Most organisms rely on innate immune receptors to recognize conserved molecular structures from invading microbes. Two essential innate immune receptors, RIG-I and MDA5, detect viral double-stranded ...RNA in the cytoplasm. The inflammatory response triggered by these RIG-I-like receptors (RLRs) is one of the first and most important lines of defense against infection. RIG-I recognizes short RNA ligands with 5'-triphosphate caps. MDA5 recognizes long kilobase-scale genomic RNA and replication intermediates. Ligand binding induces conformational changes and oligomerization of RLRs that activate the signaling partner MAVS on the mitochondrial and peroxisomal membranes. This signaling process is under tight regulation, dependent on post-translational modifications of RIG-I and MDA5, and on regulatory proteins including unanchored ubiquitin chains and a third RLR, LGP2. Here, we review recent advances that have shifted the paradigm of RLR signaling away from the conventional linear signaling cascade. In the emerging RLR signaling model, large multimeric signaling platforms generate a highly cooperative, self-propagating, and context-dependent signal, which varies with the subcellular localization of the signaling platform.
•We proposed an RP LC method for the classification of ion-pairing reagents.•Hydrophobic (stronger) alkylamine ion-pairing reagents give greater separation of oligonucleotides.•Ion-pairing RP LC of ...oligonucleotides behaves as a mixed mode chromatography.•The separation selectivity depends on the pairing reagent hydrophobicity.
We performed a systematic study of thirteen alkylamines used as ion-pairing reagents for ion-pair reversed-phase liquid chromatography (IP RP LC) separations of oligonucleotides on a C18 column. We proposed a method to classify the hydrophobicity of alkylamines by their retention in RP LC. The IP reagent hydrophobicity correlated with the retention and resolution of oligonucleotides in the corresponding IP mobile phases. The baseline resolution was achieved up to 30 mer for hydrophilic, or up to 50 mer for hydrophobic IP reagents. Hydrophobic alkylamines permitted useful oligonucleotide separations at relatively low buffer concentrations, such as 5–10 mM alkylamine-acetate IP systems. These buffers were compatible with mass spectrometry detection, however, replacement of acetic acid with hexafluoroisopropanol in the mobile phase improved the MS signal by 2–3 orders of magnitude. Experiments with native and chemically modified oligonucleotides highlighted the mixed-mode nature of IP RP LC. When using hydrophobic IP reagents, the ionic retention mechanism of oligonucleotides is enhanced while hydrophobic retention is diminished.
The human microbiota is a key contributor to many aspects of human health and its composition is largely influenced by diet. There is a growing body of scientific evidence to suggest that gut ...dysbiosis (microbial imbalance of the intestine) is associated with inflammatory and immune-mediated diseases (e.g., inflammatory bowel disease and asthma). Regular consumption of fermented foods (e.g., kimchi, kefir, etc.) may represent a potential avenue to counter the proinflammatory effects of gut dysbiosis. However, an assessment of the available literature in this research area is lacking. Here we provide a critical review of current human intervention studies that analyzed the effect of fermented foods on the composition and/or function of the human gut microbiota. A total of 19 human intervention studies were identified that met this search criteria. In this review, we discuss evidence that consumption of fermented foods may modify the gut microbiota in humans. Further, there is cursory evidence to suggest that gut microbiota compositional changes mediate associations between fermented food consumption and human health outcomes. Although promising, there remains considerable heterogeneity in the human populations targeted in the intervention studies we identified. Larger longitudinal feeding studies with longer follow-up are necessary to confirm and enhance the current data. Further, future studies should consider analyzing microbiota function as a means to elucidate the mechanism linking fermented food consumption with human health. This review highlights methodologic considerations for intervention trials, emphasizing an expanse of research opportunities related to fermented food consumption in humans.
The COVID-19 pandemic, caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has substantially impacted healthcare utilization worldwide. The objective of this ...retrospective analysis of a large hospital discharge database was to compare all-cause and cause-specific hospitalizations during the first six months of the pandemic in the United States with the same months in the previous four years.
Data were collected from all hospitals in the Premier Healthcare Database (PHD) and PHD Special Release reporting hospitalizations from January through July for each year from 2016 through 2020. Hospitalization trends were analyzed stratified by age group, major diagnostic categories (MDCs), and geographic region.
The analysis included 286 hospitals from all 9 US Census divisions. The number of all-cause hospitalizations per month was relatively stable from 2016 through 2019 and then fell by 21% (57,281 fewer hospitalizations) between March and April 2020, particularly in hospitalizations for non-respiratory illnesses. From April onward there was a rise in the number of monthly hospitalizations per month. Hospitalizations per month, nationally and in each Census division, decreased for 20 of 25 MDCs between March and April 2020. There was also a decrease in hospitalizations per month for all age groups between March and April 2020 with the greatest decreases in hospitalizations observed for patients 50-64 and ≥65 years of age.
Rates of hospitalization declined substantially during the first months of the COVID-19 pandemic, suggesting delayed routine, elective, and emergency care in the United States. These lapses in care for illnesses not related to COVID-19 may lead to increases in morbidity and mortality for other conditions. Thus, in the current stage of the pandemic, clinicians and public-health officials should work, not only to prevent SARS-CoV-2 transmission, but also to ensure that care for non-COVID-19 conditions is not delayed.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
BACKGROUND:Although deviations in intraoperative blood pressure are assumed to be associated with postoperative mortality, critical blood pressure thresholds remain undefined. Therefore, the authors ...estimated the intraoperative thresholds of systolic blood pressure (SBP), mean blood pressure (MAP), and diastolic blood pressure (DBP) associated with increased risk-adjusted 30-day mortality.
METHODS:This retrospective cohort study combined intraoperative blood pressure data from six Veterans Affairs medical centers with 30-day outcomes to determine the risk-adjusted associations between intraoperative blood pressure and 30-day mortality. Deviations in blood pressure were assessed using three methods(1) population thresholds (individual patient sum of area under threshold AUT or area over threshold 2 SDs from the mean of the population intraoperative blood pressure values), (2). absolute thresholds, and (3) percent change from baseline blood pressure.
RESULTS:Thirty-day mortality was associated with (1) population thresholdsystolic AUT (odds ratio, 3.3; 95% CI, 2.2 to 4.8), mean AUT (2.8; 1.9 to 4.3), and diastolic AUT (2.4; 1.6 to 3.8). Approximate conversions of AUT into its separate components of pressure and time were SBP < 67 mmHg for more than 8.2 min, MAP < 49 mmHg for more than 3.9 min, DBP < 33 mmHg for more than 4.4 min. (2) Absolute thresholdSBP < 70 mmHg for more than or equal to 5 min (odds ratio, 2.9; 95% CI, 1.7 to 4.9), MAP < 49 mmHg for more than or equal to 5 min (2.4; 1.3 to 4.6), and DBP < 30 mmHg for more than or equal to 5 min (3.2; 1.8 to 5.5). (3) Percent changeMAP decreases to more than 50% from baseline for more than or equal to 5 min (2.7; 1.5 to 5.0). Intraoperative hypertension was not associated with 30-day mortality with any of these techniques.
CONCLUSION:Intraoperative hypotension, but not hypertension, is associated with increased 30-day operative mortality.
Determining whether SARS-CoV-2 exhibits seasonality like other respiratory viruses is critical for public health planning. We evaluated whether COVID-19 rates follow a seasonal pattern using time ...series models. We used time series decomposition to extract the annual seasonal component of COVID-19 case, hospitalization, and mortality rates from March 2020 through December 2022 for the United States and Europe. Models were adjusted for a country-specific stringency index to account for confounding by various interventions. Despite year-round disease activity, we identified seasonal spikes in COVID-19 from approximately November through April for all outcomes and in all countries. Our results support employing annual preventative measures against SARS-CoV-2, such as administering seasonal booster vaccines in a similar timeframe as those in place for influenza. Whether certain high-risk individuals may need more than one COVID-19 vaccine booster dose each year will depend on factors like vaccine durability against severe illness and levels of year-round disease activity.
Background
To validate six‐echo, chemical‐shift based MRI with T2* correction for the quantification of bone marrow fat content in the presence of trabecular bone.
Methods
Ten bone phantoms were made ...using trabecular bone cores extracted from the distal femur and proximal tibia of 20 human cadaveric knees. Bone marrow was removed from the cores and the marrow spaces were filled with water‐fat gelatin to mimic bone marrow of known fat fractions. A chemical‐shift based water‐fat separation method with T2* correction was used to generate fat fraction maps. The proton density fat fractions (PDFF) between marrow regions with and without bone were compared with the reference standard of known fat fraction using the squared Pearson correlation coefficient and unpaired t‐test.
Results
Strong correlations were found between the known fat fraction and measured PDFF in marrow without trabecular bone (R2 = 0.99; slope = 0.99, intercept = 0.94) as well as in marrow with trabecular bone (R2 = 0.97; slope = 1.0, intercept = −3.58). Measured PDFF between regions with and without bone were not significantly different (P = 0.5). However, PDFF was systematically underestimated by −3.2% fat fraction in regions containing trabecular bone.
Conclusion
Our implementation of a six‐echo chemical‐shift based MRI pulse sequence with T2* correction provided an accurate means of determining fat content in bone marrow in the presence of trabecular bone. J. Magn. Reson. Imaging 2015;42:539–544.
Chronic obstructive pulmonary disease (COPD) is characterized by the destruction of alveolar tissue (in emphysema) and airway remodeling (leading to chronic bronchitis), which cause difficulties in ...breathing. It is a growing public health concern with few therapeutic options that can reverse disease progression or mortality. This is in part because current treatments mainly focus on ameliorating symptoms induced by inflammatory pathways as opposed to curing disease. Hence, emerging research focused on upstream pathways are likely to be beneficial in the development of efficient therapeutics to address the root causes of disease. Some of these pathways include mitochondrial function, cytoskeletal structure and maintenance, and airway hydration, which are all affected by toxins that contribute to COPD. Because of the complexity of COPD and unknown targets for disease onset, simpler model organisms have proved to be useful tools in identifying disease-relevant pathways and targets. This review summarizes COPD pathology, current treatments, and therapeutic discovery research, with a focus on the aforementioned pathways that can advance the therapeutic landscape of COPD.
We have adapted a bacterial CRISPR RNA/Cas9 system to precisely engineer the Drosophila genome and report that Cas9-mediated genomic modifications are efficiently transmitted through the germline. ...This RNA-guided Cas9 system can be rapidly programmed to generate targeted alleles for probing gene function in Drosophila.
US attributable Clostridioides difficile infection (CDI) mortality and cost data are primarily from Medicare fee-for-service populations, and little is known about Medicare Advantage Enrollees ...(MAEs). This study evaluated CDI incidence among MAEs from 2012 to 2019 and determined attributable mortality and costs by comparing MAEs with and without CDI occurring in 2018.
This retrospective cohort study assessed CDI incidence and associated mortality and costs for eligible MAEs ≥65 years of age using the de-identified Optum Clinformatics Data Mart database (Optum; Eden Prairie, Minnesota, USA). Outcomes included mortality, healthcare utilization, and costs, which were assessed via a propensity score-matched cohort using 2018 as the index year. Outcome analyses were stratified by infection acquisition and hospitalization status.
From 2012 to 2019, overall annual CDI incidence declined from 609 to 442 per 100 000 person-years. Although the incidence of healthcare-associated CDI declined overall (2012, 53.2%; 2019, 47.2%), community-associated CDI increased (2012, 46.8%; 2019, 52.8%). The 1-year attributable mortality was 7.9% (CDI cases, 26.3%; non-CDI controls, 18.4%). At the 2-month follow-up, CDI-associated excess mean total healthcare and out-of-pocket costs were $13 476 and $396, respectively. Total excess mean healthcare costs were greater among hospitalized (healthcare-associated, $28 762; community-associated, $28 330) than nonhospitalized CDI patients ($5704 and $2320, respectively), whereas total excess mean out-of-pocket cost was highest among community-associated hospitalized CDI patients ($970).
CDI represents an important public health burden in the MAE population. Preventive strategies and treatments are needed to improve outcomes and reduce costs for healthcare systems and this growing population of older US adults.
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