During the coronavirus disease pandemic, we observed a 6.4-fold increase in typhoid intestinal perforation incidence in Antananarivo, Madagascar. Thirteen perforations occurred within 6 months ...(February 2020-July 2020), compared with 13 perforations during the previous 41 months (August 2016-January 2020). The increase may be attributable to delayed healthcare seeking during the pandemic.
Hallmarks of Aging in the Liver Hunt, Nicholas J.; Kang, Sun Woo (Sophie); Lockwood, Glen P. ...
Computational and Structural Biotechnology Journal,
01/2019, Letnik:
17
Journal Article
Recenzirano
Odprti dostop
While the liver demonstrates remarkable resilience during aging, there is growing evidence that it undergoes all the cellular hallmarks of aging, which increases the risk of liver and systemic ...disease. The aging process in the liver is driven by alterations of the genome and epigenome that contribute to dysregulation of mitochondrial function and nutrient sensing pathways, leading to cellular senescence and low-grade inflammation. These changes promote multiple phenotypic changes in all liver cells (hepatocytes, liver sinusoidal endothelial, hepatic stellate and Küpffer cells) and impairment of hepatic function. In particular, age-related changes in the liver sinusoidal endothelial cells are a significant but under-recognized risk factor for the development of age-related cardiometabolic disease.
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•Liver aging is driven by transcription and metabolic epigenome alterations.•This leads to cellular senescence and low-grade inflammation.•Hepatocyte, sinusoidal endothelial, stellate and Küpffer cells undergoes the hallmarks of aging.•Each cell type demonstrates phenotypical cellular changes with age.
Abstract
Background
Typhoid fever contributes to approximately 135 000 deaths annually. Achievable improvements in household water, sanitation, and hygiene (WASH) combined with vaccination using ...typhoid conjugate vaccines (TCVs) may be an effective preventive strategy. However, little is known about how improved WASH and vaccination interact to lower the risk of typhoid.
Methods
A total of 61 654 urban Bangladeshi children aged 9 months to <16 years, residing in 150 clusters with a baseline population of 205 760 residents, were randomized 1:1 by cluster to Vi-tetanus toxoid TCV or Japanese encephalitis (JE) vaccine. Surveillance for blood culture–confirmed typhoid fever was conducted over 2 years. Existing household WASH status was assessed at baseline as Better or Not Better using previously validated criteria. The reduction in typhoid risk among all residents associated with living in TCV clusters, Better WASH households, or both was evaluated using mixed-effects Poisson regression models.
Results
The adjusted reduced risk of typhoid among all residents living in the clusters assigned to TCV was 55% (95% confidence interval CI, 43%–65%; P < .001), and that of living in Better WASH households, regardless of cluster, was 37% (95% CI, 24%–48%; P < .001). The highest risk of typhoid was observed in persons living in households with Not Better WASH in the JE clusters. In comparison with these persons, those living in households with Better WASH in the TCV clusters had an adjusted reduced risk of 71% (95% CI, 59%–80%; P < .001).
Conclusions
Implementation of TCV programs combined with achievable and culturally acceptable household WASH practices were independently associated with a significant reduction in typhoid risk.
Clinical Trials Registration
ISRCTN11643110.
Better preexisting household water, sanitation, and hygiene and delivering Vi-TT vaccine act independently to reduce typhoid risk, so that the combination of both yields greater protection against typhoid at the population level (71%) than either vaccination (55%) or improved WASH alone (37%).
Abstract
Age-related changes in the liver sinusoidal endothelium, particularly the reduction in fenestrations, contribute to insulin resistance in old age. Metformin impacts on the aging process and ...improves insulin resistance. Therefore, the effects of metformin on the liver sinusoidal endothelium were studied. Metformin increased fenestrations in liver sinusoidal endothelial cells isolated from both young and old mice. Mice administered metformin in the diet for 12 months had increased fenestrations and this was associated with lower insulin levels. The effect of metformin on fenestrations was blocked by inhibitors of AMP-activated protein kinase (AMPK), endothelial nitric oxide synthase, and myosin light chain kinase phosphorylation. Metformin led to increased transgelin expression and structural changes in the actin cytoskeleton but had no effect on lactate production. Metformin also generated fenestration-like structures in SK-Hep1 cells, a liver endothelial cell line, and this was associated with increased ATP, cGMP, and mitochondrial activity. In conclusion, metformin ameliorates age-related changes in the liver sinusoidal endothelial cell via AMPK and endothelial nitric oxide pathways, which might promote insulin sensitivity in the liver, particularly in old age.
The current global initiative to end Cholera by 2030 emphasizes the use of oral cholera vaccine (OCV) combined with feasible household Water-Sanitation-Hygiene (WASH) interventions. However, little ...is known about how improved WASH practices and behaviors and OCV interact to reduce the risk of cholera.
We reanalyzed two arms of a cluster-randomized trial in urban Bangladesh, to evaluate the effectiveness of OCV given as a 2-dose regimen. One arm (30 clusters, n = 94,675) was randomized to vaccination of persons aged one year and older with OCV, and the other arm (30 clusters, n = 80,056) to no intervention. We evaluated the prevention of cholera by household WASH, classified at baseline using a previously validated rule, and OCV over 2 years of follow-up. When analyzed by assignment to OCV clusters rather than receipt of OCV, in comparison to persons living in “Not Better WASH” households in the control clusters, reduction of severe cholera (the primary outcome) was similar for persons in “Not Better WASH” households in vaccine clusters (46%, 95% CI:24,62), for persons in “Better WASH” households in the control clusters (48%, 95% CI:25,64), and for persons in “Better WASH” households in the vaccine clusters (48%, 95% CI:16,67). In contrast, when analyzed by actual receipt of a complete OCV regimen, , in comparison to persons in “Not Better WASH” households in the control clusters, protection against severe cholera increased steadily from 39% (95% CI:13,58) in residents of “Better WASH” households in the control clusters to 57% (95% CI:35,72) in vaccinated persons in “Not Better WASH” households to 63% (95% CI:21,83) in vaccinated persons in “Better WASH” households.
This analysis suggests that improved household WASH and OCV received may interact to provide greater protection against cholera. However, the divergence between findings related to intent to vaccinate versus those pertaining to actual receipt of OCV underscores the need for further research on this topic.
Abstract
Background
An exploratory household transmission study was nested in SPECTRA, the phase 2/3 efficacy study of the adjuvanted recombinant protein-based COVID-19 vaccine SCB-2019. We compared ...the occurrence of confirmed COVID-19 infections between households and household contacts of infected SPECTRA placebo or SCB-2019 recipients.
Methods
SPECTRA participants at 8 study sites in the Philippines who developed real-time reverse transcriptase–polymerase chain reaction (rRT-PCR)–confirmed COVID-19 were contacted by a study team blinded to assignment of index cases to vaccine or placebo groups to enroll in this household transmission study. Enrolled households and household contacts were monitored for 3 weeks using rRT-PCR and anti–SARS-CoV-2 N-antigen IgG/IgM testing to detect new COVID-19 infections.
Results
One hundred fifty-four eligible COVID-19 index cases (51 vaccinees, 103 placebo) were included. The secondary attack rate per household for symptomatic COVID-19 infection was 0.76% (90% CI: .15–3.90%) if the index case was an SCB-2019 vaccinee compared with 5.88% (90% CI: 3.20–10.8%) for placebo index cases, a relative risk reduction (RRR) of 79% (90% CI: −28% to 97%). The RRR of symptomatic COVID-19 per household member was similar: 84% (90% CI: 28–97%). The impact on attack rates in household members if index cases were symptomatic (n = 130; RRR = 80%; 90% CI: 7–96%) or asymptomatic (n = 24; RRR = 100%; 90% CI: −76% to 100%) was measurable but the low numbers undermine the clinical significance.
Conclusions
In this prospective household contact study vaccination with SCB-2019 reduced SARS-CoV-2 transmission compared with placebo in households and in household members independently of whether or not index cases were symptomatic.
A blinded study of household transmission of SARS-CoV-2 conducted as part of a large, randomized efficacy study demonstrated that the adjuvanted recombinant protein-based COVID-19 vaccine SCB-2019 reduced transmission in households and to household contacts of fully vaccinated index cases.
Typhoid fever, or enteric fever, is a highly fatal infectious disease that affects over 9 million people worldwide each year, resulting in more than 110,000 deaths. Reduction in the burden of typhoid ...in low-income countries is crucial for public health and requires the implementation of feasible water, sanitation, and hygiene (WASH) interventions, especially in densely populated urban slums.
In this study, conducted in Mirpur, Bangladesh, we aimed to assess the association between household WASH status and typhoid risk in a training subpopulation of a large prospective cohort (n=98,087), and to evaluate the performance of a machine learning algorithm in creating a composite WASH variable. Further, we investigated the protection associated with living in households with improved WASH facilities and in clusters with increasing prevalence of such facilities during a 2-year follow-up period.
We used a machine learning algorithm to create a dichotomous composite variable ("Better" and "Not Better") based on 3 WASH variables: private toilet facility, safe drinking water source, and presence of water filter. The algorithm was trained using data from the training subpopulation and then validated in a distinct subpopulation (n=65,286) to assess its sensitivity and specificity. Cox regression models were used to evaluate the protective effect of living in "Better" WASH households and in clusters with increasing levels of "Better" WASH prevalence.
We found that residence in households with improved WASH facilities was associated with a 38% reduction in typhoid risk (adjusted hazard ratio=0.62, 95% CI 0.49-0.78; P<.001). This reduction was particularly pronounced in individuals younger than 10 years at the first census participation, with an adjusted hazard ratio of 0.49 (95% CI 0.36-0.66; P<.001). Furthermore, we observed an inverse relationship between the prevalence of "Better" WASH facilities in clusters and the incidence of typhoid, although this association was not statistically significant in the multivariable model. Specifically, the adjusted hazard of typhoid decreased by 0.996 (95% CI 0.986-1.006) for each percent increase in the prevalence of "Better" WASH in the cluster (P=.39).
Our findings demonstrate that existing variations in household WASH are associated with differences in the risk of typhoid in densely populated urban slums. This suggests that attainable improvements in WASH facilities can contribute to enhanced typhoid control, especially in settings where major infrastructural improvements are challenging. These findings underscore the importance of implementing and promoting comprehensive WASH interventions in low-income countries as a means to reduce the burden of typhoid and improve public health outcomes in vulnerable populations.
Background Salmonella enterica serotype Typhi (Salmonella Typhi) causes severe and occasionally life-threatening disease, transmitted through contaminated food and water. Humans are the only ...reservoir, inadequate water, sanitation, and hygiene infrastructure increases risk of typhoid. High-quality data to assess spatial and temporal relationships in disease dynamics are scarce. Methods We analyzed data from a prospective cohort conducted in an urban slum area of Dhaka City, Bangladesh. Passive surveillance at study centers identified typhoid cases by microbiological culture. Each incident case (index case) was matched to two randomly selected index controls, and we measured typhoid incidence in the population residing in a geographically defined region surrounding each case and control. Spatial clustering was evaluated by comparing the typhoid incidence in residents of geometric rings of increasing radii surrounding the index cases and controls over 28 days. Temporal clustering was evaluated by separately measuring incidence in the first and second 14-day periods following selection. Incidence rate ratios (IRRs) were calculated using Poisson regression models. Results We evaluated 141 typhoid index cases. The overall typhoid incidence was 0.44 per 100,000 person-days (PDs) (95% CI: 0.40, 0.49). In the 28 days following selection, the highest typhoid incidence (1.2 per 100,000 PDs 95% CI: 0.8, 1.6) was in the innermost cluster surrounding index cases. The IRR in this innermost cluster was 4.9 (95% CI: 2.4, 10.3) relative to the innermost control clusters. Neither typhoid incidence rates nor relative IRR between index case and control populations showed substantive differences in the first and second 14-day periods after selection. Conclusion In the absence of routine immunization programs, geographic clustering of typhoid cases suggests a higher intensity of typhoid risk in the population immediately surrounding identified cases. Further studies are needed to understand spatial and temporal trends and to evaluate the effectiveness of targeted vaccination in disrupting typhoid transmission.
Tumor heterogeneity is a hallmark of cancer but a challenging problem to dissect mechanistically. Less recognized is that cells within normal tissues are also remarkably diverse. Hepatocytes are a ...great example because their spatial positioning and the local microenvironment govern their genetic heterogeneity. Recent studies show that primary liver tumors display heterogeneity similar to that observed in the normal tissue providing clues to the cellular precursor of the tumor and how variations in the lobule microenvironment support tumor formation and aggressiveness. Identifying the principles that control cellular diversity in a healthy liver may highlight potential mechanisms driving hepatic tumor heterogeneity.
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