a case of a man with chronic hepatitis C infection treated with remdesivir for COVID-19, resulting in lowered HCV viral load, followed by a rebound after its discontinuation. Concomitant treatment with tocilizumab possibly caused loss of anti-HBs.

Organizing pneumonia and COVID-19: A report of two cases.

Organizing pneumonia (OP) is a sub-acute process of pulmonary tissue repair secondary to lung injury, defined histopathologically by intra-alveolar buds of granulation tissue within the lumen of distal pulmonary airspaces. It can be either cryptogenic or secondary (SOP) to different clinical conditions, namely infections. Despite being nonspecific, its diagnosis can be made by the association of clinical and imaging criteria. We report two cases of OP associated to SARS-CoV-2 pneumonia, admitted at a Portuguese tertiary hospital unit dedicated to COVID-19. Both patients presented with severe respiratory failure with need of invasive mechanical ventilation. After initial recovery, there was worsening of dyspnea and hypoxemic respiratory failure with increase in inflammatory markers. Chest CT revealed an OP pattern. Other conditions such as superinfection, auto-immune disease and iatrogenic etiology, were excluded and corticotherapy at a dose of 1 mg/kg/day was administered. Chest CT follow up of both our patients showed complete resolution of OP pattern, with mild to moderate residual pulmonary fibrosis without honeycombing. There is no OP to SARS-CoV-2 case series yet published describing the progress of patients after corticotherapy, although the association between systemic corticosteroids and lower all-cause mortality in patients with COVID-19 has been recently established. It is possible that, as has been described with other viruses, OP secondary to SARS-CoV-2 represents an immunological process after initial infection, presenting with elevation of inflammatory markers and cytokines storm in the bloodstream and lung tissue, which may explain the favorable response to corticosteroids.