Early Aberration Research Articles

Algorithmic Approach to Determination of Epidemic Thresholds in Infectious Disease Surveillance Systems

Introduction: This review is devoted to the algorithmic approach to establishing epidemic thresholds for a wide range of diseases, including influenza and acute respiratory infections. Objective: To compare Russian and foreign approaches to the determination of epidemic thresholds within public health surveillance systems. Materials and methods: To reveal the algorithmic approach to establishing epidemic thresholds in the epidemiological surveillance system, we summarized the results of 14 foreign scientific works and two domestic method guidelines published before December 31, 2023. The literature search was conducted in the eLibrary, CyberLeninka, PubMed, and Google Scholar databases using the keywords “epidemic threshold” and “epidemic”. We compared domestic and foreign algorithms for establishing epidemic thresholds by various characteristics, including the statistical method used, determination of a numerical value of the epidemic threshold, complexity of the algorithm, and the possibility of automating calculations. Results: Here we discuss the classification and comparative characteristics of the basic algorithms for determining epidemic thresholds used in various countries of the world when carrying out epidemiological surveillance (including the syndromic one). We describe the existing methods for establishing and presenting epidemic thresholds, as well as the sequence of steps for performing the Farrington algorithms, the Early Aberration Detection System C1–C3, the Method of Moving Epidemics, the Method of Moving Percentiles, Multi-level identification of increasing activity by indicators taking into account mixed effects, as well as algorithms provided in Russian Method Guidelines MR 3.1.2.0118–17 and MR 3.1.2.0303–22. We also dwell on the problems of development, accuracy assessment and prospects for the implementation of existing and developed algorithms. Conclusions: Current algorithms for establishing epidemic thresholds in epidemiological surveillance systems around the world are diverse; they rely on different statistical methods and vary in complexity. To date, there is no convincing evidence of higher efficiency of any algorithm.

Tumor Predisposing Post-Zygotic Chromosomal Alterations in Bladder Cancer-Insights from Histologically Normal Urothelium.

Bladder urothelial carcinoma (BLCA) is the 10th most common cancer with a low survival rate and strong male bias. We studied the field cancerization in BLCA using multi-sample- and multi-tissue-per-patient protocol for sensitive detection of autosomal post-zygotic chromosomal alterations and loss of chromosome Y (LOY). We analysed 277 samples of histologically normal urothelium, 145 tumors and 63 blood samples from 52 males and 15 females, using the in-house adapted Mosaic Chromosomal Alterations (MoChA) pipeline. This approach allows identification of the early aberrations in urothelium from BLCA patients. Overall, 45% of patients exhibited at least one alteration in at least one normal urothelium sample. Recurrence analysis resulted in 16 hotspots composed of either gains and copy number neutral loss of heterozygosity (CN-LOH) or deletions and CN-LOH, encompassing well-known and new BLCA cancer driver genes. Conservative assessment of LOY showed 29%, 27% and 18% of LOY-cells in tumors, blood and normal urothelium, respectively. We provide a proof of principle that our approach can characterize the earliest alterations preconditioning normal urothelium to BLCA development. Frequent LOY in blood and urothelium-derived tissues suggest its involvement in BLCA.

Deep Learning Concept for Early Dental Caries Detection

Identifying dental caries in a dental operatory can be challenging for pediatric dentists at times because of the fluctuating features of the lesions based on their developmental stage. Thus, pediatric dentists can suggest specific and unique treatment methods. Noninvasive interventions, such as fluoride therapy and sugar control, can successfully reverse and treat early aberrations, sometimes referred to as white spots. Dental cavities, on the other hand, lead to tooth structure deterioration and require restorative treatments of varying levels of difficulty, depending on the extent and severity of the damage that leads to the extraction of the tooth itself. These necessitate new concepts for detecting dental caries in children. The prospective review's objective was to determine the necessity of applying deep learning and contemporary principles in the diagnosis of early childhood caries.

Comparison of statistical methods for the early detection of disease outbreaks in small population settings

ObjectivesThis study examines the performance of 6 aberration detection algorithms for the early detection of disease outbreaks in small population settings using syndrome-based early warning surveillance data collected by the Pacific Syndromic Surveillance System (PSSS). Although previous studies have proposed statistical methods for detecting aberrations in larger datasets, there is limited knowledge about how these perform in the presence of small numbers of background cases. MethodsTo address this gap a simulation model was developed to test and compare the performance of the 6 algorithms in detecting outbreaks of different magnitudes, durations, and case distributions. ResultsThe study found that while the Early Aberration Reporting System–C1 algorithm developed by Hutwagner et al. outperformed others, no single approach provided reliable monitoring across all outbreak types. Furthermore, aberration detection approaches could only detect very large and acute outbreaks with any reliability. ConclusionThe findings of this study suggest that algorithm-based approaches to outbreak signal detection perform poorly when applied to settings with small numbers of background cases and should not be relied upon in these contexts. This highlights the need for alternative approaches for accurate and timely outbreak detection in small population settings, particularly those that are resource-constrained.

Inflammatory mediator-induced bystander effects and genomic instability: role of tissue-specificity

Much evidence showed that radiation-induced inflammation can cause cellular damage in direct irradiated and bystander cells, which are in vicinity of irradiated cells underlying radiation-induced bystander effects (BE). As well as radiation-induced genomic instability (GI) is observed within the progeny of irradiated and bystander cells as a delayed damage responses. This study tried to mimic the effects of radiation-induced GI and BE by exploring the inflammatory effect of lipopolysaccharide (LPS) on human primary fibroblast (HF 19) and umbilical vein endothelial (HUVEC) cells. To prove the principles of LPS can cause DNA damage in HF 19; cells were treated with 1 μg/ml LPS, and BE was induced by media transfer. Comet assay was used to estimate DNA damage in the direct treated and bystander cells. The early DNA damage result was significantly observed in the direct treated and bystander HF 19 cells. However, these cells did not show a significant delayed DNA damage within their progeny. Comet data showed that LPS frequently induced only initial DNA damage in HF 19 cells. The experiment was repeated utilising HF 19 and HUVEC cells, in order to investigate whether LPS could be involved in the induction of GI in a tissue-specificity manner. Both HF 19 and HUVEC cells were treated with 1 μg/ml LPS. BE was also induced by media transfer. Chromosomal analysis was used for early and late chromosomal damage estimation. Data showed that LPS treatment could significantly cause early chromosomal aberrations in the direct treated and bystander HF 19 and HUVEC cells. However, delayed chromosomal instability was observed only in the direct treated HUVEC cells. Our finding suggested that LPS frequently induced BE in HF 19 and HUVEC cells, which could be mediated by pro-inflammatory cytokines that stimulated by LPS treatment. Moreover, LPS could be involved in the GI induction in a tissue-specificity manner.Keywords:

Immediate and Delayed Salivary Cytokine Responses during Repeated Exposures to Cold Pressor Stress

Introduction: Excessive stress is increasingly recognized as an important trigger of many diseases prevalent in modern societies, and monitoring such stress-related effects could aid prevention. The measurement of salivary markers of inflammation is emerging as a promising tool to non-invasively quantify stress’ effects on immune processes in everyday life and thereby detect early aberrations before the manifestation of serious health problems. However, more laboratory-controlled research is needed in order to establish the timescale and determinants of salivary cytokine responses to acute stress. Methods: We repeatedly exposed participants to Cold Pressor Stress Test (CPT) or a control procedure and measured a wide array of salivary cytokines as well as subjective, cardiovascular, and cortisol stress reactions. CPT exposure was repeated every 15 min, 3 times in total, with a duration of 3 min each. Saliva was sampled immediately after the first two exposures as well as in 15-min intervals until 60 min after the onset of the first intervention. Results: We found that many cytokines were detectable in saliva. Specific stress effects were limited to IL-8 and IL-6, however, which decreased immediately or 15 min after stress onset, respectively. Moreover, IL-8 was negatively correlated to cortisol output in the stress but not in the control group. Significant increases were also observed in salivary TNFα and IFNγ; however, these effects were similar under both stress and control conditions. Discussion: Our results show that particular salivary cytokines may be sensitive to immediate effects of acute CPT-induced stress and also highlight the importance of employing control procedures to discern stress effects from unrelated variations in salivary cytokines.

Points of divergence on a bumpy road: early development of brain and immune threat processing systems following postnatal adversity.

Lifelong indices of maladaptive behavior or illness often stem from early physiological aberrations during periods of dynamic development. This is especially true when dysfunction is attributable to early life adversity (ELA), when the environment itself is unsuitable to support development of healthy behavior. Exposure to ELA is strongly associated with atypical sensitivity and responsivity to potential threats-a characteristic that could be adaptive in situations where early adversity prepares individuals for lifelong danger, but which often manifests in difficulties with emotion regulation and social relationships. By synthesizing findings from animal research, this review will consider threat sensitivity through the lenses of associated corticolimbic brain circuitry and immune mechanisms, both ofwhich are immature early in life to maximize adaptation for protection against environmental challenges to an individual's well-being. The forces that drive differential development of corticolimbic circuits include caretaking stimuli, physiological and psychological stressors, and sex, which influences developmental trajectories. These same forces direct developmental processes of the immune system, which bidirectionally communicates with sensory systems and emotion regulation circuits within the brain. Inflammatory signals offer a further force influencing the timing and nature of corticolimbic plasticity, while also regulating sensitivity to future threats from the environment (i.e., injury or pathogens). The early development of these systems programs threat sensitivity through juvenility and adolescence, carving paths for probable function throughout adulthood. To strategize prevention or management of maladaptive threat sensitivity in ELA-exposed populations, it is necessary to fully understand these early points of divergence.

Cerebrospinal Fluid Neurofilament Light Predicts Risk of Dementia Onset in Cognitively Healthy Individuals and Rate of Cognitive Decline in Mild Cognitive Impairment: A Prospective Longitudinal Study.

Background: Biomarkers that are indicative of early biochemical aberrations are needed to predict the risk of dementia onset and progression in Alzheimer’s disease (AD). We assessed the utility of cerebrospinal fluid (CSF) neurofilament light (NfL) chain for screening preclinical AD, predicting dementia onset among cognitively healthy (CH) individuals, and the rate of cognitive decline amongst individuals with mild cognitive impairment (MCI). Methods: Neurofilament light levels were measured in CSF samples of participants (CH, n = 154 and MCI, n = 32) from the Australian Imaging, Biomarkers and Lifestyle study of ageing (AIBL). Cases of preclinical AD were identified using biomarker-guided classification (CH, amyloid-β [Aβ]+, phosphorylated-tau [P-tau]+ and total-tau [T-tau]±; A+T+/N±). The prediction of dementia onset (questionable dementia) among CH participants was assessed as the risk of conversion from Clinical Dementia Rating [CDR = 0] to CDR ≥ 0.5 over 6 years. Mixed linear models were used to assess the utility of baseline CSF NfL levels for predicting the rate of cognitive decline among participants with MCI over 4.5 years. Results: Neurofilament light levels were significantly higher in preclinical AD participants (CH, A+T+/N±) as compared to A-T-N- (p < 0.001). Baseline levels of CSF NfL were higher in CH participants who converted to CDR ≥ 0.5 over 6 years (p = 0.045) and the risk of conversion to CDR ≥ 0.5 was predicted (hazard ratio [HR] 1.60, CI 1.03–2.48, p = 0.038). CH participants with CSF NfL > cut-off were at a higher risk of developing dementia (HR 4.77, CI 1.31–17.29, p = 0.018). Participants with MCI and with higher baseline levels of CSF NfL (>median) had a higher rate of decline in cognition over 4.5 years. Conclusion: An assessment of CSF NfL levels can help to predict dementia onset among CH vulnerable individuals and cognitive decline among those with MCI.

Young Adults with a Parent with Dementia Show Early Abnormalities in Brain Activity and Brain Volume in the Hippocampus: A Matched Case-Control Study.

Having a parent with Alzheimer’s disease (AD) and related dementias confers a risk for developing these types of neurocognitive disorders in old age, but the mechanisms underlying this risk are understudied. Although the hippocampus is often one of the earliest brain regions to undergo change in the AD process, we do not know how early in the lifespan such changes might occur or whether they differ early in the lifespan as a function of family history of AD. Using a rare sample, young adults with a parent with late-onset dementia, we investigated whether brain abnormalities could already be detected compared with a matched sample. Moreover, we employed simple yet novel techniques to characterize resting brain activity (mean and standard deviation) and brain volume in the hippocampus. Young adults with a parent with dementia showed greater resting mean activity and smaller volumes in the left hippocampus compared to young adults without a parent with dementia. Having a parent with AD or a related dementia was associated with early aberrations in brain function and structure. This early hippocampal dysfunction may be due to aberrant neural firing, which may increase the risk for a diagnosis of dementia in old age.

Joint-Tissue Integrative Analysis Identified Hundreds of Schizophrenia Risk Genes.

Genome-wide association studies (GWAS) have identified a large number of schizophrenia risk variants, and most of them are mapped to noncoding regions. By leveraging multiple joint-tissue gene expression data and GWAS data, we herein performed a transcriptome-wide association study (TWAS) and Mendelian randomization (MR) analysis and identified 144 genes whose mRNA levels were related to genetic risk of schizophrenia. Most of these genes exhibited diametrically opposite trends of expression in prenatal and postnatal brain tissues, despite that their expression levels in dorsolateral prefrontal cortex (DLPFC) tissues did not significantly differ between schizophrenics and healthy controls. We then found significant enrichment of these genes in dopamine-related pathways that were repeatedly implicated in schizophrenia pathogenesis and in the action of antipsychotic drugs. Gene expression analysis using single cell RNA-sequencing (scRNA-seq) data of mid-gestation fetal brains further revealed enrichment of these genes in glutamatergic excitatory neurons and cycling progenitors. These lines of evidence, in consistency with previous findings, confirmed the polygenic nature of schizophrenia and highlighted involvement of early neurodevelopment aberrations in this disorder. Further investigations using advanced algorithms in both bulk brain tissues and in single cells and at different developmental stages are necessary to characterize transcriptomic features of schizophrenia pathogenesis along brain development.

Effects of SMILE and FS-LASIK on early postoperative corneal higher order aberrations in patients with high myopia

Effects of SMILE and FS-LASIK on early postoperative corneal higher order aberrations in patients with high myopia

Distinct Outcome Based on Fusion Transcript in t(16;21) Rearranged Pediatric AML, a Collaborative Retrospective Analysis By the I-BFM SG

Despite the use of of intensive chemotherapy, and allogeneic stem cell transplant (HSCT) in selected cases, children with acute myeloid leukemia (AML) have 5-year overall survival (OS) rates of ~65%. Apart from early clinical response, cytogenetic and molecular aberrations are the most reliable prognostic factors for survival. Identifying prognostic subgroups to stratify patients for treatment in future trials is clinically important. The study of rare AML subtypes can be facilitated by international collaborations. AML with t(16;21) rearrangements includes 2 different translocations: t(16;21)(p11;q22) resulting in the FUS-ERG fusion, and t(16;21)(q24;q22) resulting in the RUNX1-CBFA2T3 fusion.To study outcomes and associated prognostic factors, clinical data from children with t(16;21) AML were collected from 14 study groups participating in the international Berlin-Frankfurt-Munster (I-BFM) network. Patients (age 0-18 years) diagnosed from January 1, 1995, to January 1, 2016, were included. The AML-BFM study group provided data from 1326 unselected patients diagnosed between 1997 and 2013 as a reference cohort. All karyotypes were centrally reviewed by 2 independent cytogeneticists according to the International System for Human Cytogenetic Nomenclature (ISCN 2005). Patients with inconclusive karyotypes were screened by reverse-transcription PCR. Chi-squared and Fisher exact tests were used to compare clinical characteristics. OS and event free survival (EFS) analysis was performed by the Kaplan-Meier method. Cumulative incidence of relapse (CIR) was calculated according to Kalbfleisch and Prentice. The Cox proportional hazards model was used for multivariate analysis, considering as covariables age, white blood cell (WBC) count at diagnosis, cytogenetic risk group and allogeneic hematopoietic stem cell transplantation (HSCT) as time-dependent variable.There were 54 patients with t(16;21): 32 with FUS-ERG and 22 with RUNX1-CBFA2T3 . There were no significant differences in sex and age between patients in the FUS-ERG- or RUNX1-CBFA2T3- groups and the reference cohort. Median WBC at diagnosis was significantly lower for patients with RUNX1-CBFA2T3 (12.5×109/L, range 0.01-185×109/L) than for the reference cohort (19.4×109/L, range 0.01-1900×109/L, P=0.030). Patients with FUS-ERG had no predominant French-American-British (FAB) type, whereas 76.4% of those with RUNX1-CBFA2T3 had a granulocytic FAB type (M1, M2) compared with 42.1% in the reference cohort (P=0.004).The 4-year EFS, OS, and CIR for the reference cohort were 51% [standard error (SE)=1%], 68% (SE=1%), and 32% (SE=1%), respectively. Median follow up for survivors in the t(16;21) cohort was 1.6 years for those with FUS-ERG and 5.0 years for RUNX1-CBFA2T3 . Patients with FUS-ERG had a 4-year EFS of 7% (SE=5%, P <0.0001), 4-year OS of 21% (SE=8%, P <0.0001), and CIR of 74% (SE=8%, P <0.0001). Patients with RUNX1-CBFA2T3 had a 4-year EFS of 77% (SE=9%, P=0.06), OS of 81% (SE=8%, P=0.34) and a CIR of 0%. When patients in the reference cohort were classified in SR patients comprising (inv(16)/t(8;21), and HR patients comprising other cytogenetic subtypes excluding t(16;21), EFS rates were 74% (SE=3%) and 45% (SE=2%), respectively (Fig. 1). Hence, patients with RUNX1-CBFA2T3 had a similar outcomes as SR patients (Figure 1). In multivariate analysis, presence of FUS-ERG and RUNX1-CBFA2T3 were independent risk factors for EFS, with hazard ratios of 1.93 (P <0.0001) and 0.325 (P=0.025), respectively. HSCT was performed in 14 (45.2%) patients with FUS-ERG in first complete remission (CR1). The 4-year EFS for transplanted patients was 15% (SE=15%) compared with 0% (SE=13%) for patients receiving chemotherapy only (p=NS).We identified 2 clinically relevant, distinct subtypes of pediatric AML patients with different t(16;21) rearrangements: FUS-ERG had poor outcomes, whereas RUNX1-CBFA2T3 had favorable outcomes. Patients with RUNX1-CBFA2T3 -rearranged AML might benefit from inclusion in the SR group and receiving less intensive treatment, whereas those with FUS-ERG rearranged AML should be stratified in the HR group. In this study, only patients with FUS-ERG receiving HSCT in CR1 did not relapse. Most current pediatric AML trials consider children with a 5-year OS below 25%-30% for HSCT in CR1. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Microvascular degeneration occurs before plaque onset and progresses with age in 3xTg AD mice

Heart disease and vascular disease positively correlate with the incidence of Alzheimer's disease (AD). Although there is ostensible involvement of dysfunctional cerebrovasculature in AD pathophysiology, the characterization of the specific changes and development of vascular injury during AD remains unclear. In the present study, we established a time-course for the structural changes and degeneration of the angioarchitecture in AD. We used cerebrovascular corrosion cast and µCT imaging to evaluate the geometry, topology, and complexity of the angioarchitecture in the brain of wild type and 3xTg AD mice. We hypothesized that changes to the microvasculature occur early during the disease, and these early identifiable aberrations would be more prominent in the brain subregions implicated in the cognitive decline of AD. Whole-brain analysis of the angioarchitecture indicated early morphological abnormalities and degeneration of microvascular networks in 3xTg AD mice. Our analysis of the hippocampus and cortical subregions revealed microvascular degeneration with onset and progression that was subregion dependent.

Comparing malaria early detection methods in a declining transmission setting in northwestern Ethiopia

BackgroundDespite remarkable progress in the reduction of malaria incidence, this disease remains a public health threat to a significant portion of the world’s population. Surveillance, combined with early detection algorithms, can be an effective intervention strategy to inform timely public health responses to potential outbreaks. Our main objective was to compare the potential for detecting malaria outbreaks by selected event detection methods.MethodsWe used historical surveillance data with weekly counts of confirmed Plasmodium falciparum (including mixed) cases from the Amhara region of Ethiopia, where there was a resurgence of malaria in 2019 following several years of declining cases. We evaluated three methods for early detection of the 2019 malaria events: 1) the Centers for Disease Prevention and Control (CDC) Early Aberration Reporting System (EARS), 2) methods based on weekly statistical thresholds, including the WHO and Cullen methods, and 3) the Farrington methods.ResultsAll of the methods evaluated performed better than a naïve random alarm generator. We also found distinct trade-offs between the percent of events detected and the percent of true positive alarms. CDC EARS and weekly statistical threshold methods had high event sensitivities (80–100% CDC; 57–100% weekly statistical) and low to moderate alarm specificities (25–40% CDC; 16–61% weekly statistical). Farrington variants had a wide range of scores (20–100% sensitivities; 16–100% specificities) and could achieve various balances between sensitivity and specificity.ConclusionsOf the methods tested, we found that the Farrington improved method was most effective at maximizing both the percent of events detected and true positive alarms for our dataset (> 70% sensitivity and > 70% specificity). This method uses statistical models to establish thresholds while controlling for seasonality and multi-year trends, and we suggest that it and other model-based approaches should be considered more broadly for malaria early detection.

Multiregional assessment of CIMP in primary colorectal cancers: Phenotype concordance but marker variability.

Intratumor heterogeneity of colorectal cancers (CRCs) is manifested both at the genomic and epigenomic levels. Early genetic aberrations in carcinogenesis are clonal and present throughout the tumors, but less is known about the heterogeneity of the epigenetic CpG island methylator phenotype (CIMP). CIMP characterizes a subgroup of CRCs thought to originate from specific precursor lesions, and it is defined by widespread DNA methylation within promoter regions. In this work, we investigated CIMP in two to four multiregional samples from 30 primary tumors (n = 86 samples) using the consensus Weisenberger gene panel (CACNA1G, IGF2, NEUROG1, RUNX3 and SOCS1). Twenty‐nine of 30 tumors (97%) showed concordant CIMP status in all samples, and percent methylated reference (PMR) values of all five markers had higher intertumor than intratumor variation (P value = 1.5e−09). However, a third of the CIMP+ tumors exhibited discrepancies in methylation status in at least one of the five gene markers. To conclude, CIMP status was consistent within primary CRCs, and it is likely a clonal phenotype. However, spatial discordances of the individual genes suggest that large‐scale analysis of multiregional samples could be of interest for identifying CIMP markers that are robust to intratumor heterogeneity.

Alpha lipoic acid attenuates ER stress and improves glucose uptake through DNAJB3 cochaperone

Persistent ER stress, mitochondrial dysfunction and failure of the heat shock response (HSR) are fundamental hallmarks of insulin resistance (IR); one of the early core metabolic aberrations that leads to type 2 diabetes (T2D). The antioxidant α-lipoic acid (ALA) has been shown to attenuate metabolic stress and improve insulin sensitivity in part through activation of the heat shock response (HSR). However, these studies have been focused on a subset of heat shock proteins (HSPs). In the current investigation, we assessed whether ALA has an effect on modulating the expression of DNAJB3/HSP40 cochaperone; a potential therapeutic target with a novel role in mitigating metabolic stress and promoting insulin signaling. Treatment of C2C12 cells with 0.3 mM of ALA triggers a significant increase in the expression of DNAJB3 mRNA and protein. A similar increase in DNAJB3 mRNA was also observed in HepG2 cells. We next investigated the significance of such activation on endoplasmic reticulum (ER) stress and glucose uptake. ALA pre-treatment significantly reduced the expression of ER stress markers namely, GRP78, XBP1, sXBP1 and ATF4 in response to tunicamycin. In functional assays, ALA treatment abrogated significantly the tunicamycin-mediated transcriptional activation of ATF6 while it enhanced the insulin-stimulated glucose uptake and Glut4 translocation. Silencing the expression of DNAJB3 but not HSP72 abolished the protective effect of ALA on tunicamycin-induced ER stress, suggesting thus that DNAJB3 is a key mediator of ALA-alleviated tunicamycin-induced ER stress. Furthermore, the effect of ALA on insulin-stimulated glucose uptake is significantly reduced in C2C12 and HepG2 cells transfected with DNAJB3 siRNA. In summary, our results are supportive of an essential role of DNAJB3 as a molecular target through which ALA alleviates ER stress and improves glucose uptake.

Epigenetic Changes in Islets of Langerhans Preceding the Onset of Diabetes.

The identification of individuals with a high risk of developing type 2 diabetes (T2D) is fundamental for prevention. Here, we used a translational approach and prediction criteria to identify changes in DNA methylation visible before the development of T2D. Islets of Langerhans were isolated from genetically identical 10-week-old female New Zealand Obese mice, which differ in their degree of hyperglycemia and in liver fat content. The application of a semiexplorative approach identified 497 differentially expressed and methylated genes (P = 6.42e-09, hypergeometric test) enriched in pathways linked to insulin secretion and extracellular matrix-receptor interaction. The comparison of mouse data with DNA methylation levels of incident T2D cases from the prospective European Prospective Investigation of Cancer (EPIC)-Potsdam cohort, revealed 105 genes with altered DNA methylation at 605 cytosine-phosphate-guanine (CpG) sites, which were associated with future T2D. AKAP13, TENM2, CTDSPL, PTPRN2, and PTPRS showed the strongest predictive potential (area under the receiver operating characteristic curve values 0.62–0.73). Among the new candidates identified in blood cells, 655 CpG sites, located in 99 genes, were differentially methylated in islets of humans with T2D. Using correction for multiple testing detected 236 genes with an altered DNA methylation in blood cells and 201 genes in diabetic islets. Thus, the introduced translational approach identified novel putative biomarkers for early pancreatic islet aberrations preceding T2D.

DOT: a crowdsourcing Mobile application for disease outbreak detection and surveillance in Mauritius.

Early detection of disease outbreaks is crucial and even small improvements in detection can significantly impact on a country’s public health. In this work, we investigate the use of a crowdsourcing application and a real-time disease outbreak surveillance system for five diseases; Influenza, Gastroenteritis, Upper Respiratory Tract Infection (URTI), Scabies and Conjunctivitis, that are closely monitored in Mauritius. We also analyze and correlate the collected data with past statistics. A crowdsourcing mobile application known as Disease Outbreak Tracker (DOT) was implemented and made public. A real-time disease surveillance system using the Early Aberration Reporting System algorithm (EARS) for analysis of the collected data was also implemented. The collected data were correlated to historical data for 2017. Data were successfully collected and plotted on a daily basis. The results show that a few cases of Flu and Scabies were reported in some districts. The EARS methods C1, C2 and C3 also depicted spikes above the set threshold on some days. The study covers data collected over a period of one month. Once symptoms data were collected using DOT, probabilistic methods were used to find the disease or diseases that the user was suffering from. The data were further processed to find the extent of the disease outbreak district-wise, per disease. These data were represented graphically for a rapid understanding of the situation in each district. Our findings concur with existing data for the same period for previous years showing that the crowdsourcing application can aid in the detection of disease outbreaks.

Alpha Lipoic Acid Attenuates ER Stress and Improves Glucose Uptake Through DNAJB3 Cochaperone

Persistent ER stress, mitochondrial dysfunction and failure of the heat shock response (HSR) are fundamental hallmarks of insulin resistance (IR); one of the early core metabolic aberrations that leads to type 2 diabetes (T2D). The antioxidant α‐lipoic acid (ALA) has been shown to attenuate metabolic stress and improve insulin sensitivity in part through activation of the heat shock response (HSR). However, these studies have been focused on a subset of heat shock proteins (HSPs). In the current investigation, we assessed whether ALA has an effect on modulating the expression of DNAJB3/HSP40 cochaperone; a potential therapeutic target with a novel role in mitigating metabolic stress and promoting insulin signaling. Treatment of C2C12 cells with 0.3 mM of ALA triggers a significant increase in the expression of DNAJB3 mRNA and protein. A similar increase in DNAJB3 mRNA was also observed in HepG2 cells. We next investigated the significance of such activation on endoplasmic reticulum (ER) stress and glucose uptake. ALA pre‐treatment significantly reduced the expression of ER stress markers namely, GRP78, XBP1, sXBP1 and ATF4 in response to both tunicamycin and glucolipotoxicity. In functional assays, ALA treatment abrogated significantly the tunicamycin‐mediated transcriptional activation of ATF6 while it enhanced the insulin‐stimulated glucose uptake. Silencing the expression of DNAJB3 but not HSP72 abolished the protective effect of ALA on tunicamycin‐induced ER stress, suggesting thus that DNAJB3 is a key mediator of ALA‐alleviated tunicamycin‐induced ER stress. Furthermore, the effect of ALA on insulin‐stimulated glucose uptake is reduced significantly in C2C12 cells transfected with DNAJB3 siRNA.In summary, our results are supportive of an essential role of DNAJB3 as a molecular target through which ALA alleviates ER stress and improve glucose uptake.Support or Funding InformationThis work was supported by Qatar Biomedical Research Institute, Hamad Bin Khalifa University intramural grant (IGP 2014‐001) to MD

Lean back and wait for the alarm? Testing an automated alarm system for nosocomial outbreaks to provide support for infection control professionals.

IntroductionOutbreaks of communicable diseases in hospitals need to be quickly detected in order to enable immediate control. The increasing digitalization of hospital data processing offers potential solutions for automated outbreak detection systems (AODS). Our goal was to assess a newly developed AODS.MethodsOur AODS was based on the diagnostic results of routine clinical microbiological examinations. The system prospectively counted detections per bacterial pathogen over time for the years 2016 and 2017. The baseline data covers data from 2013–2015. The comparative analysis was based on six different mathematical algorithms (normal/Poisson and score prediction intervals, the early aberration reporting system, negative binomial CUSUMs, and the Farrington algorithm). The clusters automatically detected were then compared with the results of our manual outbreak detection system.ResultsDuring the analysis period, 14 different hospital outbreaks were detected as a result of conventional manual outbreak detection. Based on the pathogens’ overall incidence, outbreaks were divided into two categories: outbreaks with rarely detected pathogens (sporadic) and outbreaks with often detected pathogens (endemic). For outbreaks with sporadic pathogens, the detection rate of our AODS ranged from 83% to 100%. Every algorithm detected 6 of 7 outbreaks with a sporadic pathogen. The AODS identified outbreaks with an endemic pathogen were at a detection rate of 33% to 100%. For endemic pathogens, the results varied based on the epidemiological characteristics of each outbreak and pathogen.ConclusionAODS for hospitals based on routine microbiological data is feasible and can provide relevant benefits for infection control teams. It offers in-time automated notification of suspected pathogen clusters especially for sporadically occurring pathogens. However, outbreaks of endemically detected pathogens need further individual pathogen-specific and setting-specific adjustments.