Background
Cyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling ...and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.
Methods and Results
We assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.
Conclusions
Both saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.
El presente artículo resume la guía de práctica clínica (GPC) para el tamizaje y el manejo del episodio depresivo leve en el primer nivel de atención en el Seguro Social del Perú (EsSalud). Para el ...desarrollo de esta GPC, se conformó un grupo elaborador de la guía (GEG) que incluyó especialistas clínicos y metodólogos, el cual formuló 06 preguntas clínicas. Para responder cada pregunta se realizó búsquedas sistemáticas en PubMed y en repositorios de GPC, y se seleccionó la evidencia pertinente. La certeza de la evidencia fue evaluada usando la metodología Grading of Recommendations Assessment, Development, and Evaluation (GRADE). En reuniones periódicas, el GEG usó la metodología GRADE para revisar la evidencia y emitir las recomendaciones. Se emitieron siete recomendaciones (tres fuertes y cuatro condicionales), 28 puntos de buena práctica clínica, y dos flujogramas.
The present study aimed to develop norms applicable to Spanish-speakers living in the United States (U.S.)- Mexico border region for the Halstead Category Test (HCT), a test of executive function.
...Healthy native Spanish-speakers (N = 252; Age: range 19-60 years, M = 37.28, SD = 10.24; Education: range 0-20 years; M = 10.65, SD = 4.33; 58.33% women) living in the U.S.-Mexico border region of California and Arizona completed the HCT as part of a comprehensive neuropsychological test battery. The univariable and interactive effects of demographic variables on HCT raw scores were examined. Total scores were normed using fractional polynomial equations, controlling for age, education, and gender. T-scores were also computed for HCT scores of the current Spanish-speaking normative sample using published, demographically-adjusted norms for English-speaking non-Hispanic Whites and Blacks. Impairment rates (T-Scores < 40) were calculated using published and current norms.
Age was significantly associated with increased number of errors, and education and male gender were associated with decreased number of HCT errors (total raw scores). Applying norms developed for English-speaking non-Hispanic Whites and Blacks resulted in overestimation of impairment rates in the current sample (impairment: 48% with White norms and 27% with Black norms). This pattern was evident across levels of education except in participants with 13+ years of education, where rates of impairment using non-Hispanic Black norms were comparable to those based on newly developed norms.
The present study presents norms for the HCT in a sample of U.S. Spanish-speakers, providing an important tool for identifying executive dysfunction in this population.
Leptospirosis is one of the most common zoonotic diseases in the world and endemic in the Caribbean Islands. Bovine leptospirosis is an important reproductive disease. Globally, cattle are recognized ...as a reservoir host for
L. borgpetersenii
serovar Hardjo, which is transmitted
via
urine, semen, and uterine discharges, and can result in abortion and poor reproductive performance. The dairy industry in Puerto Rico comprises up to 25% of agriculture-related income and is historically the most financially important agricultural commodity on the island. In this study, we report the isolation of two different pathogenic
Leptospira
species, from two different serogroups, from urine samples collected from dairy cows in Puerto Rico:
L. borgpetersenii
serogroup Sejroe serovar Hardjo and
L. santarosai
serogroup Pyrogenes. Recovered isolates were classified using whole-genome sequencing, serotyping with reference antisera and monoclonal antibodies, and immunoblotting. These results demonstrate that dairy herds in Puerto Rico can be concurrently infected with more than one species and serovar of
Leptospira
, and that bacterin vaccines and serologic diagnostics should account for this when applying intervention and diagnostic strategies.
DNA polymerase stalling activates the ATR checkpoint kinase, which in turn suppresses fork collapse and breakage. Herein, we describe use of ATR inhibition (ATRi) as a means to identify genomic sites ...of problematic DNA replication in murine and human cells. Over 500 high-resolution ATR-dependent sites were ascertained using two distinct methods: replication protein A (RPA)-chromatin immunoprecipitation (ChIP) and breaks identified by TdT labeling (BrITL). The genomic feature most strongly associated with ATR dependence was repetitive DNA that exhibited high structure-forming potential. Repeats most reliant on ATR for stability included structure-forming microsatellites, inverted retroelement repeats, and quasi-palindromic AT-rich repeats. Notably, these distinct categories of repeats differed in the structures they formed and their ability to stimulate RPA accumulation and breakage, implying that the causes and character of replication fork collapse under ATR inhibition can vary in a DNA-structure-specific manner. Collectively, these studies identify key sources of endogenous replication stress that rely on ATR for stability.
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•>500 ATR-dependent sites were identified in the mouse and human genomes•ATR-inhibitor-driven fork collapse occurs primarily at structure-forming repeats•Repeat structures include non-B form DNA and hairpins (AT-rich and inverted repeats)•Discrete repeat types accumulate RPA differentially upon fork collapse
Shastri et al. have identified new classes of difficult-to-replicate sequences in the mouse and human genomes that are highly dependent on ATR function for stability during DNA replication. Structure-forming short tandem repeats, inverted retroelements, and quasi-palindromic AT-rich repeats characterize the sites for fork collapse caused by ATR inhibition.
The year 2020 has been challenging for many, particularly for young adults who have been adversely affected by the COVID-19 pandemic. Emerging adulthood is a developmental phase with significant ...changes in the patterns of daily living; it is a risky phase for the onset of major mental illness. College students during the pandemic face significant risk, potentially losing several protective factors (eg, housing, routine, social support, job, and financial security) that are stabilizing for mental health and physical well-being. Individualized multiple assessments of mental health, referred to as multimodal personal chronicles, present an opportunity to examine indicators of health in an ongoing and personalized way using mobile sensing devices and wearable internet of things.
To assess the feasibility and provide an in-depth examination of the impact of the COVID-19 pandemic on college students through multimodal personal chronicles, we present a case study of an individual monitored using a longitudinal subjective and objective assessment approach over a 9-month period throughout 2020, spanning the prepandemic period of January through September.
The individual, referred to as Lee, completed psychological assessments measuring depression, anxiety, and loneliness across 4 time points in January, April, June, and September. We used the data emerging from the multimodal personal chronicles (ie, heart rate, sleep, physical activity, affect, behaviors) in relation to psychological assessments to understand patterns that help to explicate changes in the individual's psychological well-being across the pandemic.
Over the course of the pandemic, Lee's depression severity was highest in April, shortly after shelter-in-place orders were mandated. His depression severity remained mildly severe throughout the rest of the months. Associations in positive and negative affect, physiology, sleep, and physical activity patterns varied across time periods. Lee's positive affect and negative affect were positively correlated in April (r=0.53, P=.04) whereas they were negatively correlated in September (r=-0.57, P=.03). Only in the month of January was sleep negatively associated with negative affect (r=-0.58, P=.03) and diurnal beats per minute (r=-0.54, P=.04), and then positively associated with heart rate variability (resting root mean square of successive differences between normal heartbeats) (r=0.54, P=.04). When looking at his available contextual data, Lee noted certain situations as supportive coping factors and other situations as potential stressors.
We observed more pandemic concerns in April and noticed other contextual events relating to this individual's well-being, reflecting how college students continue to experience life events during the pandemic. The rich monitoring data alongside contextual data may be beneficial for clinicians to understand client experiences and offer personalized treatment plans. We discuss benefits as well as future directions of this system, and the conclusions we can draw regarding the links between the COVID-19 pandemic and college student mental health.
Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome of pathologic immune activation in children that is increasingly being recognized in adults. Efficacy data for the HLH-04 protocol in ...adults is lacking. This study retrospectively analyzed 31 adult patients, median age 46 years, who received HLH-04 from 1/1/2004 to 5/1/2018. HLH etiology included malignancy (n = 9), autoimmune (n = 8), infection (n = 8), and idiopathic (n = 6). Eighteen patients were evaluable for response at week 4 with 7 having no response, 11 reaching partial response, and 0 reaching complete response (CR). Six patients eventually achieved CR at a median 195 days. The 1-year overall survival (OS) was 35% and median OS was 3.2 months. Univariate analysis showed shorter survival for hemoglobin <9 g/dL (HR 4.29, p = 0.003), platelets <100 × 10
9
/L (HR 4.06, p = 0.027), ANC <1 × 10
9
/L (HR 5.24, p = 0.001), and total bilirubin >1.2 mg/dL (HR 3.30, p = 0.022). Outcomes of adults treated with HLH-04 remain dismal and newer treatment modalities are needed.
During chronic infection, memory T cells acquire a unique phenotype and become dependent on different survival signals than those needed for memory T cells generated during an acute infection. The ...distinction between the role of effector and memory T cells in an environment of persistent antigen remains unclear. Here, in the context of chronic
infection, we demonstrate that a population of CD8 T cells exhibiting a tissue-resident memory (T
) phenotype accumulates within the brain. We show that this population is distributed throughout the brain in both parenchymal and extraparenchymal spaces. Furthermore, this population is transcriptionally distinct and exhibits a transcriptional signature consistent with the T
observed in acute viral infections. Finally, we establish that the CD103
T
population has an intrinsic capacity to produce both IFN-γ and TNF-α, cytokines critical for parasite control within the central nervous system (CNS). The contribution of this population to pro-inflammatory cytokine production suggests an important role for T
in protective and ongoing immune responses in the infected CNS.
.
Control of intracellular parasites responsible for malaria requires host IFN-y+T-bet+CD4+ T cells (Th1 cells) with IL-10 produced by Th1 cells to mitigate the pathology induced by this inflammatory ...response. However, these IL-10-producing Th1 (induced type I regulatory Tr1) cells can also promote parasite persistence or impair immunity to reinfection or vaccination. Here, we identified molecular and phenotypic signatures that distinguished IL-10-Th1 cells from IL-10 +T r1 cells in Plasmodium falciparum-infected people who participated in controlled human malaria infection studies, as well as C57BL/6 mice with experimental malaria caused by P. berghei ANKA. We also identified a conserved Tr1 cell molecular signature shared between patients with malaria, dengue, and graft-versus-host disease. Genetic manipulation of primary human CD4+ T cells showed that the transcription factor cMAF played an important role in the induction of IL-10, while BLIMP-1 promoted the development of human CD4+ T cells expressing multiple coinhibitory receptors. We also describe heterogeneity of Tr1 cell coinhibitory receptor expression that has implications for targeting these molecules for clinical advantage during infection. Overall, this work provides insights into CD4+ T cell development during malaria that offer opportunities for creation of strategies to modulate CD4+ T cell functions and improve antiparasitic immunity.
This study sought to evaluate COVID-19 associated physical and mental health symptoms among adults with allergies compared to the general U.S. adult population.
Data for these analyses were obtained ...from the publicly available COVID-19 Household Impact Survey, which provides national and regional statistics about physical health, mental health, economic security, and social dynamics among U.S. adults (ages 18 and older). Data from 20-26 April 2020; 4-10 May 2020; and 30 May-8 June 2020 were included. Our primary outcomes for this analysis were physical and mental health symptoms experienced in the last seven days. The primary predictor was participants' self-report of a physician diagnosis of an allergy.
This study included 10,760 participants, of whom 44% self-reported having allergies. Adults with allergies were more likely to report physical symptoms compared to adults without allergies including fever (aOR 1.7, 95% CI 1.44-1.99), cough (aOR 1.9, 95% CI 1.60-2.26), shortness of breath (aOR 2.04, 95% CI 1.71-2.43), and loss of taste or sense of smell (aOR 1.9, 95% CI 1.58-2.28). Adults with allergies were more likely to report feeling nervous (cOR 1.34, 95% CI 1.13, 1.60), depressed (cOR 1.32, 95% CI 1.11-1.57), lonely (cOR 1.23, 95% CI 1.04-1.47), hopeless (cOR 1.44, 95% CI 1.21-1.72), or having physical reactions when thinking about COVID-19 pandemic (cOR 2.01, 95% CI 1.44-2.82), compared to those without allergies. During the COVID-19 pandemic, adults with allergies are more likely to report physical and mental health symptoms compared to individuals without allergies. These findings have important implications for diagnostic and treatment challenges for allergy physicians.
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