The Skeletal Muscle, the Heart, and the Liver Are the Major Organs of the Accumulation of Nitric Oxide Metabolites after Oral Nitrite Treatment.

Nitrite is a nitric oxide (NO) metabolite, which may be bioactivated to generate NO in vivo and supplement endogenous NO formation, especially in cardiovascular and metabolic diseases. However, it is not known whether treatment with oral nitrite results in the accumulation of NO metabolites in different organs. Moreover, treatment with omeprazole, an inhibitor of gastric acid secretion, severely affects the gastric formation of S-nitrosothiols induced with oral nitrite treatment. However, no previous study has examined whether omeprazole affects the nitrite-induced accumulation of NO metabolites in different organs. This study examined in rats the effects of oral sodium nitrite treatment (15 mg/kg via gavage for 1 or 7 days) associated with omeprazole (10 mg/kg or vehicle) on nitrite and nitrate and nitrosylated species (RXNO) concentrations (measured using ozone-based chemiluminescence methods) assessed in the plasma, aorta, heart, liver, brain, and muscle. While our results showed that NO metabolite accumulation in different organs is not uniform, we found that the skeletal muscle, the heart, and the liver accumulate NO metabolites, particularly RXNO. This response was significantly attenuated by omeprazole in the heart and in the skeletal muscle. Together, these findings may indicate that the skeletal muscle, the heart, and the liver are major reservoir sites for NO metabolites after oral nitrite treatment, with major increases in nitrosylated species.

Lewy body dementia: Overcoming barriers and identifying solutions.

Despite its high prevalence among dementias, Lewy body dementia (LBD) remains poorly understood with a limited, albeit growing, evidence base. The public-health burden that LBD imposes is worsened by overlapping pathologies, which contribute to misdiagnosis, and lack of treatments. For this report, we gathered and analyzed public-domain information on advocacy, funding, research outputs, and the therapeutic pipeline to identify gaps in each of these key elements. To further understand the current gaps, we also conducted interviews with leading experts in regulatory/governmental agencies, LBD advocacy, academic research, and biopharmaceutical research, as well as with funding sources. We identified wide gaps across the entire landscape, the most critical being in research. Many of the experts participated in a workshop to discuss the prioritization of research areas with a view to accelerating therapeutic development and improving patient care. This white paper outlines the opportunities for bridging the major LBD gaps and creates the framework for collaboration in that endeavor. HIGHLIGHTS: A group representing academia, government, industry, and consulting expertise was convened to discuss current progress in Dementia with Lewy Body care and research. Consideration of expert opinion,natural language processing of the literature as well as publicly available data bases, and Delphi inspired discussion led to a proposed consensus document of priorities for the field.

Hemispheric-scale heavy metal pollution from South American and Australian mining and metallurgy during the Common Era.

Records from polar and alpine ice reflect past changes in background and industrial toxic heavy metal emissions. While Northern Hemisphere records have been used to evaluate environmental effects and linkages to historical events such as foreign conquests, plagues, economic downturns, and technological developments during the past three millennia, little is known about the magnitude and environmental effects of such emissions in the Southern Hemisphere or their historical linkages, especially prior to late 19th century industrialization. Here we used detailed measurements of the toxic heavy metals lead, cadmium, and thallium, as well as non-toxic bismuth, cerium, and sulfur in an array of five East Antarctic ice cores to investigate hemispheric-scale pollution during the Common Era. While thallium showed no anthropogenic increases, the other three metals increased by orders of magnitude in recent centuries after accounting for crustal and volcanic components. These first detailed records indicate that East Antarctic lead pollution started in the 13th century coincident with Late Intermediate Period metallurgy in the Andes and was pervasive during the Spanish Colonial period in parallel with large-scale exploitation of Andean silver and other ore deposits. Lead isotopic variations suggest that 19th-century increases in lead, cadmium, and bismuth resulted from Australian lead and Bolivian tin mining emissions, with 20th century pollution largely the result of the latter. As in the Northern Hemisphere, variations in heavy metal pollution coincided with plagues, cultural and technological developments, as well as global economic and political events including the Great Depression and the World Wars. Estimated atmospheric heavy metal emissions from Spanish Colonial-era mining and smelting during the late 16th and early 17th century were comparable to estimated European emissions during the 1st-century apex of the Roman Empire, with atmospheric model simulations suggesting hemispheric-scale toxic heavy metal pollution during the past five centuries as a result.

LATE-NC in Alzheimer's disease: Molecular aspects and synergies.

Alzheimer's disease (AD) is classically characterized by senile plaques and neurofibrillary tangles (NFTs). However, multiple copathologies can be observed in the AD brain and contribute to the development of cognitive decline. Limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC) accumulates in the majority of AD cases and leads to more severe cognitive decline compared with AD pathology alone. In this review, we focus on the synergistic relationship between LATE-NC and tau in AD, highlighting the aggravating role of TDP-43 aggregates on tau pathogenesis and its impact on the clinical picture and therapeutic strategies. Additionally, we discuss to what extent the molecular patterns of LATE-NC in AD differ from frontotemporal lobar degeneration with TDP-43 pathology (FTLD-TDP) neuropathological changes. Thus, we highlight the importance of tau and TDP-43 synergies for subtyping AD patients, which may respond differently to therapeutic interventions depending on the presence of comorbid LATE-NC.

TDP-43 pathology is associated with increased tau burdens and seeding.

BACKGROUND: Most Alzheimer's Disease (AD) cases also exhibit limbic predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), besides amyloid-ß plaques and neurofibrillary tangles (NFTs) containing hyperphosphorylated tau (p-tau). LATE-NC is characterized by cytoplasmic aggregates positive for pathological TDP-43 and is associated with more severe clinical outcomes in AD, compared to AD cases lacking TDP-43 pathology TDP-43: AD(LATE-NC-). Accumulating evidence suggests that TDP-43 and p-tau interact and exhibit pathological synergy during AD pathogenesis. However, it is not yet fully understood how the presence of TDP-43 affects p-tau aggregation in symptomatic AD. METHODS: In this study, we investigated the impact of TDP-43 proteinopathy on p-tau pathology with different approaches: histologically, in a human post-mortem cohort (n = 98), as well as functionally using a tau biosensor cell line and TDP-43A315T transgenic mice. RESULTS: We found that AD cases with comorbid LATE-NC, AD(LATE-NC+), have increased burdens of pretangles and/or NFTs as well as increased brain levels of p-tau199, compared to AD(LATE-NC-) cases and controls. The burden of TDP-43 pathology was also correlated with the Braak NFT stages. A tau biosensor cell line treated with sarkosyl-insoluble, brain-derived homogenates from AD(LATE-NC+) cases displayed exacerbated p-tau seeding, compared to control and AD(LATE-NC-)-treated cells. Consistently, TDP-43A315T mice injected with AD(LATE-NC+)-derived extracts also exhibited a more severe hippocampal seeding, compared to the remaining experimental groups, albeit no TDP-43 aggregation was observed. CONCLUSIONS: Our findings extend the current knowledge by supporting a functional synergy between TDP-43 and p-tau. We further demonstrate that TDP-43 pathology worsens p-tau aggregation in an indirect manner and increases its seeding potential, probably by increasing p-tau levels. This may ultimately contribute to tau-driven neurotoxicity and cell death. Because most AD cases present with comorbid LATE-NC, this study has an impact on the understanding of TDP-43 and tau pathogenesis in AD and LATE, which account for the majority of dementia cases worldwide. Moreover, it highlights the need for the development of a biomarker that detects TDP-43 during life, in order to properly stratify AD and LATE patients.

Heart failure and diabetes: Understanding the bidirectional relationship.

Heart failure and diabetes mellitus are 2 common and closely intertwined chronic conditions that often coexist in individuals. The relationship between heart failure and diabetes is bidirectional, meaning that each condition can influence the development and progression of the other. Understanding this complex interplay is crucial for optimizing the management and outcomes of patients with these comorbidities. This review comprehensively analyzed the literature to examine the bidirectional relationship between heart failure and diabetes. We searched various electronic databases and included studies that explored the pathophysiological mechanisms, epidemiology, clinical implications, and therapeutic considerations associated with this relationship. The bidirectional relationship between heart failure and diabetes is multifactorial and involves several interconnected mechanisms. Diabetes is a recognized risk factor for heart failure, increasing the risk of its development and accelerating its progression. On the other hand, heart failure can contribute to the development of insulin resistance and worsen glycemic control in patients with diabetes. Shared risk factors, such as obesity, hypertension, and dyslipidemia, contribute to development of both conditions. Additionally, hyperglycemia, insulin resistance, chronic inflammation, oxidative stress, and mitochondrial dysfunction play significant roles in the pathogenesis of heart failure in individuals with diabetes. The bidirectional relationship between heart failure and diabetes has important clinical implications. Patients with heart failure and diabetes have worse outcomes, including higher hospitalization rates, morbidity, and mortality, than those without diabetes. Optimal management strategies should target both conditions simultaneously, focusing on lifestyle modifications, pharmacotherapy, glycemic control, and cardiovascular risk reduction.

Racial Disparities In In-Hospital Mortality of Children and Adolescents Under 20 Years With Type 1 Diabetes Mellitus.

BACKGROUND: In the United States, racial disparities in health outcomes continue to be a major problem with far-reaching effects on equity in healthcare and public health. Children and teenagers with type 1 diabetes are a disadvantaged demographic that has particular difficulties in managing their condition and getting access to healthcare. Despite improvements in the treatment of diabetes, little study has examined how much racial disparities in in-hospital mortality affect this particular demographic. By examining racial differences in in-hospital mortality rates among children and adolescents with type 1 diabetes in the United States, this study seeks to close this gap. METHODS: This cross-sectional study utilized data from the Healthcare Cost and Utilization Project's (HCUP) Kids' Inpatient Database (KID) for 2012. The KID is a nationally representative sample of pediatric discharges from US hospitals. A total of 20,107 patients who were admitted with type 1 diabetes were included in this study. The primary outcome was the patient's in-hospital mortality status. The primary predictor variable was the race of the patient. Six potential confounders were chosen based on previous literature: age, sex, hospital location, obesity, weight loss, electrolyte disorders status, and median household income. Descriptive statistics and bivariate analyses were done. Multivariate analysis was conducted while controlling for potential confounders. Odd ratios with a 95% confidence interval and probability value were reported. Statistical Analysis System (SAS) version 9.4 for Windows (SAS Institute Inc., Cary, NC, USA) was used for the statistical analysis. RESULTS: A total of 20,107 patients were included in this study. Of the patients included, 78.6%, 5.3%, 5.9%, and 10.2% were of age groups <4, 5-9, 10-14, and 15-18, respectively. Among the patients, 64.3% were female. Whites stood at 54.3%, while Hispanic, Black, and other races accounted for 17.2%, 21.8%, and 6.7% respectively. After adjusting for all other variables, children, and young adults of Asian and Pacific Islanders (OR=1.948; 95% CI 1.015,3.738) had 94% higher odds of in-hospital mortality compared to their White counterparts. Children and young adults aged 5-9 (OR=0.29; 95% CI 0.13,0.649) had 71% lower odds of in-hospital mortality compared to those aged 4 or under. Those aged 10-14 (OR=0.155; 95% CI 0.077,0.313) had 85% lower odds of in-hospital mortality compared to those aged 4 or under, while those aged 15-19 (OR=0.172; 95% CI 0.100,0.296) had 83% lower odds of in-hospital mortality compared to those aged 4 or under. Children and young adults who had weight loss (OR=4.474; 95% CI 2.557,7.826) had almost five times higher odds of in-hospital mortality compared to those without weight loss, while children and young adults who had electrolyte disorders (OR=5.131; 95% CI 3.429,7.679) had five times higher odds of in-hospital mortality compared to those without electrolyte disorders. CONCLUSION: The results show young adults of Asian and Pacific Islanders have higher odds of in-hospital mortality compared to their White counterparts and this study highlights the urgent need for focused measures designed to lessen these inequalities and enhance health equity. The implementation of culturally sensitive healthcare practices, addressing social determinants of health, and enhancing access to high-quality diabetes care should all be priorities.

Nativity Status Predicts Tobacco Use: A Comparative Analysis of US-Born and Foreign-Born Adults From the Health Information National Trends Survey (HINTS).

Introduction Tobacco smoking remains one of the leading causes of morbidity and mortality globally and in the United States (USA). We hypothesize that US-born naturals have higher odds of tobacco smoking compared to their foreign-born counterparts, and our study aims to assess the relationship between nativity status and odds of tobacco smoking using a nationally representative sample. Methods We utilized the Health Information National Trends Survey (HINTS) 5 Cycle 1 (2017) and Cycle 2 (2018) for this study. Our main outcome variable was smoking status divided as ever smoker and never smoker. The main predictor was US birth status. We controlled for sociodemographic characteristics such as age, race, gender, educational status, and marital status. We performed weighted descriptive statistics and bivariate analysis with chi-square for our variables. Unadjusted and adjusted logistic regression was used to ascertain the odds of our outcome given our predictor. Significance was set at 95% confidence, and the alpha level was set to 0.05. All analyses were performed using SAS version 9.4 (SAS Institute Inc., Cary, NC, USA). Results Our final sample consisted of 5,677 individuals (weighted: 429,613,693). Of our sample, 36.89% were ever smokers, females were 50.73%, and the majority (57.90%) were high school graduates. In terms of nativity status, those born in the USA were 85.65%, while the non-US-born population was 14.35%. After adjusting for confounders, we found that non-US-born respondents had 42% lower odds of being ever smokers compared to their US-born counterparts (adjusted odds ratio (AOR) = 0.576; 95% confidence interval (CI) = 0.388-0.854; P = 0.0062). Females were 24% less likely to be ever smokers compared to males (AOR = 0.758; 95% CI = 0.644-0.893; P = 0.0010). Having a bachelor's degree or a graduate degree was associated with 42% and 53% lower odds of being ever smokers compared to high school graduates (AOR = 0.583; 95% CI = 0.474-0.717; P < 0.0001) (AOR = 0.471; 95% CI = 0.377-0.588; P < 0.0001). Whites had 97% higher odds of being ever smokers compared to Hispanics (AOR = 1.977; 95% CI = 1.459-2.679; P < 0.0001). Conclusion Our finding of lower odds of tobacco use among foreign-born nationals compared to US-born nationals is consistent with previous studies and suggests the need for equity in tobacco use prevention between the two populations assessed in our study. This is poised to improve overall tobacco use burden, morbidity, and mortality.

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.

Cinnamomum cassia on Arterial Stiffness and Endothelial Dysfunction in Type 2 Diabetes Mellitus: Outcomes of a Randomized, Double-Blind, Placebo-Controlled Clinical Trial.

Cinnamomum cassia is a medicinal plant whose use has demonstrated benefits on body weight, blood pressure, glucose, and lipids. This study aimed to evaluate the effect of C. cassia on arterial stiffness and endothelial dysfunction (ED) in patients with type 2 diabetes mellitus (T2DM). A randomized, double-blind, placebo-controlled clinical trial was carried out in 18 subjects aged 40-65 years, with a diagnosis of T2DM of one year or less since diagnosis and treated with Metformin 850 mg daily. Patients were randomly assigned to receive either C. cassia or a placebo in 1000 mg capsules, thrice a day, before each meal for 12 weeks. At baseline and after 12 weeks of intervention, brachial-ankle pulse wave velocity and Flow Mediated Dilation were measured, as well as body weight, body mass index (BMI), blood pressure (BP), fasting glucose (FG), glycated hemoglobin A1c (HbA1c), total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, and very low density lipoprotein cholesterol, respectively, triglycerides, creatinine, and transaminases. The Mann-Whitney U test for differences between groups and the Wilcoxon signed-rank test for intragroup differences were used, and a P ≤ .05 was considered statistically significant. After C. cassia administration, statistically significant reductions in body weight (81.4 ± 10.4 kg vs. 79.9 ± 9.0 kg, P = .037), BMI (30.6 ± 4.2 kg/m2 vs. 30.1 ± 4.2 kg/m2, P = .018), and HbA1c (53 ± 5.4 mmol/mol vs. 45 ± 2.1 mmol/mol, P = .036) were observed. No changes statistically significant on arterial stiffness, ED, FG, BP, and lipids were observed. C. cassia administration decreases body weight, BMI, and HbA1c without statistically significant changes on arterial stiffness, ED, FG, BP, and lipids. CTR Number: NCT04259606.

The intersection between climate change, COVID-19, and future pandemics - Perspectives among American transportation network drivers.

Introduction: Drivers of Transportation Network Companies (TNC) are an essential workforce that is affected by extreme weather events and high exposure risk to airborne infectious diseases due to their proximity with customers. The purpose of this study was to understand TNC drivers' professional experience during the COVID-19 pandemic and their opinions about climate change and the development of future pandemics. Methods: Open- and closed-ended responses were collected during TNC rides and analyzed with content analysis and descriptive statistics. Results: We found more participants believed in the COVID-19 pandemic compared to participants who believed in climate change. Overall, participants were less concerned about COVID-19 than climate change. However, several participants felt that the pandemic had a positive impact on the climate system, specifically by reducing air pollution from traffic. Few participants felt that climate change could lead to the development of future pandemics. Conclusions: The TNC essential workforce could be integral for identifying transportation and public health sectors solutions for addressing the occupational health needs of an essential workforce, and response to climate change and pandemics.

LATE-NC staging in routine neuropathologic diagnosis: an update.

An international consensus report in 2019 recommended a classification system for limbic-predominant age-related TDP-43 encephalopathy neuropathologic changes (LATE-NC). The suggested neuropathologic staging system and nomenclature have proven useful for autopsy practice and dementia research. However, some issues remain unresolved, such as cases with unusual features that do not fit with current diagnostic categories. The goal of this report is to update the neuropathologic criteria for the diagnosis and staging of LATE-NC, based primarily on published data. We provide practical suggestions about how to integrate available genetic information and comorbid pathologies [e.g., Alzheimer's disease neuropathologic changes (ADNC) and Lewy body disease]. We also describe recent research findings that have enabled more precise guidance on how to differentiate LATE-NC from other subtypes of TDP-43 pathology [e.g., frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS)], and how to render diagnoses in unusual situations in which TDP-43 pathology does not follow the staging scheme proposed in 2019. Specific recommendations are also made on when not to apply this diagnostic term based on current knowledge. Neuroanatomical regions of interest in LATE-NC are described in detail and the implications for TDP-43 immunohistochemical results are specified more precisely. We also highlight questions that remain unresolved and areas needing additional study. In summary, the current work lays out a number of recommendations to improve the precision of LATE-NC staging based on published reports and diagnostic experience.

Percentage of change and increment of the glucose level after a normal oral tolerance curve between 24 and 28 weeks of pregnancy.

AIM: To determine the percentage of change and increment in glucose levels after a normal oral glucose tolerance test between 24 and 28 weeks of pregnancy. METHODS: We studied 3510 pregnant women who attended their obstetric delivery at a tertiary care hospital in Guadalajara, Mexico in 2018, according to characteristics and risk 1647 (47%) patients were screened for diabetes diagnosis using the oral glucose tolerance test, 501 patients reported normal values between their 24th and 28th week of pregnancy, only 400 patients had their fasting glucose level measured on the same day of their obstetric delivery, to be compared. RESULTS: Average age was 30 years, with an average of 25.3 weeks of pregnancy. The fasting serum glucose levels taken after 28 weeks of pregnancy and before the obstetrical delivery showed an increase of 1.1 mmol/L in women who develop gestational diabetes mellitus, in contrast to women who did not develop gestational diabetes mellitus after 28 weeks their blood glucose only increased on average 0.4 mmol/L. The incidence of gestational diabetes mellitus in the study population during 2018 was 32.7%. Patients who developed gestational diabetes mellitus after a normal oral glucose tolerance test had greater body mass index before the pregnancy and newborns had a higher weight than babies born to mothers without gestational diabetes mellitus. CONCLUSION: Changes in glucose levels after the oral tolerance test of normal glucose require strict monitoring, in that it was demonstrated that 3% of patients developed gestational diabetes mellitus after week 28 of gestation.

Neuronal loss of the nucleus basalis of Meynert in primary progressive aphasia is associated with Alzheimer's disease neuropathological changes.

INTRODUCTION: Imaging studies indicated basal forebrain reduction in primary progressive aphasia (PPA), which might be a candidate marker for cholinergic treatment. Nucleus basalis of Meynert (nbM) neuronal loss has been reported, but a systematic quantitative neuropathological assessment including the three clinical PPA variants is lacking. METHODS: Quantitative assessment of neuronal density and pathology was performed on nbM tissue of 47 cases: 15 PPA, constituting the different clinicopathological phenotypes, 14 Alzheimer's disease (AD), and 18 cognitively normals. RESULTS: Group-wise, reduced nbM neuronal density was restricted to AD. At the individual level, semantic variant PPA with underlying AD neuropathological change (ADNC) had lower neuronal densities, while those with frontotemporal lobar degeneration (FTLD) transactive response DNA binding protein 43 kDa (TDP-43) type C pathology were unaffected. Higher Braak stages and increased numbers of nbM-related pretangles were associated with nbM neuronal loss. DISCUSSION: nbM neuronal loss in PPA is related to ADNC. This study cautions against overinterpreting MRI-based basal forebrain volumes in non-AD PPA as neuronal loss.

Índice biespectral y tasa de supresión tras parada cardiaca: ¿son útiles para individualizar planes de escalada terapéutica? / Bispectral index and suppression ratio after cardiac arrest: are they useful as bedside tools for rational treatment escalation plans?

Introducción y objetivos: La disfunción miocárdica contribuye a la mortalidad precoz (24-72 horas) de los supervivientes de parada cardiaca (PC). Actualmente, la decisión de implantar un dispositivo de soporte circulatorio en este contexto se toma con información limitada acerca del potencial de recuperación neurológica (PRN) del paciente, lo que en muchas ocasiones termina en infratratamiento. Por tanto, requerimos de herramientas accesibles y fiables que añadan información sobre el PRN y ayuden a establecer planes individualizados de escalada terapéutica. Métodos: Se recogieron valores de índice biespectral (BIS) y tasa de supresión (TS) en supervivientes de una PC sometidos a control de la temperatura corporal. La función neurológica se evaluó con la escala Cerebral Performance Category (CPC). Resultados: Se incluyeron 340 pacientes. En la primera evaluación neurológica completa, 211 (62,1%) alcanzaron buen pronóstico (CPC 1-2). Los valores de BIS fueron significativamente mayores y los de TS menores, en pacientes con CPC 1-2. Un BIS promedio> 26 en las primeras 12 horas predijo buena evolución neurológica (sensibilidad 89,5%; especificidad 75,8%; AUC=0,869), mientras que una TS promedio> 24 en las primeras 12 horas predijo mala evolución o CPC 3-5 (sensibilidad 91,5%; especificidad 81,8%; AUC=0,906). Los valores horarios de BIS/TS mostraron buena capacidad predictiva (AUC> 0,85) desde la 2.a hora para TS y 4.a para BIS. Conclusiones: El BIS/TS permiten estimar el PRN tras una PC. Este hallazgo puede contribuir a crear conciencia con respecto a evitar la limitación de escalada terapéutica en pacientes potencialmente recuperables.(AU)

Introduction and objectives: Myocardial dysfunction contributes to early mortality (24-72 hours) among survivors of a cardiac arrest (CA). The benefits of mechanical support in refractory shock should be balanced against the patient's potential for neurological recovery. To date, these early treatment decisions have been taken based on limited information leading mainly to undertreatment. Therefore, there is a need for early, reliable, accessible, and simple tools that offer information on the possibilities of neurological improvement. Methods: We collected data from bispectral index (BIS) and suppression ratio (SR) monitoring of adult comatose survivors of CA managed with targeted temperature management (TTM). Neurological status was assessed according to the Cerebral Performance Category (CPC) scale. Results: We included 340 patients. At the first full neurological evaluation, 211 patients (62.1%) achieved good outcome or CPC 1-2. Mean BIS values were significantly higher and median SR lower in patients with CPC 1-2. An average BIS> 26 during first 12hours of TTM predicted good outcome with 89.5% sensitivity and 75.8% specificity (AUC of 0.869), while average SR values> 24 during the first 12hours of TTM predicted poor outcome (CPC 3-5) with 91.5% sensitivity and 81.8% specificity (AUC, 0.906). Hourly BIS and SR values exhibited good predictive performance (AUC> 0.85), as soon as hour 2 for SR and hour 4 for BIS. Conclusions: BIS/SR are associated with patients’ potential for neurological recovery after CA. This finding could help to create awareness of the possibility of a better outcome in patients who might otherwise be wrongly considered as nonviable and to establish personalized treatment escalation plans.(AU)

The central role of tau in Alzheimer's disease: From neurofibrillary tangle maturation to the induction of cell death.

The tau protein (τ) is one of the two hallmark proteins of Alzheimer's disease (AD) together with the amyloid ß protein (Aß). In contrast to Aß, abnormally phosphorylated τ (p-τ) can also be found in non-AD tauopathies. In AD, p-τ is the main component of intraneuronal neurofibrillary tangles, which result from aggregation of abnormally phosphorylated and folded τ. In this review, we discuss the role of p-τ pathology in Alzheimer's disease considering neuropathological, biochemical, cellular, animal model, and clinical findings. We discuss the relationship between p-τ and other AD-related proteins such as Aß and transactive response DNA-binding protein 43 (TDP-43). In light of the current state of knowledge, we conclude that p-τ aggregation known as primary age-related tauopathy (PART) may represent a prerequisite for the development of AD rather that a downstream effect of Aß toxicity. However, Aß as well as TDP-43 pathology appear to accelerate accumulation and propagation of p-τ pathology once initiated, ultimately leading to the full-blown picture of AD. In this context, τ seeds can induce granulovacuolar degeneration (GVD), AD-typical lesions in which the activated necrosome - required for the execution of necroptosis, a programmed form of cell death - can be found. Moreover, necrosome-exhibiting GVD is associated with a decreased neuronal density. Thus, we speculate that p-τ pathology is a major driver for neuron loss in AD via GVD-mediated necroptosis. Overall, p-τ seems to play a central role in AD as it appears to constitute a prerequisite for AD development which can then be accelerated by co-factors. This would fit in a probabilistic model of AD, in which the presence and severity of the respective co-factors such as Aß, TDP-43, and others contribute separately to AD pathogenesis as probabilistic factors with a certain weight.

First-In-Human Computer-Optimized Endobronchial Ultrasound-Guided Interstitial Photodynamic Therapy for Patients With Extrabronchial or Endobronchial Obstructing Malignancies.

Objective: Patients with inoperable extrabronchial or endobronchial tumors who are not candidates for curative radiotherapy have dire prognoses with no effective long-term treatment options. To reveal that our computer-optimized interstitial photodynamic therapy (I-PDT) is safe and potentially effective in the treatment of patients with inoperable extra or endobronchial malignancies inducing central airway obstructions. Methods: High-spatial resolution computer simulations were used to personalize the light dose rate and dose for each tumor. Endobronchial ultrasound with a transbronchial needle was used to place the optical fibers within the tumor according to an individualized plan. The primary and secondary end points were safety and overall survival, respectively. An exploratory end point evaluated changes in immune markers. Results: Eight patients received I-PDT with planning, and five of these received additional external beam PDT. Two additional patients received external beam PDT. The treatment was declared safe. Three of 10 patients are alive at 26.3, 12, and 8.3 months, respectively, after I-PDT. The treatments were able to deliver a prescribed light dose rate and dose to 87% to 100% and 18% to 92% of the tumor volumes, respectively. A marked increase in the proportion of monocytic myeloid-derived suppressor cells expressing programmed death-ligand 1 was measured in four of seven patients. Conclusions: Image-guided light dosimetry for I-PDT with linear endobronchial ultrasound transbronchial needle is safe and potentially beneficial in increasing overall survival of patients. I-PDT has a positive effect on the immune response including an increase in the proportion of programmed death-ligand 1-expressing monocytic myeloid-derived suppressor cells.

LATE-NC aggravates GVD-mediated necroptosis in Alzheimer's disease.

It has become evident that Alzheimer's Disease (AD) is not only linked to its hallmark lesions-amyloid plaques and neurofibrillary tangles (NFTs)-but also to other co-occurring pathologies. This may lead to synergistic effects of the respective cellular and molecular players, resulting in neuronal death. One of these co-pathologies is the accumulation of phosphorylated transactive-response DNA binding protein 43 (pTDP-43) as neuronal cytoplasmic inclusions, currently considered to represent limbic-predominant age-related TDP-43 encephalopathy neuropathological changes (LATE-NC), in up to 70% of symptomatic AD cases. Granulovacuolar degeneration (GVD) is another AD co-pathology, which also contains TDP-43 and other AD-related proteins. Recently, we found that all proteins required for necroptosis execution, a previously defined programmed form of neuronal cell death, are present in GVD, such as the phosphorylated necroptosis executioner mixed-lineage kinase domain-like protein (pMLKL). Accordingly, this protein is a reliable marker for GVD lesions, similar to other known GVD proteins. Importantly, it is not yet known whether the presence of LATE-NC in symptomatic AD cases is associated with necroptosis pathway activation, presumably contributing to neuron loss by cell death execution. In this study, we investigated the impact of LATE-NC on the severity of necroptosis-associated GVD lesions, phosphorylated tau (pTau) pathology and neuronal density. First, we used 230 human post-mortem cases, including 82 controls without AD neuropathological changes (non-ADNC), 81 non-demented cases with ADNC, i.e.: pathologically-defined preclinical AD (p-preAD) and 67 demented cases with ADNC. We found that Braak NFT stage and LATE-NC stage were good predictors for GVD expansion and neuronal loss in the hippocampal CA1 region. Further, we compared the impact of TDP-43 accumulation on hippocampal expression of pMLKL-positive GVD, pTau as well as on neuronal density in a subset of nine non-ADNC controls, ten symptomatic AD cases with (ADTDP+) and eight without LATE-NC (ADTDP-). Here, we observed increased levels of pMLKL-positive, GVD-exhibiting neurons in ADTDP+ cases, compared to ADTDP- and controls, which was accompanied by augmented pTau pathology. Neuronal loss in the CA1 region was increased in ADTDP+ compared to ADTDP- cases. These data suggest that co-morbid LATE-NC in AD impacts not only pTau pathology but also GVD-mediated necroptosis pathway activation, which results in an accelerated neuronal demise. This further highlights the cumulative and synergistic effects of comorbid pathologies leading to neuronal loss in AD. Accordingly, protection against necroptotic neuronal death appears to be a promising therapeutic option for AD and LATE.

Impact of the withdrawal of renin-angiotensin-aldosterone inhibitors on mortality in COVID-19 patients.

Background: Chronic use of Angiotensin-converting enzyme (ACE) inhibitors (ACEi) and aldosterone-receptor blockers (ARB) is not associated with worse outcomes in patients with COVID-19. However, evidence on the impact of their discontinuation during hospital admission is scarce. Our aim was to determine whether withdrawal of ACEi, ARB and mineralocorticoid receptor antagonists (MRA) is associated with all-cause mortality in a real-life large cohort of patients with SARS-CoV-2 infection. Methods: Observational cohort study from a large referral center from 1 March 2020 to 20 April 2020. Withdrawal of renin-angiotensin-aldosterone system inhibitors was defined as the absence of any received dose during hospital admission in patients receiving chronic treatment. Prescriptions during admission were confirmed by data from the central pharmacy computerized system. Results: A total of 2042 patients (mean age 68.4±17.6, 57.1% male) with confirmed COVID-19 were included. During a median follow-up of 57 (21-55) days, 583 (28.6%) died. Prior to hospital admission 468 (22.9%), 343 (16.8%) and 83 (4.1%) patients were receiving ACEi, ARB and MRA respectively. During the study period, 216 (46.2%), 193 (56.3%) and 41 (49.4%) were withdrawn from the corresponding drug. After adjusting for age, cardiovascular risk factors, baseline comorbidities and in-hospital COVID-19 dedicated treatment, withdrawal of ACE inhibitors (hazard ration [HR] 1.48 [95% confidence interval -CI- 1.16-1.89]) and MRA (HR 2.01 [95% CI 1.30-3.10]) were shown to be independent predictors of all-cause mortality. No independent relationship between ARB withdrawal and mortality was observed. Conclusion: ACEi and MRA withdrawal were associated with higher mortality. Strong consideration should be given to not discontinuing these medications during hospital admission.

Introdução: O uso crónico de inibidores da ECA (IECA) e de antagonistas dos recetores de aldosterona (ARA) não está associado a resultados piores em doentes com Covid-19. No entanto, a evidência relativa ao impacto da sua retirada durante a admissão hospitalar é escassa. O nosso objetivo foi determinar se a retirada do IECA, ARA e antagonistas dos recetores dos mineralocorticóides (ARM) está associada à mortalidade por todas as causas numa grande coorte real de doentes com infeção por SRA-CoV-2. Métodos: Estudo coorte observacional a partir de um grande centro de referência de 1 de março de 2020 a 20 de abril de 2020. A retirada dos inibidores do sistema RAAS foi definida como a ausência de qualquer dose recebida durante a admissão hospitalar em doentes que recebem tratamento prolongado. As prescrições durante a admissão foram confirmadas por dados do sistema informático da farmácia central. Resultados: Um total de 2042 doentes (idade média de 68,4 ±17,6, 57,1% do sexo masculino) com COVID-19 confirmado foram incluídos. Durante um acompanhamento médio de 57 (21-55) dias, 583 (28,6%) morreram. Conclusão: A retirada do IECA e do ARM foi associada a uma mortalidade mais elevada. Deve ser dada grande atenção para não interromper estes medicamentos durante a admissão hospitalar.