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© 2019 Elsevier Ltd Whilst humans evolved in the earth's Electro-Magnetic-Field (EMF) and sun-light, both being essential to life but too much sun and we burn. What happens if background EMF rise to critical levels, coinciding with increasing environmental pollutants? Two of the authors can look back over 50 clinical years and appreciate the profound changes in human morbidity across a range of disparate conditions – autoimmune diseases, asthma, earlier cancer incidence and reduced male sperm counts. In particular have been increased autism, dyslexia, Attention Deficit Hyperactivity Disorder and neurological diseases, such as Amyotrophic Lateral Sclerosis, Multiple Sclerosis, Parkinson's Disease, Early Onset Dementia, Multiple System Atrophy and Progressive Supranuclear Palsy. What might have caused these changes-whilst genetic factors are taken as given, multiple environmental pollutants are associated with neurological disease although the mechanisms are unclear. The pace of increased neurological deaths far exceeds any Gompertzian explanation - that because people are living longer they are more likely to develop more age-related problems such as neurological disease. Using WHO global mortality categories of Neurological Disease Deaths (NDD) and Alzheimer's and Dementia deaths (Alz), updated June 2018, together they constitute Total Neurological Mortality (TNM), to calculate mortality rates per million for people aged 55–74 and for the over-75's in twenty-one Western countries. Recent increases in American people aged over-75's rose 49% from 1989 to 2015 but US neurological deaths increased five-fold. In 1989 based on Age-Standardised-Deaths-Rates America USA was 17th at 324 pm but rising to 539 pm became second highest. Different environmental/occupational factors have been found to be associated with neuro-degenerative diseases, including background EMF. We briefly explore how levels of EMF interact upon the human body, which can be described as a natural antennae and provide new evidence that builds upon earlier research to propose the following hypothesis. Based upon recent and new evidence we hypothesise that a major contribution for the relative sudden upsurge in neurological morbidity in the Western world (1989–2015), is because of increased background EMF that has become the tipping point-impacting upon any genetic predisposition, increasing multiple-interactive pollutants, such as rises in petro-chemicals, hormone disrupting chemicals, industrial, agricultural and domestic chemicals. The unprecedented neurological death rates, all within just twenty-five years, demand a re-examination of long-term EMF safety related to the increasing background EMF on human health. We do not wish to 'stop the modern world’, only make it safer.

Streptococcus suis (S. suis) is an important zoonotic pathogen that causes huge economic losses in the pig industry, as well as severe illness and even death in humans. The outbreak of human infection of S. suis in China in 2005 led to significant human morbidity and death, prompting an increase in global studies of S. suis. In recent years, important advances have been made regarding the etiology, genomics, excavation of virulence genes, and vaccine research in S. suis. A number of countries and regions have identified their predominantly serotypes. The development of genome sequencing technology has laid an important foundation for the study of pathogenic mechanisms. For example, 89K PAI was found in representative virulence strains in China, and several studies have been carried out to confirm multiple genes which carries are closely related to virulence. Also, the functions of some regulatory genes represented by the two-component signal transduction system have been analyzed. The development of inactivated vaccines, natural avirulent vaccines, gene-deletion attenuated vaccines, subunit vaccines, and glycoconjugate vaccines have greatly contributed to the prevention and control of the disease in the future. This article aims to summarize the research progress to provide directions for future research and the prevention of S. suis.

SummaryAberrant macrophage activation during intracellular infection generates important immunopathologies that can cause severe human morbidity. A better understanding of microbial immune subversion strategies and macrophage phenotypic and functional responses is a prerequisite for the design of novel, host-directed intervention strategies. Here, we uncover a fine-tuned transcriptional response induced in primary macrophages infected by the human parasite Leishmania amazonensis that prevents NF-κB and NLRP3 inflammasome activation. This unusual subversion is characterized by respectively suppression and induction of activating and de-activating components of the NF-κB and NLRP3 pathways. This dichotomic modulation was associated with histone H3 hypoacetylation at promoters of NF-κB-related, pro-inflammatory genes. Our results reveal a novel Leishmania immune subversion strategy targeting host cell epigenetic regulation to modulate the macrophage phenotype. Modulation of the macrophage epigenetic landscape establishes conditions beneficial for intracellular parasite survival, and opens interesting new venues for host-directed, anti-microbial drug discovery.

INTRODUCTION:Hantaviruses are a group of globally distributed rodent-associated viruses, some of which are responsible for human morbidity and mortality. Sin Nombre orthohantavirus, a particularly virulent species of hantavirus associated with Peromyscus spp. mice, is actively monitored by the Department of Public Health in California (CDPH). Recently, CDPH documented high (40%) seroprevalence in a potentially novel reservoir species, the cactus mouse (Peromyscus eremicus) in Death Valley National Park. METHODS:This study was performed in the extremely isolated Mojave Desert Amargosa River valley region of southeastern Inyo County, California, 105 km from Death Valley, approximately over the same time interval as the CDPH work in Death Valley (between 2011 and 2016). Similar rodent species were captured as in Death Valley and were tested for select hantaviruses using serology and RT-PCR to assess risk to human health and the conservation of the endemic endangered Amargosa vole. RESULTS:Among 192 rodents tested, including 56 Peromyscus spp., only one seropositive harvest mouse (Reithrodontomys megalotis) was detected. DISCUSSION:These data highlight the heterogeneity in the prevalence of hantavirus infection even among nearby desert communities and suggest that further studies of hantavirus persistence in desert environments are needed to more accurately inform the risks to public health and wildlife conservation.

Background Wound infections are responsible for significant human morbidity and mortality worldwide. Specifically, surgical site infections are the third most commonly reported nosocomial infections accounting approximately a quarter of such infections. This systematic review and meta-analysis is, therefore, aimed to determine microbial profiles cultured from wound samples and their antimicrobial resistance patterns in Ethiopia. Methods Literature search was carried out through visiting electronic databases and indexing services including PubMed, MEDLINE, EMBASE, CINAHL, and Google Scholar. Original records, available online from 2000 to 2018, addressing the research question and written in English were identified and screened. The relevant data were extracted from included studies using a format prepared in Microsoft Excel and exported to STATA 15.0 software for analyses of outcome measures and subgrouping. Der-Simonian-Laird’s random effects model was applied for pooled estimation of outcome measures at 95% confidence level. Comprehensive meta-analysis version-3 software was used for assessing publication bias across studies. The study protocol is registered on PROSPERO with reference number ID: CRD42019117638. Results A total of 21 studies with 4284 wound samples, 3012 positive wound cultures and 3598 bacterial isolates were included for systematic review and meta-analysis. The pooled culture positivity was found to be 70.0% (95% CI: 61, 79%). Regarding the bacterial isolates recovered, the pooled prevalence of S. aureus was 36% (95% CI: 29, 42%), from which 49% were methicillin resistant strains. The pooled estimate of E. coli isolates was about 13% (95% CI: 10, 16%) followed by P. aeruginosa, 9% (95% CI: 6, 12%), K. pneumoniae, 9% (95% CI: 6, 11%) and P. mirabilis, 8% (95% CI: 5, 11%). Compared to other antimicrobials, S. aureus has showed lower estimates of resistance against ciprofloxacin, 12% (95% CI: 8, 16%) and gentamicin, 13% (95% CI: 8, 18%). E. coli isolates exhibited the highest point estimate of resistance towards ampicillin (P = 84%; 95% CI: 76, 91%). Gentamicin and ciprofloxacin showed relatively lower estimates of resistance with pooled prevalence being 24% (95% CI: 16, 33%) and 27% (95% CI: 16, 37%), respectively. Likewise, P. aeruginosa showed the lowest pooled estimates of resistance against ciprofloxacin (P = 16%; 95% CI: 9, 24%). Conclusion Generally, the wound culture positivity was found very high indicating the likelihood of poly-microbial contamination. S. aureus is by far the most common bacterial isolate recovered from wound infection. The high estimate of resistance was observed among β-lactam antibiotics in all bacterial isolates. Ciprofloxacin and gentamicin were relatively effective in treating wound infections with poly-microbial etiology. Electronic supplementary material The online version of this article (10.1186/s40360-019-0315-9) contains supplementary material, which is available to authorized users.

Aedes aegypti and Anopheles gambiae harbor the causative agents of diseases such as dengue fever and malaria, afflicting human morbidity and mortality worldwide. Given the worldwide emergence of resistance to insecticides, the current mainstay for vector control, identification of alternative modes of action for future insecticides is paramount. The serotonergic (5-HT) system has been documented to impact physiological mechanisms involved in disease transmission, suggesting its potential as a new mode of action target for future insecticide development. Target 5-HT receptors were cloned and expressed in the HEK293 cell line for functional and pharmacological characterization. Manipulation of the 5-HT system through microinjection of compounds suggests its involvement in the modulation of flight performance and blood-feeding behavior. By attenuating these two determinants of vectorial capacity, transmission and burden of disease could effectively be reduced. Considering these positive global health implications, the 5-HT system is a compelling target for the novel insecticide pipeline.

Rift Valley fever virus (RVFV) poses a major threat of introduction to several continents, including North America. Such an introduction could cause significant losses to the livestock industry, in addition to substantial human morbidity and mortality. Because of the opportunistic blood host selection of Culex tarsalis mosquitoes, we hypothesized that this species could be an important bridge vector of RVFV near feedlots in the event of an introduction. We investigated the mosquito community composition at livestock feedlots and surrounding natural and residential areas to determine differences in mosquito relative abundance and blood feeding patterns attributed to cattle feeding operations. DNA extracted from abdomens of blood-fed mosquitoes were sequenced to determine host identity. Multivariate regression analyses revealed differences between mosquito community assemblages at feedlots and non-feedlot sites (p

Cancer is a principal cause of human morbidity and mortality, with gastrointestinal malignancies, in particular, resulting in a marked number of tumor-associated mortalities. The progression of gastrointestinal malignancy is regulated by a variety of aberrantly expressed proteins, a number of which facilitate tumor progression, whereas, others function as tumor suppressors. The detection of such proteins not only contributes to the early diagnosis of cancer, they may additionally serve as potential therapeutic targets. In normal tissues, numerous proteins encoded by proto-oncoproteins are degraded by ubiquitylation enzymes, consisting of F-box/WD-40 repeat-containing protein 7 (Fbw7) and other proteins, thus avoiding tumorigenesis and maintaining homeostasis. In tumor tissues, the downregulation of Fbw7, caused by various factors, leads to disorders in ubiquitinase synthesis, which may induce tumor progression and chemoresistance, particularly in gastrointestinal malignancy. Therefore, an in-depth study of the regulatory mechanisms involved in disorders of Fbw7 expression and the role of Fbw7 in chemoresistance of gastrointestinal tumors may suggest improvements for early diagnostic screening and targeted therapy.

Manganese (Mn) is an essential micronutrient critical for the pathogenesis of Staphylococcus aureus, a significant cause of human morbidity and mortality. Paradoxically, excess Mn is toxic; therefore, maintenance of intracellular Mn homeostasis is required for survival. Here we describe a Mn exporter in S. aureus, MntE, which is a member of the cation diffusion facilitator (CDF) protein family and conserved among Gram-positive pathogens. Upregulation of mntE transcription in response to excess Mn is dependent on the presence of MntR, a transcriptional repressor of the mntABC Mn uptake system. Inactivation of mntE or mntR leads to reduced growth in media supplemented with Mn, demonstrating MntE is required for detoxification of excess Mn. Inactivation of mntE results in elevated levels of intracellular Mn, but reduced intracellular iron (Fe) levels, supporting the hypothesis that MntE functions as a Mn efflux pump and Mn efflux influences Fe homeostasis. Strains inactivated for mntE are more sensitive to the oxidants NaOCl and paraquat, indicating Mn homeostasis is critical for resisting oxidative stress. Furthermore, mntE and mntR are required for full virulence of S. aureus during infection, suggesting S. aureus experiences Mn toxicity in vivo. Combined, these data support a model in which MntR controls Mn homeostasis by balancing transcriptional repression of mntABC and induction of mntE, both of which are critical for S. aureus pathogenesis. Thus, Mn efflux contributes to bacterial survival and virulence during infection, establishing MntE as a potential antimicrobial target and expanding our understanding of Mn homeostasis. IMPORTANCE Manganese (Mn) is generally viewed as a critical nutrient that is beneficial to pathogenic bacteria due to its function as an enzymatic cofactor and its capability of acting as an antioxidant; yet paradoxically, high concentrations of this transition metal can be toxic. In this work, we demonstrate Staphylococcus aureus utilizes the cation diffusion facilitator (CDF) family protein MntE to alleviate Mn toxicity through efflux of excess Mn. Inactivation of mntE leads to a significant reduction in S. aureus resistance to oxidative stress and S. aureus-mediated mortality within a mouse model of systemic infection. These results highlight the importance of MntE-mediated Mn detoxification in intracellular Mn homeostasis, resistance to oxidative stress, and S. aureus virulence. Therefore, this establishes MntE as a potential target for development of anti-S. aureus therapeutics.

Aedes aegypti is an important mosquito vector of several arboviruses, including dengue, yellow fever, Zika, and Chikungunya, which cause significant human morbidity and mortality globally. In certain populations of this mosquito, a native meiotic drive system causes abnormal spermatogenesis that results in highly male-biased progenies from some matings. Although the basic genetics and cytogenetics of the drive mechanism were elucidated, very little is known on a transcriptome level about how the meiotic drive phenotype is expressed in individual males. To address this question, we conducted a whole-genome microarray expression study of testes from a meiotic-drive-carrying strain (T37) in comparison with testes from a non-drive-carrying strain (RED). Based on bioinformatics analyses of the microarray data, we identified 209 genes associated with the meiotic drive phenotype that were significantly differentially expressed between the two strains. K-means cluster analysis revealed nine clusters, in which genes upregulated in T37 testes were assigned to five clusters and genes downregulated in T37 testes were assigned to four clusters. Our data further revealed that genes related to protein translation, phosphorylation, and binding, as well as to G-protein-coupled receptor (GPCR) and peptidase activities, are differentially upregulated in testes from males with the meiotic drive genotype. Based on pathway analysis of these differentially expressed genes, it was observed that the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway may play a role in the meiotic drive system. Overall, this investigation enhances our understanding of whole-genome gene expression associated with the meiotic drive system in Ae. aegypti.

Colitis caused by Clostridium difficile infection is a growing cause of human morbidity and mortality, especially after antibiotic use in health care settings. The natural immunity of newborn infants and protective host immune mediators against C. difficile infection are not fully understood, with data suggesting that inflammation can be either protective or pathogenic. Here, we show an essential role for IL-17A produced by γδ T cells in host defense against C. difficile infection. Fecal extracts from children with C. difficile infection showed increased IL-17A and T cell receptor γ chain expression, and IL-17 production by intestinal γδ T cells was efficiently induced after infection in mice. C. difficile–induced tissue inflammation and mortality were markedly increased in mice deficient in IL-17A or γδ T cells. Neonatal mice, with naturally expanded RORγt(+) γδ T cells poised for IL-17 production were resistant to C. difficile infection, whereas elimination of γδ T cells or IL-17A each efficiently overturned neonatal resistance against infection. These results reveal an expanded role for IL-17–producing γδ T cells in neonatal host defense against infection and provide a mechanistic explanation for the clinically observed resistance of infants to C. difficile colitis.

Influenza A virus (IAV), a major cause of human morbidity and mortality, continuously evolves in response to selective pressures. Stem-directed, broadly neutralizing antibodies (sBnAbs) targeting the influenza virus hemagglutinin (HA) are a promising therapeutic strategy, but neutralization escape mutants can develop. We used an integrated approach combining viral passaging, deep sequencing, and protein structural analyses to define escape mutations and mechanisms of neutralization escape in vitro for the F10 sBnAb. IAV was propagated with escalating concentrations of F10 over serial passages in cultured cells to select for escape mutations. Viral sequence analysis revealed three mutations in HA and one in neuraminidase (NA). Introduction of these specific mutations into IAV through reverse genetics confirmed their roles in resistance to F10. Structural analyses revealed that the selected HA mutations (S123G, N460S, and N203V) are away from the F10 epitope but may indirectly impact influenza virus receptor binding, endosomal fusion, or budding. The NA mutation E329K, which was previously identified to be associated with antibody escape, affects the active site of NA, highlighting the importance of the balance between HA and NA function for viral survival. Thus, whole-genome population sequencing enables the identification of viral resistance mutations responding to antibody-induced selective pressure. IMPORTANCE Influenza A virus is a public health threat for which currently available vaccines are not always effective. Broadly neutralizing antibodies that bind to the highly conserved stem region of the influenza virus hemagglutinin (HA) can neutralize many influenza virus strains. To understand how influenza virus can become resistant or escape such antibodies, we propagated influenza A virus in vitro with escalating concentrations of antibody and analyzed viral populations by whole-genome sequencing. We identified HA mutations near and distal to the antibody binding epitope that conferred resistance to antibody neutralization. Additionally, we identified a neuraminidase (NA) mutation that allowed the virus to grow in the presence of high concentrations of the antibody. Virus carrying dual mutations in HA and NA also grew under high antibody concentrations. We show that NA mutations mediate the escape of neutralization by antibodies against HA, highlighting the importance of a balance between HA and NA for optimal virus function.

Infectious diseases are menace to the mankind, having a major contribution to the human morbidity and mortality. Trypanosomatids have a pervasive effect in the world, causing devastating but neglected diseases such as leishmaniasis, Chagas disease, and African sleeping sickness affecting 27 million people worldwide with 150,000 deaths annually. Trypanosomatids developing drug resistance is the current bottleneck in providing promising chemotherapeutics for these diseases which forces the continuous quest for new drugs and drug candidates. Balancing redox homeostasis is crucial for cell survival which has various implications in the biology of these parasites. Reactive oxygen species (ROS) act as signaling molecules, involving in various pathways and crucial for survival. Conversely, various chemotherapeutic drugs against trypanosomatids-caused ROS induction result in oxidative stress, eventually leading to apoptotic manifestations. Oxidative stress is one of the host defense mechanisms to control the infection, while detoxification is one of the crucial counteracts at the parasite front for successful host-parasite interaction. Therefore, oxidative stress is a good tool for better understanding of parasite biology, pathogenesis, and host-pathogen interactions. It is noteworthy that trypanosomatids have divergence from all other prokaryotes and eukaryotes at their redox system, majorly trypanothione-trypanothione reductase (TR)-based redox metabolism. The absence of this system in mammalians and structural/functional differences from host enzymes make it a lucrative target for studying its role in oxidative stress control and also to develop effective chemotherapeutics. One of the causes for drug resistance of trypanosomatids is due to their action of inducing oxidative stress which in turn activates repair mechanisms resulting in the development of drug resistance. Hence, studying oxidative stress mechanism of trypanosomatids gives insights into drug resistance, which is an impendence in attaining efficacious chemotherapy. In this chapter, we have tried to give an outline of the significance of redox stress and its role in different cellular metabolisms of trypanosomatids, with a special focus on trypanothione-trypanothione reductase (TR)-based redox system as a peculiar system to study trypanosomatids oxidative stress mechanism, also for drug designing.

Microbial contamination poses a substantial threat of human morbidity and mortality through drinking water, partly as a very diverse assemblage of microbes can contaminate drinking water. Methods to purify drinking water encompass many approaches, from relatively simple (boiling water) to technologically sophisticated (membrane filtration systems) and from very widely used techniques (chlorination) to experimental scale methods (sonication). Point-of-use decontamination methods are more diverse, but limited in their application in comparison with the needs for residual decontamination capability required by larger water treatment and distribution systems.

Particulate matter (PM) air pollution is associated with human morbidity and mortality. Measuring PM oxidative potential has been shown to provide a predictive measurement between PM exposure and adverse health impacts. The dithiothreitol (DTT) assay is commonly used to measure the oxidative potential of PM(2.5) (PM less than 2.5 μm aerodynamic diameter). In the common, kinetic form of this assay, the decay of DTT is quantified over time (indirectly) using 5,5’-dithiobis(2-nitrobenzoic acid) (DTNB, Ellman’s reagent) via UV/vis absorbance spectroscopy. The loss of DTT can also be quantified directly using electrochemical detection. The objectives of this work were (1) to evaluate the electrochemical assay, using commercially available equipment, relative to the UV/vis absorbance assay, and (2) to apply the electrochemical method to a large (>100) number of PM(2.5) aerosol filter samples. Also presented here is the comparison an end-point assay to the kinetic assay, in an attempt to reduce the time, labor, and materials neccssary to quantify PM oxidative potential. The end-point, electrochemical assay gave comparable results to the UV/vis absorbance assay for PM filter sample analysis. Finally, high filter mass loadings (higher than about 0.5 μg PM per mm(2) filter) lead to sub-optimal DTT assay performance, which suggests future studies should limit particle mass loadings on filters.

Helicobacter pylori chronically infects nearly half the world's population, yet most of those infected remain asymptomatic throughout their lifetime. The outcome of infection-peptic ulcer disease or gastric cancer versus asymptomatic colonization-is a product of host genetics, environmental influences, and differences in bacterial virulence factors. Here, we review the current understanding of the cag pathogenicity island (cagPAI), the vacuolating cytotoxin (VacA), and a large family of outer membrane proteins (OMPs), which are among the best understood H. pylori virulence determinants that contribute to disease. Each of these virulence factors is characterized by allelic and phenotypic diversity that is apparent within and across individuals, as well as over time, and modulates inflammation. From the bacterial perspective, inflammation is probably a necessary evil because it promotes nutrient acquisition, but at the cost of reduction in bacterial load and therefore decreases the chance of transmission to a new host. The general picture that emerges is one of a chronic bacterial infection that is dependent on both inducing and carefully regulating the host inflammatory response. A better understanding of these regulatory mechanisms may have implications for the control of chronic inflammatory diseases that are increasingly common causes of human morbidity and mortality.

Background: Pathogenic Escherichia coli is responsible for serious diseases; i.e.: Peritonitis, colitis, and urinary tract infections (UTIs) and even cancer, resulting in human morbidity and mortality. Environmental strains are increasingly spreading through food and dairy products, contributing to the pathogenetic burden of E. coli infections. Objectives: This study was performed to compare phylogeny, virulence factors, pathogenicity islands (PAIs), and pathotypes inbetween clinical and environmental E. coli isolates. Methods: A total of 105 clinical (72) and environmental (33) E. coli isolates were collected. All isolates were subjected to phylogenetic typing using a new quadruplex polymerase chain reaction (PCR). Wide array of virulence genes (VGs) and PAI markers were assessed for both subtypes, as well as, the distribution of different pathotypes among the phylogenetic groups. Results: Seven phylogenetic groups were detected; clinical isolates were more prevalent in phylogenetic groups B2 (22.2%) and D (23.6%), whereas environmental isolates were in groups A (24.2%) and B1 (60.6%). Majority of VGs were higher in clinical E. coli isolates. Environmental isolates showed higher percentage of some other VGs including; stx2 and hlyA. PAI markers were widespread among both categories, showing high extra-intestinal pathogenic E. coli (ExPEC) PAIs combination in environmental isolates. Enteropathogenic E. coli (EPEC) was the most widespread pathotype in clinical isolates versus enterohemorrhagic E. coli (EHEC) in environmental ones. Conclusions: Escherichia coli pathogenicity armoury was not only confined to clinical isolates, but to environmental ones as well. Therefore, environmental E. coli isolates can serve as reservoirs for transmission of E. coli pathogenicity

Staphylococcus aureus is a common Gram-positive bacteria that is a major cause of human morbidity and mortality. The SaeR/S two-component sensory system of S. aureus is important for virulence gene transcription and pathogenesis. However, the influence of SaeR phosphorylation on virulence gene transcription is not clear. To determine the importance of potential SaeR phosphorylation sites for S. aureus virulence, we generated genomic alanine substitutions at conserved aspartic acid residues in the receiver domain of the SaeR response regulator in clinically significant S. aureus pulsed-field gel electrophoresis (PFGE) type USA300. Transcriptional analysis demonstrated a dramatic reduction in the transcript abundance of various toxins, adhesins, and immunomodulatory proteins for SaeR with an aspartic acid to alanine substitution at residue 51. These findings corresponded to a significant decrease in cytotoxicity against human erythrocytes and polymorphonuclear leukocytes, the ability to block human myeloperoxidase activity, and pathogenesis during murine soft-tissue infection. Analysis of SaeR sequences from over 8,000 draft S. aureus genomes revealed that aspartic acid residue 51 is 100% conserved. Collectively, these results demonstrate that aspartic acid residue 51 of SaeR is essential for S. aureus virulence and underscore a conserved target for novel antimicrobial strategies that treat infection caused by this pathogen.

Cardiovascular disease (CVD), especially coronary artery disease (CAD) is a leading cause of human morbidity and mortality. CVD involves blockage in the heart or blood vessels (arteries, capillaries and veins). Different techniques are used to check the condition and blockage in the heart. Electrocardiogram (ECG) is one of the medical techniques employed to monitor heart performance and used for the detection of different arrhythmias. Secured transmission of ECG system has transpired as a prospective solution to help the medical practitioner to check the patient’s heart condition; either the heart is working normally or has some abnormalities like tachycardia or bradycardia. This study aims to design and develop security enhanced ECG system for secure and privacy-preserving, ECG diagnosing and ECG visualization. The QRS complex method will be used in this work to diagnose the acquired ECG signal. The result obtained from QRS complex method is used to display a healthy or unhealthy patient’s condition. The system will alert for further diagnosis if the condition is critical, so it will help medical practitioner for further detection of arrhythmias and medical researcher for further studies. The security and privacy features of the system protect the authenticity and confidentiality of the patient’s medical data and are implemented using security enhancing techniques. This problem will be solved by encrypting the signals, using the proposed fully homomorphic encryption (FHE) technique. This study demonstrates contributions by applying these ideas to two classical problems on the natural algorithm calculation and signal processing.

Pseudomonas aeruginosais a ubiquitous opportunistic pathogen that causes considerable human morbidity and mortality, particularly in nosocomial infections and individuals with cystic fibrosis.P.aeruginosacan adapt to surface growth by undergoing swarming motility, a rapid multicellular movement that occurs on viscous soft surfaces with amino acids as a nitrogen source. Here we tested the small synthetic host defense peptide, innate defense regulator 1018, and found that it inhibited swarming motility at concentrations as low as 0.75 μg/ml, well below the MIC for strain PA14 planktonic cells (64 μg/ml). A screen of the PA14 transposon insertion mutant library revealed 29 mutants that were more tolerant to peptide 1018 during swarming, five of which demonstrated significantly greater swarming than the WT in the presence of peptide. Transcriptional analysis (RNA-Seq) of cells that were inoculated on swarming plates containing 1.0 μg/ml peptide revealed differential expression of 1,190 genes compared to cells swarming on plates without peptide. Furthermore, 1018 treatment distinctly altered the gene expression profile of cells when compared to that untreated cells in the centre of the swarm colonies. Peptide-treated cells exhibited changes in the expression of genes implicated in the stringent stress response including those regulated byanr, which is involved in anaerobic adaptation, indicative of a mechanism by which 1018 might inhibit swarming motility. Overall, this study illustrates potential mechanisms by which peptide 1018 inhibits swarming surface motility, an important bacterial adaptation associated with antibiotic resistance, virulence, and dissemination ofP.aeruginosa.

Ross River virus (RRV) is the most medically significant mosquito-borne virus of Australia, in terms of human morbidity. RRV cases, characterised by febrile illness and potentially persistent arthralgia, have been reported from all Australian states and territories. RRV was the cause of a large-scale epidemic of multiple Pacific Island countries and territories (PICTs) from 1979 to 1980, involving at least 50,000 cases. Historical evidence of RRV seropositivity beyond Australia, in populations of Papua New Guinea (PNG), Indonesia and the Solomon Islands, has been documented. We describe the genomic characterisation and timescale analysis of the first isolate of RRV to be sampled from PNG to date. Our analysis indicates that RRV has evolved locally within PNG, independent of Australian lineages, over an approximate 40 year period. The mean time to most recent common ancestor (tMRCA) of the unique PNG clade coincides with the initiation of the PICTs epidemic in mid-1979. This may indicate that an ancestral variant of the PNG clade was seeded into the region during the epidemic, a period of high RRV transmission. Further epidemiological and molecular-based surveillance is required in PNG to better understand the molecular epidemiology of RRV in the general Australasian region.

The cyanotoxin cylindrospermopsin (CYN), a toxic metabolite from cyanobacteria, is of particular concern due to its cosmopolitan occurrence, aquatic bioaccumulation, and multi-organ toxicity. CYN is the second most often recorded cyanotoxin worldwide, and cases of human morbidity and animal mortality are associated with ingestion of CYN contaminated water. The toxin poses a great challenge for drinking water treatment plants and public health authorities. CYN, with the major toxicity manifested in the liver, is cytotoxic, genotoxic, immunotoxic, neurotoxic and may be carcinogenic. Adverse effects are also reported for endocrine and developmental processes. We present a comprehensive review of CYN over the past four decades since its first reported poisoning event, highlighting its global occurrence, biosynthesis, toxicology, removal, and monitoring. In addition, current data gaps are identified, and future directions for CYN research are outlined. This review is beneficial for understanding the ins and outs of this environmental pollutant, and for robustly assessing health hazards posed by CYN exposure to humans and other organisms.

Considering that several meteorological variables can contribute to weather vulnerability, the estimation of their synergetic effects on health is particularly useful. The spatial synoptic classification (SSC) has been used in biometeorological applications to estimate the effect of the entire suite of weather conditions on human morbidity and mortality. In this study, we assessed the relationships between extremely hot and dry (dry tropical plus, DT+) and hot and moist (moist tropical plus, MT+) weather types in summer and extremely cold and dry (dry polar plus, DP+) and cold and moist (moist polar, MP+) weather types in winter and cardiovascular and respiratory hospitalizations by age and sex. Time-series quasi-Poisson regression with distributed lags was used to assess the relationship between oppressive weather types and daily hospitalizations over 14 subsequent days in the extended summer (May to August) and 28 subsequent days during the extended winter (November to March) over 24 years in 4 Swedish locations from 1991 to 2014. In summer, exposure to hot weather types appeared to reduce cardiovascular hospitalizations while increased the risk of hospitalizations for respiratory diseases, mainly related to MT+. In winter, the effect of cold weather on both cause-specific hospitalizations was small; however, MP+ was related to a delayed increase in cardiovascular hospitalizations, whilst MP+ and DP + increased the risk of hospitalizations due to respiratory diseases. This study provides useful information for the staff of hospitals and elderly care centers who can help to implement protective measures for patients and residents. Also, our results could be helpful for vulnerable people who can adopt protective measures to reduce health risks.

The correct prediction of air pollutants dispersed in urban areas is of paramount importance to safety, public health and a sustainable environment. Vehicular traffic is one of the main sources of nitrogen oxides (NO x ) and particulate matter (PM), strongly related to human morbidity and mortality. In this study, the pollutant level and distribution in a section of one of the main road arteries of Antwerp (Belgium, Europe) are analyzed. The assessment is performed through computational fluid dynamics (CFD), acknowledged as a powerful tool to predict and study dispersion phenomena in complex atmospheric environments. The two main traffic lanes are modeled as emitting sources and the surrounding area is explicitly depicted. A Reynolds-averaged Navier–Stokes (RANS) approach specific for Atmospheric Boundary Layer (ABL) simulations is employed. After a validation on a wind tunnel urban canyon test case, the dispersion within the canopy of two relevant urban pollutants, nitrogen dioxide (NO 2 ) and particulate matter with an aerodynamic diameter smaller than 10 μ m (PM10), is studied. An experimental field campaign led to the availability of wind velocity and direction data, as well as PM10 concentrations in some key locations within the urban canyon. To accurately predict the concentration field, a relevant dispersion parameter, the turbulent Schmidt number, S c t , is prescribed as a locally variable quantity. The pollutant distributions in the area of interest – exhibiting strong heterogeneity – are finally demonstrated, considering one of the most frequent and concerning wind directions. Possible local remedial measures are conceptualized, investigated and implemented and their outcomes are directly compared. A major goal is, by realistically reproducing the district of interest, to identify the locations inside this intricate urban canyon where the pollutants are stagnating and to analyze which solution acts as best mitigation measure. It is demonstrated that removal by electrostatic precipitation (ESP), an active measure, and by enhancing the dilution process through wind catchers, a passive measure, are effective for local pollutant removal in a realistic urban canyon. It is also demonstrated that the applied ABL methodology resolves some well known problems in ABL dispersion modeling.

Malaria is an ancient disease that continues to cause enormous human morbidity and mortality mainly due to the invasion of the erythrocyte by the merozoite stage of the Parasite (Plasmodium falciparum), as the parasite spend much of it life intracellularly. Therefore the aim of this paper was to review the state of knowledge on the mechanism of erythrocytic invasion by the merozoite of Plasmodium falciparum. The invasion process is a coordinated series of protein/protein interactions, protease cleavage events, intracellular signals, organelle release and engagement of an actin-myosin motor. The invasion is achieved through either, sialic acid dependent which uses EBA-140,EBA-175,EBA-181 and PfRH1 or sialic acid in-dependent pathways which uses PfRH2 and PfRH4. Successful invasion process is completed in the following steps; Meroziote activation, Merozoite binding, Reorientation and deformation, Junction formation and Parasite entry. Merozoite acitivation involve egresses of the merozite from the erythrocyte where exoneme secretes the first protein called subtisilin-like protease-1 (PfSUB-1) in to the parasitophorous vacuole which ensure primary proteolysis of Serine-Repeat antingen (SERA) which in turn act on Parasitophorous Vacoule and Red Blood Cell to initiate host cell rupture. Dipeptidyl peptidase 3 (DPAP3) also contribute to the egress by regulating the maturation of PfSUB-1. The initial interaction between the merozoite and the erythrocyte is due to random and weak collision and presumptively involves in the first instance a reversible interaction between proteins on the merozoite surface and the host erythrocyte. In this ligands bind to specific receptors on the merozoite, where Erythrocyte Binding Anitigen-175 (EBA-175) bind to Glycophorin A, EBA-140 binds to Glycophorin C, Erythrocyte Binding-like-1 protein (EBL-1) binds to Glycophorin B and PfRh4 binds to Complement Receptor-1 (CR-1) and PfRh5 binds to Basigin (CD147) on the erythrocyte. This is followed by permanent positioning of the apical organelles of the merozoite on to the red blood cell (re-orientation) and release of adhesive proteins (adhesins), Protease and membrane altering agent specifically Subtisilin-2 (PfSUB-2), Apical Membrane Antigen-1 (AMA1).Junction formation is an intimate circumferential contact with the host cell called tight junction and it is formed under the influence of Apical Membrane Antigen 1 (AMA1) and Rhoptery neck (RON). Finally the merozoite penetrates in to the erythrocyte bilayer with the help of Actin- Myosin motor, Thrombospondin-Related Anonymous Protein family (TRAP) and aldolase

Compared with mortality, the impact of weather and climate on human morbidity is less well understood, especially in the cold season. We examined the relationships between weather and emergency department (ED) visitation at hospitals in Roanoke and Charlottesville, Virginia, two locations with similar climates and population demographic profiles. Using patient-level data obtained from electronic medical records, each patient who visited the ED was linked to that day's weather from one of 8 weather stations in the region based on each patient's ZIP code of residence. The resulting 2010-2017 daily ED visit time series were examined using a distributed lag non-linear model to account for the concurrent and lagged effects of weather. Total ED visits were modeled separately for each location along with subsets based on gender, race, and age. The relationship between the relative risk of ED visitation and temperature or apparent temperature over lags of one week was positive and approximately linear at both locations. The relative risk increased about 5% on warm, humid days in both cities (lag 0 or lag 1). Cold conditions had a protective effect, with up to a 15% decline on cold days, but ED visits increased by 4% from 2 to 5 days after the cold event. The effect of thermal extremes tended to be larger for non-whites and the elderly, and there was some evidence of a greater lagged response for non-whites in Roanoke. Females in Roanoke were more impacted by winter cold conditions than males, who were more likely to show a lagged response at high temperatures. In Charlottesville, males sought ED attention at lower temperatures than did females. The similarities in the ED response patterns between these two hospitals suggest that certain aspects of the response may be generalizable to other locations that have similar climates and demographic profiles.

Epidemiological studies show that there is a link between urban water pollution and increase in human morbidity and mortality. With the increase in number of new substances arising from the chemical, pharmaceutical, and agricultural industries, there is an urgent need to develop biological test systems for fast evaluation of potential risks to humans and the environmental ecosystems. Here, a combined cellular reporter assay based on the cellular survival and the stress-induced activation of the survival-promoting factor nuclear factor κB (NF-κB) and its use for the detection of cytotoxicity and cancer-related stress responses is presented. A total of 14 chemicals that may be found in trace-amounts in ground water levels are applied and tested with the presented assay. The project is embedded within the joint research project TOX-BOX which aims to develop a harmonized testing strategy for risk management of anthropogenic trace substances in potable water. The assay identified carbendazim as a NF-κB-activating agent in mammalian cells.

Background Cardiovascular diseases (CVDs) are one of the main factors responsible for human morbidity and mortality. Since mitochondria play a critical role in the regulation of cardiac tissue homeostasis, this organelle is a critical target for the protective effects of several pharmaceuticals. Although specific mitochondria-targeted antioxidants and some pharmacological agents are described as potential cardioprotective agents, there are still a few effective mitochondrial therapies for the treatment of CVDs. Agents which have potential cardioprotective effects by directly targeting mitochondria in vitro and in vivo are still in pre-clinical or clinical trials, hence their widespread use in the clinic is still far. Also, some of these agents have a decreased bioavailability or show some intrinsic toxicity, which also limits their working mitochondrial concentrations. Methods By initially using PubMed specific queries for literature search, we review here cardiac mitochondrial effects of specific targeted and non-targeted antioxidants and pharmacological agents, including MitoE, MitoQ, MitoSNO, Mito-TEMPOL, SkQ1, SkQR1, carvedilol, trimetazidine, ranolazine, diazoxide and propofol. Results The present review emphasizes new mitochondrial-targeting strategies which have emerged to address difficulties arising from current approaches. We also describe the strengths and weaknesses of these cardioprotective approaches. Conclusion Although effective therapies to target mitochondria in the context of CVDs are not under widespread clinical use, the new strategies proposed constitute a real promise for the development of therapies which may effectively prevent CVDs in the near future.

Rationale Although cancer is a main cause of human morbidity worldwide, relatively small numbers of new cancer cases are recorded annually in single urban areas. This makes the association between cancer morbidity and environmental risk factors, such as ambient air pollution, difficult to detect using traditional methods of analysis based on age standardized rates and zonal estimates. Study goal The present study investigates the association between air pollution and cancer morbidity in the Greater Haifa Metropolitan Area in Israel by comparing two analytical techniques: the traditional zonal approach and more recently developed Double Kernel Density (DKD) tools. While the first approach uses age adjusted Standardized Incidence Ratios (SIRs) for small census areas, the second approach estimates the areal density of cancer cases, normalized by the areal density of background population in which cancer events occurred. Both analyses control for several potential confounders, including air pollution, proximities to main industrial facilities and socio-demographic attributes. Results Air pollution variables and distances to industrial facilities emerged as statistically significant predictors of lung and NHL cancer morbidity in the DKD-based models (p 0.2). Conclusion DKD models appear to be a more sensitive tool for assessing potential environmental risks than traditional SIR-based models, because DKD estimates do not depend on a priory geographic delineations of statistical zones and produce a smooth and continuous disease ‘risk surface’ covering the entire study area. We suggest using the DKD method in similar studies of the effect of ambient air pollution on chronic morbidity, especially in cases in which the number of statistical areas available for aggregation and comparison is small and recorded morbidity events are relatively rare.

Prevention the development of malignant tumors and treatment of cancer patients remains an important problem today. In spite of substantive progress in the cancer diagnostics and treatment cancer occupies one of the main places in human morbidity and mortality in the World. Targeted therapy is an alternative to traditional one through targeted action on tumor cells and relatively low toxicity. Inhibitor of membrane tyrosine kinases dihydropyrrole derivative 5-amino-4-(1,3-benzothiazole-2-yl)-1-(3- methoxyphenyl)-1,2-dihydro-3Н-pyrrol-3-one (D-1) has significant antitumor activity on colorectal cancer and low toxicity acting in effective dose. However, to assess the D-1 therapeutic gap the investigation of its higher doses is necessary. The investigation was aimed at D-1 effects applied at different doses compared to 5-fluorouracil one on rats ascending colon mucosa. The research has found out that the dihydropyrrole derivative has no damaging effect on the colon of rats, whereas the administration of 5-fluorouracil causes marked mucosal lesion of the ascending colon. Hereby D-1 low toxicity to ascending colon mucosa compared to 5-FU and wide therapeutic gap of the first was concluded.

Influenza is a contagious respiratory illness that causes significant human morbidity and mortality, affecting 5-15% of the population in a typical epidemic season. Human influenza epidemics are caused by types A and B, with roughly 25% of human cases due to influenza B. Influenza B is a single-stranded RNA virus with a high mutation rate, and both prior immune history and vaccination put significant pressure on the virus to evolve. Due to the high rate of viral evolution, the influenza B vaccine component of the annual influenza vaccine is updated, roughly every other year in recent years. To predict when an update to the vaccine is needed, an estimate of expected vaccine effectiveness against a range of viral strains is required. We here introduce a method to measure antigenic distance between the influenza B vaccine and circulating viral strains. The measure correlates well with effectiveness of the influenza B component of the annual vaccine in humans between 1979 and 2014. We discuss how this measure of antigenic distance may be used in the context of annual influenza vaccine design and prediction of vaccine effectiveness., 28 pages, 4 figures, 2 tables

Yellow fever virus (YFV) is an arbovirus that causes significant human morbidity and mortality. This virus has been studied intensively over the past century, although there are still no treatment options for those who become infected. Periodic and unpredictable yellow fever (YF) outbreaks in Africa and South America continue to occur and underscore the ongoing need to further understand this viral disease and to develop additional countermeasures to prevent or treat cases of illness. The use of animal models of YF is critical to accomplishing this goal. There are several animal models of YF that replicate various aspects of clinical disease and have provided insight into pathogenic mechanisms of the virus. These typically include mice, hamsters and non-human primates (NHP). The utilities and shortcomings of the available animal models of YF are discussed. Information on recent discoveries that have been made in the field of YFV research is also included as well as important future directions in further ameliorating the morbidity and mortality that occur as a result of YFV infection. It is anticipated that these model systems will help facilitate further improvements in the understanding of this virus and in furthering countermeasures to prevent or treat infections.

Human trichinellosis is an important food-borne zoonotic disease that causes financial losses and health problems for the population. Sporadic cases and outbreaks of different intensities are recorded each year in Bulgaria. With this work we attempt to clarify the main reasons leading to outbreaks of trichinellosis in the country and to compare the recorded incidence with that in other European countries. In the present study, the epidemiological, clinical, and laboratory data of the trichinellosis outbreaks recorded in the country from 2008 to 2014 were analyzed. Epidemiological data based on a standard protocol with full case descriptions were collected for each region of the country and analyzed at the National Center of Infectious and Parasitic Diseases in Sofia. Between 2008 and 2014, 29 outbreaks were recorded in Bugaria. Of 1670 people who consumed meat or meat products contaminated with Trichinella larvae, 710 were infected. The annual incidence of human trichinellosis for the period varied from 0.22 to 5.82 per 100,000 population. Studies using the polymerase chain reaction technique identified Trichinella spiralis and Trichinella britovi as the causative agents of trichinellosis among humans in Bulgaria. Of all food-borne parasitic diseases, trichinellosis has the most pronounced negative effect on human health in the Republic of Bulgaria, and the country is still one of the European Union member states with a high human morbidity rate from trichinellosis.

Chronic noncommunicable diseases (NCDs), including can- cer, have become the leading cause of human morbidity and mortality. In Mexico, cancer is the third leading cause of death, with a high incidence among the economically active popula- tion, a high proportion of advanced stages at diagnosis and limited care coverage for patients. However, no public policy aimed at managing this important public health problem has been developed and implemented to date. This manuscript describes the first interinstitutional proposal of a National Program for Cancer Control, considering the known risk factors, early detection, treatment, palliative care and patient rehabilitation. This manuscript also outlines a series of thoughts on the difficulties and needs that the Mexican health system faces in achieving the main objectives of the program: to decrease the incidence of cancer, to increase survival and to improve the quality of life for this group of patients. DOI: http://dx.doi.org/10.21149/spm.v58i2.7804

The genus Mycobacterium includes some of the most common causes of human morbidity and mortality worldwide. Mycobacterium tuberculosis is a commonly cited example, resulting in almost 10 million new cases of tuberculosis and 1.5 million deaths each year, although in some regions, nontuberculous mycobacteria (NTM) probably cause more disease. Mycobacteria represent challenging pathogens, as they are intrinsically resistant to many commonly used antimicrobials. Therefore, with the acquisition of mutations conferring additional resistance phenotypes, these pathogens can readily lead to disease with essentially no effective chemotherapeutic options. This review provides a brief overview of the broad spectrum of mycobacterial resistance to antimicrobials and the limitations it places on therapeutic options.

BACKGROUND Blindness due to cataract presents an enormous problem in India, not just in terms of human morbidity but also in terms of economic loss and social burden. Cataract surgery constitutes by far the most common surgical procedure performed under local anaesthesia. Therefore, it is the need of the hour to make the anaesthetic technique painless and effective. OBJECTIVES To compare sub-tenon’s anaesthesia and peribulbar anaesthesia with respect to pain/analgesia. METHODS This hospital based prospective study was conducted between December 2012 and May 2014 at Basaveshwar Teaching and General Hospital affiliated to M. R. Medical College, Gulbarga, Karnataka. During the above mentioned period, 200 randomly selected patients fulfilling the criteria framed were included for the study. They were randomly divided into group P (n=100), who underwent manual small incision cataract surgery under peribulbar anaesthesia and group S (n=100) patients underwent manual small incision cataract surgery by sub-tenon’s anaesthesia. After the procedure the efficacy and safety of the two methods of anaesthesia in SICS with respect to intraoperative pain, akinesia, lid movements, rise in IOP and complications were compared. RESULTS Perioperative pain was dramatically lower in the sub-tenon’s group of patients with significantly fewer patients experiencing unacceptable levels of pain. CONCLUSION

Infections caused by drug-resistant Gram-negative pathogens continue to be significant contributors to human morbidity. The recent advent of New Delhi metallo-β-lactamase-1 (blaNDM-1) producing pathogens, against which few drugs remain active, has aggravated the problem even further. This paper shows that aryl-alkyl-lysines, membrane-active small molecules, are effective in treating infections caused by Gram-negative pathogens. One of the compounds of the study was effective in killing planktonic cells as well as dispersing biofilms of Gram-negative pathogens. The compound was extremely effective in disrupting preformed biofilms and did not select resistant bacteria in multiple passages. The compound retained activity in different physiological conditions and did not induce any toxic effect in female Balb/c mice until concentrations of 17.5 mg/kg. In a murine model of Acinetobacter baumannii burn infection, the compound was able to bring the bacterial burden down significantly upon topical application for 7 days.

Bacteria and their toxins are associated with significant human morbidity and mortality. While a few bacterial toxins are well characterized, the mechanism of action for most toxins has not been elucidated, thereby limiting therapeutic advances. One such example is the highly potent pore-forming toxin hemolysin BL (HBL), produced by the gram-positive pathogen Bacillus cereus. However, how HBL exerts its effects and whether it requires any host factors is unknown. Here, we describe an unbiased genome-wide CRISPR/Cas9 knockout screen that identified LPS-Induced TNF-α Factor (LITAF) as the HBL receptor. Using LITAF-deficient cells, a second, subsequent whole-genome CRISPR/Cas9 screen identified the LITAF-like protein CDIP1 as a second, alternative receptor. We generated LITAF-deficient mice, which exhibit marked resistance to lethal HBL challenges. This work outlines and validates an approach to use iterative genome-wide CRISPR/Cas9 screens to identify the complement of host factors exploited by bacterial toxins to exert their myriad of biological effects.

Brucella spp. as animal pathogens causes human brucellosis, the most momentous zoonotic diseases all over the world that result in economic pressure, human morbidity, and poverty. Brucellosis is commonly transmitted by infected dairy products. The prevalence of Brucella spp. and high consumption of unpasteurized dairy products in urban areas of Iran imposes further studies to clarify the prevalence of Brucella species. This molecular survey was purposefully designed to determine the prevalence of Brucella in raw milk collected from milk sellers using PCR in Zanjan province, Iran. In this molecular cross-sectional study, 73 raw milk samples with a volume of 40 ml gathered (6 samples from sheep and 67 samples from bovine) from raw milk vendors in Zanjan province. DNA of bacteria was extracted from the raw milk samples using (GeneALL, South Korea) kit according to the manufacturer protocol. Specific primers (B4 and B5) were used to the amplification of BCSP31 gene. Five primers (Ba-sp, Bm-sp, Bo-sp, Bs-sp, and IS711-sp) were used to detect Brucella spp. (Brucella abortus, Brucella melitens, Brucella ovis, and Brucella suis) among the positive samples for bcsp31 gene. From the 73 raw milk samples collected, 38 cases (52%) were positive for Brucella genus, 3 cases (7.8%) belonged to Brucella abortus and 2 cases (5.2%) belonged to Brucella melitensis. There were no positive cases for both Brucella ovis and Brucella suis. Results of this study proved that the prevalence of Brucella in raw milk is still a threat to public health, which should have a deeper look at the control strategies and methods of the prevention of brucellosis in the livestock.

Diurnal temperature range (DTR) is a key indicator reflecting climate stability. Many previous studies have examined the effects of ambient temperature, both hot and cold, on human morbidity and mortality, but few studies have evaluated health effects of DTR, especially those in developing countries. This study aimed to investigate the association between short-term exposure to DTR and hospital admissions for cardiovascular and respiratory diseases in Bangkok, Thailand. We obtained daily meteorological variables from the Thai Meteorological Department from January 2006 through December 2014 and daily hospital admissions from the National Health Security Office during the same period. Quasi-Poisson generalized linear regression model combined with distributed lag non-linear model was used to examine the association between DTR and cardiovascular and respiratory hospital admissions controlling for daily average temperature, relative humidity, day of the week, public holiday, and seasonal and long-term trend. A J-shape relationship between DTR and hospital admissions was observed. With 7.8 °C DTR as a reference value, the relative risks for cardiovascular and respiratory hospital admission associated with extremely high DTR (11.6 °C) at cumulative lag 0-21 (21-day cumulative effects) were 1.206 (95% CI: 1.002-1.452) and 1.021 (95% CI: 0.856-1.218), respectively. The effects of extremely high DTR relative to a reference value did not significantly differ between males and females, as well as between young people (65 years) and the elderly (≥65 years) for both cardiovascular and respiratory admission. When stratifying the effects by season, the effect of extremely high DTR in winter was greater than that in summer and rainy season. This study showed that short-term exposure to extremely high DTR was significantly associated with increased risk of hospital admissions for cardiovascular disease in Bangkok, especially during winter. Results from this study could provide important scientific evidence for policy decision making to protect populations from adverse health effects of DTR.

Metabolic diseases have a tremendous impact on human morbidity and mortality. Numerous targets regulating adenosine monophosphate kinase (AMPK) have been identified for treating the metabolic syndrome (MetS), and many compounds are being used or developed to increase AMPK activity. In parallel, the cyclic nucleotide phosphodiesterase families (PDEs) have emerged as new therapeutic targets in cardiovascular diseases, as well as in non-resolved pathologies. Since some PDE subfamilies inactivate cAMP into 5'-AMP, while the beneficial effects in MetS are related to 5'-AMP-dependent activation of AMPK, an analysis of the various controversial relationships between PDEs and AMPK in MetS appears interesting. The present review will describe the various PDE families, AMPK and molecular mechanisms in the MetS and discuss the PDEs/PDE modulators related to the tissues involved, thus supporting the discovery of original molecules and the design of new therapeutic approaches in MetS.

Particulate matter (PM) has been shown to have strong link with a variety of human morbidity and mortality. World Health Organization (WHO) recognizes air pollution as an invisible killer responsible for around 7 million global deaths per year, including 43% from chronic obstructive pulmonary disease (COPD), 29% from lung cancer, 25% from heart diseases, 24% from stroke, and 24% from pneumonia. Cardiopulmonary disease is considered as the leading PM-induced complication. The main mechanism involved in PM-induced cardiopulmonary disease is through upregulation of redox-sensitive signaling pathways, mediated by nuclear factor kappa B (NF-κB). We analyzed transcriptomics data by microarray chips in human pulmonary fibroblasts (HPF) after being treated by different doses of PM, and our result identified sterol regulatory element-binding protein 1 (SREBP1) as the top 1 transcription factor activated after PM exposure in HPF. Our analysis showed that Pirin (PIR), an iron-dependent redox regulator of NF-κB, was the most significantly and plausible transcriptional targets of SREBP1. Additionally, SREBP1, directly deacetylated and inhibited by Sirtuin 1 (SIRT1), increased the expression of inflammasome markers, e.g., NACHT, LRR and PYD domains containing protein 3 (NLPR3), Apoptosis-Associated Speck-Like Protein Containing CARD (ASC), and interleukin-1β (IL-1β), were documented. Our results further showed PM-induced inflammation could be reversed by inhibitors of SIRT1, SREBF1, and PIR. We concluded that SIRT1-SREBP1-PIR/NLRP3 inflammasome axis may play a key role in PM-induced sequel and may present new targets. Fenofibrate, clinically prescribed for dyslipidemia, prevented atrial fibrillation rabbits from atrial metabolic remodeling through the SIRT1-SREBP1 pathway. Moreover, in vivo fenofibrate was reported to regulate hyperglycemia-induced metabolic memory and reduce the inflammatory response via SIRT1-dependent suppression of NF-κB. On the basis of previous work and this study, we may repurpose fenofibrate as an anti-PM drug to prevent and treat PM-induced cardiopulmonary disease, which can be used in combination with COPD, heart disease, or anticancer medicines in future research. Citation Format: Chia-Ping Tien, Yu-Chan Chang, Shih-Chieh Hung, Michael Hsiao. Repurposing of fenofibrate to prevent and treat PM-induced pulmonary fibroblast-mediated inflammation: Mechanism involved in SIRT1-SREBP1-PIR/NLRP3 inflammasome axis [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2019 Nov 17-20; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(3 Suppl):Abstract nr B20.

A negligência relacionada ao saneamento inadequado e à destinação incorreta de lixo tornam-se fatores que contribuem para a contaminação hídrica, assim como, a problemática da poluição ambiental é notória. O objetivo do estudo consistiu em analisar e estabelecer o grau de risco dos municípios do Rio Grande do Sul em relação à morbimortalidade humana associada ao saneamento, destinação do lixo e abastecimento e tratamento de água.A análise das áreas mais suscetíveis é relevante, uma vez que possibilita o planejamento e execução das ações emergentes, bem como, estratégias de promoção da saúde. Trata-se de um estudo quantitativo e ecológico, cuja unidade de análise caracteriza-se pelo conjunto de internações hospitalares e de óbitos, ocasionados pelas doenças de transmissão hídrica e alimentar (DTHA), em relação às condições de abastecimento e tratamento de água, condições sanitárias e de destinação de lixo.Para a análise, utilizou-se a correlação de Pearson, o Índice de Moran Global e a Interpolação Linear Simples. Como resultados mapas de distribuição espacial das variáveis e mapa final de suscetibilidade às DTHA foram organizados. Aponta-se associação significativa entre a destinação de fezes/urina em esgoto e, o consumo de água sem tratamento com os coeficientes de internação e de óbito pelas DTHA. Os resultados apresentam a escala do cálculo de risco, para as DTHA, em mapa temático. Existe associação entre a morbimortalidade com variáveis de saneamento, assim como a existência de municípios com grau máximo de suscetibilidade para as DTHA. Spatial analysis of human morbidity and mortality associated with sanitation, waste disposal, water supply and treatmentABSTRACTNeglect related to inadequate sanitation and improper disposal of waste become factors that contribute to water contamination, as well as the problem of environmental pollution is notorious. The objective of the study was to analyze and establish the degree of risk of the municipalities of Rio Grande do Sul in relation to human morbidity and mortality associated with sanitation, waste disposal and water supply and treatment. The analysis of the most susceptible areas is relevant, since it allows the planning and execution of the emergent actions, as well as health promotion strategies. This is a quantitative and socioenvironmental study, whose unit of analysis is characterized by the set of hospital admissions and deaths, caused by water and food transmission diseases (DTHA), in relation to water supply and treatment conditions, conditions sanitation and waste disposal. For the analysis, the Pearson correlation, the Moran Global Index and the Simple Linear Interpolation were used. As results spatial distribution maps of the variables and final map of susceptibility to DTHA were organized. A significant association between the use of feces / urine in sewage and the consumption of untreated water with the hospitalization and death coefficients by DTHA is indicated. The results show the scale of the risk calculation, for the DTHA, in the thematic map. There is an association between morbidity and mortality with sanitation variables, as well as the existence of municipalities with a maximum degree of susceptibility to DTHA.Keywords: water contamination, environmental pollution, water and food transmission diseases, environment and development, sustainability.

Allostatic load, or the physiological dysregulation accumulated due to senescence and stress, is an established predictor of human morbidity and mortality and has been proposed as a tool for monitoring health and welfare in captive wildlife. It is estimated by combining biomarkers from multiple somatic systems into allostatic load indices (ALIs), providing a score representing overall physiological dysregulation. Such ALIs have been shown to predict disease and mortality risk in western lowland gorillas. In these prior analyses, we were unable to include lipid markers, a potential limitation as they are key biomarkers in human models. Recently, we were able to assay serum cholesterol and triglycerides and add them to our previous ALI. We then re-examined associations with health outcomes using binomial generalized linear models. We constructed ALIs using 2 pooling strategies and 2 methods. By itself, a 1-unit increase in allostatic load was associated with higher odds of all-cause morbidity and mortality, but results were mixed for cardiac disease. However, the best fit models for all-cause morbidity and cardiac disease included only age and sex. Allostatic load was retained alongside age in the best fit models for mortality, with a 1-unit increase associated with 23% to 45% higher odds of death. Compared with previous results, ALIs containing cholesterol and triglycerides better predict disease risk in zoo-housed western lowland gorillas, as evidenced by larger effect sizes for some models and better goodness of fit for all ALIs. Based on these results, we address methodology for future allostatic load research on wildlife.

Respiratory Syncytial Virus is a yearly respiratory virus that causes significant frequencies of morbidities, particularly in the young and elderly populations. However, preventive vaccines and/or treatment therapies are generally lacking, although much attention is now being placed on this virus. Moreover, there are now multiple strategies currently being explored in a race to the first licensed vaccine. While vaccines are being developed, multiple treatment strategies are being explored to attenuate the severity of infection and thus reduce hospitalization rates in vulnerable populations. This review outlines current strategies to prevent or treat this virus in the hopes of reducing significant human morbidity and mortality that occurs yearly with this seasonal virus.

SummaryAging is a major risk factor for human morbidity and mortality. Thus, the identification of compounds that defer aging, also known as ‘geroprotectors’, could greatly improve our health and promote a longer life. Here we screened for geroprotectors, employing the power of human transcriptomics to predict biological age. We used age-stratified human tissue transcriptomes to generate machine-learning-based classifiers capable of distinguishing transcriptomes from young versus old individuals. Then we applied these classifiers to transcriptomes induced by 1300 different compounds in human cell lines and ranked these compounds by their ability to induce a ‘youthful’ transcriptional state. Besides known geroprotectors, several new candidate compounds emerged from this ranking. Testing these in the model organismC. elegans, we identified two Hsp90 inhibitors, Monorden and Tanespimycin, which substantially extended the animals’ lifespan and improved their health. Hsp90 inhibition specifically induces the expression of heat shock proteins, known to improve protein homeostasis. Consistently, Monorden treatment improved the survival ofC. elegansunder proteotoxic stress, and its lifespan benefits were fully dependent on the master regulator of the cytosolic unfolded protein response, the transcription factor HSF-1. Taken together, we present an innovative transcriptomics-based screening approach to discover aging-preventive compounds and highlight Hsp90 inhibitors as powerful geroprotectors that could be of great value, to target the aging process in humans.

Background: Candidiasis is a major cause of human morbidity and mortality. Human uterine cervical stem cells conditioned medium (hUCESC-CM) is obtained from stromal stem cells of the cervical transformation zone, which are in permanent contact with a wide array of potential vaginal pathogens. In previous reports we have found that hUCESC-CM has antitumor and antibacterial potential. Since Candida is the most prevalent yeast in the human vagina, it seems plausible that hUCESC-CM might also show activity against it. Methods: In a preliminary step, to evaluate if hUCESC-CM showed any activity at all on Candida growth, in vitro activities of hUCESC-CM against fluconazole-susceptible reference strains of Candida albicans, Candida glabrata, Candida krusei, and Candida parapsilosis were studied with a microdilution method on RPMI 1640, using the BioScreen C microbiological incubator. Each measurement was repeated five times. The same methodology was used subsequently on fluconazole-susceptible and fluconazole-resistant Candida isolates from blood and vagina of those species corresponding to the reference strains of Candida against which activity had been detected in the previous study. Moreover, two fluconazole-resistant clinical isolates of Candida auris from blood and urine were also included. Findings: In vitro inhibitory activity of hUCESC-CM ranged from 57.5 to 96.6% growth-reduction against fluconazole-susceptible reference strains of Candida albicans, Candida glabrata, and Candida parapsilosis. hUCESC-CM also reduced the growth of all fluconazole-susceptible tested vaginal isolates by more than 50%. For fluconazole-resistant isolates, growth-reduction was higher than 67% for Candida albicans, regardless of its origin (vagina or blood). The isolate of Candida auris from urine with a MIC > 128 μ/ml for fluconazole was also significantly inhibited. However, hUCESC-CM was almost inactive against any of the fluconazole-resistant blood isolates of Candida glabrata, Candida parapsilosis, and Candida auris tested. Interpretation: This is the first report about the growth-inhibiting properties of conditioned medium from human stromal stem cells against different species of Candida. Antifungal activity of stromal stem cells depends on their site of origin, being most effective against Candida species most prevalent at that particular location. If confirmed in further studies, these findings might result in a completely new therapeutic approach against superficial and invasive candidiasis CM-A was a recipient of a grant from Fundación Once (Oportunidad al Talento). EM, CM-A, EE, and GQ have received grant support from Consejería de Educación, Universidades e Investigación (GIC15 IT-990-16), Fondo de Investigación Sanitaria (FIS PI11/00203), and UPV/EHU (UFI 11/25) SI

Invasive fungal infections are an increasingly important cause of human morbidity and mortality. We generated a next-generation sequencing (NGS)-based method designed to detect a wide range of fungi and applied it to analysis of the fungal microbiome (mycobiome) of the lung during fungal infection. Internal transcribed spacer 1 (ITS1) amplicon sequencing and a custom analysis pipeline detected 96% of species from three mock communities comprised of potential fungal lung pathogens with good recapitulation of the expected species distributions (Pearson correlation coefficients r = 0.63, p = 0.004; r = 0.71, p < 0.001; r = 0.62, p = 0.002). We used this pipeline to analyze mycobiomes of bronchoalveolar lavage (BAL) specimens classified as culture-negative (n = 50) or culture-positive (n = 39) for Blastomyces dermatitidis/gilchristii, the causative agent of North America blastomycosis. Detected in 91.4% of the culture-positive samples, Blastomyces dominated (>50% relative abundance) the mycobiome in 68.6% of these culture-positive samples but was absent in culture-negative samples. To overcome any bias in relative abundance due to between-sample variation in fungal biomass, an abundance-weighting calculation was used to normalize the data by accounting for sample-specific PCR cycle number and PCR product concentration data utilized during sample preparation. After normalization, there was a statistically significant greater overall abundance of ITS1 amplicon in the Blastomyces-culture-positive samples versus culture-negative samples. Moreover, the normalization revealed a greater biomass of yeast and environmental fungi in several Blastomyces-culture-positive samples than in the culture-negative samples. Successful detection of Coccidioides, Scedosporium, Phaeoacremonium, and Aspergillus in 6 additional culture-positive BALs by ITS1 amplicon sequencing demonstrates the ability of this method to detect a broad range of fungi from clinical specimens, suggesting that it may be a potentially useful adjunct to traditional fungal microbiological testing for the diagnosis of respiratory mycoses.