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PloS One 2024The Neutrophil-to-Lymphocyte Ratio (NLR) is a clinical indicator of peripheral inflammation that is easily accessible. It is worth noting that the formation of... (Meta-Analysis)
Meta-Analysis
BACKGROUND
The Neutrophil-to-Lymphocyte Ratio (NLR) is a clinical indicator of peripheral inflammation that is easily accessible. It is worth noting that the formation of amyloid-β (Aβ) plaques and neurofibrillary tangles has been linked to inflammation and immune dysregulation. The main objective of this systematic review and meta-analysis is to comprehensively evaluate the existing body of research concerning the NLR in the context of Alzheimer's disease (AD) and mild cognitive impairment (MCI).
METHOD
We conducted a comprehensive online search and included studies that evaluated the NLR in 1) patients with AD or MCI and 2) healthy control (HC) participants. We also pooled mean and standard deviation (SD) data for each group.
RESULTS
Ultimately, 12 studies encompassed 1,309 individuals diagnosed with AD with mean NLR levels of 2.68, 1,929 individuals with MCI with mean NLR levels of 2.42, and 2,064 HC with mean NLR levels of 2.06 were included in this systematic review and meta-analysis. The mean NLR was 0.59 higher in AD patients compared to HC participants (mean difference (MD) = 0.59 [0.38; 0.80]). Similarly, the mean NLR was higher in AD than MCI patients (MD = 0.23 [0.13; 0.33]). Additionally, the mean NLR was higher in individuals with MCI compared to HC participants (MD = 0.37 [0.22; 0.52]). In the subgroup meta-analysis based on the Mini-Mental State Examination (MMSE), AD patients with lower MMSE scores (using a cut-off of 20) exhibited significantly higher mean NLR (3.10 vs. 2.70, with a p-value for subgroup differences < 0.01).
CONCLUSION
The NLR, which serves as a marker of peripheral inflammation, shows increased levels in individuals with AD and MCI compared to HC participants. Furthermore, our study indicates that NLR levels are significantly higher in AD than MCI. Additionally, our novel finding suggests significantly higher NLR levels among AD patients with more severe cognitive decline compared to AD patients with less severe cognitive decline. So, it can be concluded that the higher cognitive decline in humans is accompanied by higher NLR levels. Further longitudinal researches are needed to explore more details about the relationship between inflammation and dementia.
Topics: Alzheimer Disease; Humans; Neutrophils; Lymphocytes; Cognitive Dysfunction; Lymphocyte Count
PubMed: 38917167
DOI: 10.1371/journal.pone.0305322 -
Prevalence of and Risk Factors for Post-COVID-19 Condition during Omicron BA.5-Dominant Wave, Japan.Emerging Infectious Diseases Jul 2024The increased risk for post-COVID-19 condition after the Omicron-dominant wave remains unclear. This population-based study included 25,911 persons in Japan 20-69 years...
The increased risk for post-COVID-19 condition after the Omicron-dominant wave remains unclear. This population-based study included 25,911 persons in Japan 20-69 years of age with confirmed SARS-CoV-2 infection enrolled in the established registry system during July-August 2022 and 25,911 age- and sex-matched noninfected controls who used a self-reported questionnaire in January-February 2023. We compared prevalence and age- and sex-adjusted odds ratios of persistent COVID-19 symptoms (lasting ≥2 months). We evaluated factors associated with post-COVID-19 condition by comparing cases with and without post-COVID-19 condition. We analyzed 14,710 (8,392 cases and 6,318 controls) of 18,183 respondents. Post-COVID-19 condition proportion among cases was 11.8%, higher by 6.3% than 5.5% persistent symptoms among controls. Female sex, underlying medical conditions, mild to moderate acute COVID-19, and vaccination were associated with post-COVID-19 condition. Approximately 12% had post-COVID-19 condition during the Omicron-dominant wave, indicating the need for longer follow-up.
Topics: Humans; COVID-19; Middle Aged; Female; Male; Japan; Adult; Risk Factors; Aged; SARS-CoV-2; Prevalence; Young Adult; Post-Acute COVID-19 Syndrome; Case-Control Studies
PubMed: 38916571
DOI: 10.3201/eid3007.231723 -
Microbiology Spectrum Jun 2024Real-life data on doravirine (DOR) in different drug combinations are limited. We evaluated the effectiveness of DOR plus two nucleos(t)ide reverse transcriptase...
Real-life data on doravirine (DOR) in different drug combinations are limited. We evaluated the effectiveness of DOR plus two nucleos(t)ide reverse transcriptase inhibitors (NRTI), mainly abacavir/lamivudine, and dual therapies in people with HIV (PWH), mostly virologically suppressed. Ambispective observational study that enrolled adults PWH who initiated a DOR-based regimen from September 2020 to February 2022 at a referral center in Spain. Participants were grouped as follows: A, received DOR plus two NRTI; B, dual therapy (DT) with DOR plus dolutegravir (DTG) or darunavir/cobicistat (DRVc); C, DOR plus ≥two antiretroviral drugs. The primary endpoints were treatment effectiveness at week 48 by intention-to-treat (ITT) and per-protocol analysis (OT). A cohort of 187 participants, 91% virologically suppressed, were analyzed after a median follow-up of 112 weeks (80-136). Group A received DOR plus abacavir/lamivudine (ABV/3TC) ( = 109) or tenofovir/emtricitabine (TFV/3TC) ( = 45). At week 48, the effectiveness of DOR plus ABV/3TC by ITT was 90.8% (CI, 88.0-93.6), better than with TFV/FTC [73.3% (66.7-79.9); = 0.003]. Only one virologic failure was observed. Mild adverse effects were the cause of treatment discontinuation in 7.8%, followed by switching to a single-tablet regimen. In group B, the effectiveness by ITT was 92.9% (CI, 88.0-97.8) at week 48. No adverse effects or virologic failure were registered in this group. DOR plus two NRTI or DT have long-term effectiveness and safety as a switching option for PWH, mostly virologically suppressed. The DOR plus ABV/3TC combination has shown even better effectiveness than TFV/FTC.IMPORTANCEDOR-based regimens have shown long-term effectiveness and safety in PWH, mostly virologically suppressed. The combination of DOR plus ABV/3TC has shown even better safety and effectiveness than TFV/FTC. DOR plus two NRTI offers cost benefits compared to other regimens.
PubMed: 38916326
DOI: 10.1128/spectrum.00654-24 -
Microbiology Spectrum Jun 2024O1 causes the diarrheal disease cholera, and the small intestine is the site of active infection. During cholera, cholera toxin is secreted from and induces a massive...
UNLABELLED
O1 causes the diarrheal disease cholera, and the small intestine is the site of active infection. During cholera, cholera toxin is secreted from and induces a massive fluid influx into the small intestine, which causes vomiting and diarrhea. Typically, genomes are sequenced from bacteria passed in stool, but rarely from vomit, a fluid that may more closely represents the site of active infection. We hypothesized that O1 population bottlenecks along the gastrointestinal tract would result in reduced genetic variation in stool compared to vomit. To test this, we sequenced genomes from 10 cholera patients with paired vomit and stool samples. Genetic diversity was low in both vomit and stool, consistent with a single infecting population rather than coinfection with divergent O1 lineages. The amount of single-nucleotide variation decreased from vomit to stool in four patients, increased in two, and remained unchanged in four. The variation in gene presence/absence decreased between vomit and stool in eight patients and increased in two. Pangenome analysis of assembled short-read sequencing demonstrated that the toxin-coregulated pilus operon more frequently contained deletions in genomes from vomit compared to stool. However, these deletions were not detected by PCR or long-read sequencing, indicating that interpreting gene presence or absence patterns from short-read data alone may be incomplete. Overall, we found that O1 isolated from stool is genetically similar to recovered from the upper intestinal tract.
IMPORTANCE
O1, the bacterium that causes cholera, is ingested in contaminated food or water and then colonizes the upper small intestine and is excreted in stool. Shed genomes from stool are usually studied, but isolated from vomit may be more representative of where colonizes in the upper intestinal epithelium. may experience bottlenecks, or large reductions in bacterial population sizes and genetic diversity, as it passes through the gut. Passage through the gut may select for distinct mutants that are adapted for survival and gut colonization. We did not find strong evidence for such adaptive mutations, and instead observed that passage through the gut results in modest reductions in genetic diversity, and only in some patients. These results fill a gap in our understanding of the life cycle, transmission, and evolution.
PubMed: 38916318
DOI: 10.1128/spectrum.00785-24 -
Frontiers in Endocrinology 2024The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or...
OBJECTIVE
The co-occurrence of kidney disease in patients with type 2 diabetes (T2D) is a major public health challenge. Although early detection and intervention can prevent or slow down the progression, the commonly used estimated glomerular filtration rate (eGFR) based on serum creatinine may be influenced by factors unrelated to kidney function. Therefore, there is a need to identify novel biomarkers that can more accurately assess renal function in T2D patients. In this study, we employed an interpretable machine-learning framework to identify plasma metabolomic features associated with GFR in T2D patients.
METHODS
We retrieved 1626 patients with type 2 diabetes (T2D) in Liaoning Medical University First Affiliated Hospital (LMUFAH) as a development cohort and 716 T2D patients in Second Affiliated Hospital of Dalian Medical University (SAHDMU) as an external validation cohort. The metabolite features were screened by the orthogonal partial least squares discriminant analysis (OPLS-DA). We compared machine learning prediction methods, including logistic regression (LR), support vector machine (SVM), random forest (RF), and eXtreme Gradient Boosting (XGBoost). The Shapley Additive exPlanations (SHAP) were used to explain the optimal model.
RESULTS
For T2D patients, compared with the normal or elevated eGFR group, glutarylcarnitine (C5DC) and decanoylcarnitine (C10) were significantly elevated in GFR mild reduction group, and citrulline and 9 acylcarnitines were also elevated significantly (FDR<0.05, FC > 1.2 and VIP > 1) in moderate or severe reduction group. The XGBoost model with metabolites had the best performance: in the internal validate dataset (AUROC=0.90, AUPRC=0.65, BS=0.064) and external validate cohort (AUROC=0.970, AUPRC=0.857, BS=0.046). Through the SHAP method, we found that C5DC higher than 0.1μmol/L, Cit higher than 26 μmol/L, triglyceride higher than 2 mmol/L, age greater than 65 years old, and duration of T2D more than 10 years were associated with reduced GFR.
CONCLUSION
Elevated plasma levels of citrulline and a panel of acylcarnitines were associated with reduced GFR in T2D patients, independent of other conventional risk factors.
Topics: Humans; Diabetes Mellitus, Type 2; Glomerular Filtration Rate; Machine Learning; Male; Female; Middle Aged; Aged; Biomarkers; Metabolomics; Carnitine; Cohort Studies; Diabetic Nephropathies
PubMed: 38915893
DOI: 10.3389/fendo.2024.1279034 -
Frontiers in Neurology 2024The objective of this study was to investigate alterations in functional connectivity density (FCD) mapping and their impact on functional connectivity (FC) among...
PURPOSE
The objective of this study was to investigate alterations in functional connectivity density (FCD) mapping and their impact on functional connectivity (FC) among individuals diagnosed with Type 2 diabetes mellitus (T2DM) across different cognitive states. Moreover, the study sought to explore the potential association between aberrant FCD/FC patterns and clinical or cognitive variables.
METHODS
A total of 211 participants were recruited for this study, consisting of 75 healthy controls (HCs), 89 T2DM patients with normal cognitive function (DMCN), and 47 T2DM patients with mild cognitive impairment (DMCI). The study employed FCD analysis to pinpoint brain regions exhibiting significant FCD alterations. Subsequently, these regions showing abnormal FCD served as seeds for FC analysis. Exploratory partial correlations were conducted to explore the relationship between clinical biochemical indicators, neuropsychological test scores, and altered FCD or FC.
RESULTS
The FCD analysis revealed an increased trend in global FCD (gFCD), local FCD (lFCD), and long-range FCD (lrFCD) within the bilateral supramarginal gyrus (SMG) among individuals with DMCN. Additionally, significant lFCD alterations were observed in the right inferior frontal gyrus and left precuneus when comparing DMCN to HCs and DMCI.
CONCLUSION
When comparing individuals with T2DM and healthy controls (HCs), it was revealed that DMCN exhibited significant improvements in FCD. This suggests that the brain may employ specific compensatory mechanisms to maintain normal cognitive function at this stage. Our findings provide a novel perspective on the neural mechanisms involved in cognitive decline associated with T2DM.
PubMed: 38915801
DOI: 10.3389/fneur.2024.1418714 -
Frontiers in Neurology 2024A common practice in clinical settings is the use of the Epworth Sleepiness Scale (ESS) and apnea-hypopnea index (AHI) to demonstrate the severity of obstructive sleep...
INTRODUCTION
A common practice in clinical settings is the use of the Epworth Sleepiness Scale (ESS) and apnea-hypopnea index (AHI) to demonstrate the severity of obstructive sleep apnea (OSA). However, several instances were noted where there were discrepancies in the reported severity between Epworth scores and AHI in our patient sample, prompting an investigation into whether OSA severity as demonstrated by AHI or predicted by ESS quantification of sleepiness is primarily responsible for inconsistencies.
METHODS
Discrepancies were examined between Epworth scores and AHI by categorizing patients into two categories of inconsistency: individuals with either ESS < 10 and AHI ≥ 15 events/h or ESS ≥ 10 and AHI < 15 events/h. The potential influence of sex on these categories was addressed by assessing whether a significant difference was present between mean Epworth scores and AHI values for men and women in the sample. We investigated BMI both by itself as its own respective variable and with respect to the sex of the individuals, along with a consideration into the role of anxiety. Furthermore, we tested anxiety with respect to sex.
RESULTS
In the first category of inconsistency the average ESS of 5.27 ± 0.33 suggests a normal level of daytime sleepiness. However, this contrasts with the average AHI of 32.26 ± 1.82 events/h which is indicative of severe OSA. In the second category the average ESS of 14.29 ± 0.47 suggests severe daytime sleepiness, contradicting the average AHI of 9.16 ± 0.44 events/h which only indicates mild OSA. Sex, BMI (both as a variable by itself and with respect to sex), and anxiety (both as a variable by itself and with respect to sex) contributed to observed inconsistencies.
CONCLUSION
The findings of our study substantiate our hypothesis that Epworth scores should be de-emphasized in the assessment of OSA and a greater importance should be placed on measures like AHI. While Epworth scores offer insights into patients' daytime sleepiness levels and the perceived severity of their OSA, the inconsistencies highlighted in our results when compared to AHI-based OSA severity underscore their potential inaccuracy. Caution is advised when utilizing Epworth scores for evaluating OSA severity in clinical settings.
PubMed: 38915794
DOI: 10.3389/fneur.2024.1387924 -
BioRxiv : the Preprint Server For... Jun 2024Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated...
INTRODUCTION
Proteome changes associated with APOE4 variant carriage that are independent of Alzheimer's disease (AD) pathology and diagnosis are unknown. This study investigated APOE4 proteome changes in people with AD, mild cognitive impairment, and no impairment.
METHODS
Clinical, APOE genotype, and cerebrospinal fluid (CSF) proteome and AD biomarker data was sourced from the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Proteome profiling was done using supervised machine learning.
RESULTS
We found an APOE4-specific proteome signature that was independent of cognitive diagnosis and AD pathological biomarkers, and increased risk of progression to cognitive impairment. Proteins were enriched in brain regions including the caudate and cortex and cells including endothelial cells, oligodendrocytes, and astrocytes. Enriched peripheral immune cells included T cells, macrophages, and B cells.
DISCUSSION
APOE4 carriers have a unique CSF proteome signature associated with a strong brain and peripheral immune and inflammatory phenotype that likely underlies APOE4 carriers' vulnerability to cognitive decline and AD.
PubMed: 38915547
DOI: 10.1101/2024.04.18.590160 -
BioRxiv : the Preprint Server For... Jun 2024is a key genetic determinant of syndromic and non-syndromic cleft lip and palate. The ability to interrogate post-embryonic requirements of has been hindered, as...
is a key genetic determinant of syndromic and non-syndromic cleft lip and palate. The ability to interrogate post-embryonic requirements of has been hindered, as global ablation in the mouse causes neonatal lethality. Prior work analyzing in mouse models defined its role in the embryonic surface epithelium and periderm where it is required to regulate cell proliferation and differentiation. Several reports have also described gene expression in other cell types, such as muscle, and neuroectoderm. However, analysis of a functional role in non-epithelial cell lineages has been incomplete due to the severity and lethality of the knockout model and the paucity of work with a conditional allele. Here we describe the generation and characterization of a new floxed mouse model and analysis of ablation in periderm and neural crest lineages. This work found that loss of in periderm recapitulates a mild null phenotype, suggesting that -mediated signaling in periderm plays a crucial role in regulating embryonic development. Further, conditional ablation of in neural crest cells resulted in an anterior neural tube defect of variable penetrance. The generation of this conditional allele allows for new insights into craniofacial development and new exploration into the post-natal role of .
PubMed: 38915513
DOI: 10.1101/2024.06.11.598425 -
BioRxiv : the Preprint Server For... Jun 2024ADP-ribosylation, the transfer of ADP-ribose (ADPr) from nico-tinamide adenine dinucleotide (NAD+) groups to proteins, is a conserved post-translational modification...
ADP-ribosylation, the transfer of ADP-ribose (ADPr) from nico-tinamide adenine dinucleotide (NAD+) groups to proteins, is a conserved post-translational modification (PTM) that occurs most prominently in response to DNA damage. ADP-ribosylation is a dynamic PTM regulated by writers (PARPs), erasers (ADPr hy-drolases), and readers (ADPR binders). PARP1 is the primary DNA damage-response writer responsible for adding a polymer of ADPR to proteins (PARylation). Real-time monitoring of PARP1-mediated PARylation, especially in live cells, is critical for under-standing the spatial and temporal regulation of this unique PTM. Here, we describe a genetically encoded FRET probe (pARS) for semi-quantitative monitoring of PARylation dynamics. pARS feature a PAR-binding WWE domain flanked with turquoise and Venus. With a ratiometric readout and excellent signal-to-noise characteristics, we show that pARS can monitor PARP1-dependent PARylation temporally and spatially in real-time. pARS provided unique insights into PARP1-mediated PARylation kinetics in vitro and high-sensitivity detection of PARylation in live cells, even under mild DNA damage. We also show that pARS can be used to determine the potency of PARP inhibitors in vitro and, for the first time, in live cells in response to DNA damage. The robustness and ease of use of pARS make it an important tool for the PARP field.
PubMed: 38915511
DOI: 10.1101/2024.06.11.598597