Eucalyptus. Eucalyptus leaves can alter soil chemistry and negatively affect underground macro- and microbial communities. Amphibians serve as excellent models to evaluate the effect of Eucalyptus invasion on ground-dwelling species as they predate on soil arthropods and incorporate soil microbes into their microbiotas. The skin microbiota is particularly important to amphibian health, suggesting that invasive plant species could ultimately affect amphibian populations. To investigate the potential for invasive vegetation to induce changes in microbial communities, we sampled microbial communities in the soil and on the skin of local amphibians. Specifically, we compared Batrachoseps attenuatus skin microbiomes in both Eucalyptus globulus (Myrtaceae) and native Quercus agriflolia (Fagaceae) dominated forests in the San Francisco Bay Area. We determined whether changes in microbial diversity and composition in both soil and Batrachoseps attenuatus skin were associated with dominant vegetation type. To evaluate animal health across vegetation types, we compared Batrachoseps attenuatus body condition and the presence/absence of the amphibian skin pathogen Batrachochytrium dendrobatidis. We found that Eucalyptus invasion had no measurable effect on soil microbial community diversity and a relatively small effect (compared to the effect of site identity) on community structure in the microhabitats sampled. In contrast, our results show that Batrachoseps attenuatus skin microbiota diversity was greater in Quercus dominated habitats. One amplicon sequence variant identified in the family Chlamydiaceae was observed in higher relative abundance among salamanders sampled in Eucalyptus dominated habitats. We also observed that Batrachoseps attenuatus body condition was higher in Quercus dominated habitats. Incidence of Batrachochytrium dendrobatidis across all individuals was very low . The effect on body condition demonstrates that although Eucalyptus may not always decrease amphibian abundance or diversity, it can potentially have cryptic negative effects. Our findings prompt further work to determine the mechanisms that lead to changes in the health and microbiome of native species post-plant invasion.Invasive plants are major drivers of habitat modification and the scale of their impact is increasing globally as anthropogenic activities facilitate their spread. In California, an invasive plant genus of great concern is  Anthropogenic habitat modification has dramatic direct and indirect effects on wild animal populations . InvasivOne way that invasive plants impact native animal populations is by altering their microbial commensals. Plant invasions could influence the microbial community structure of native fauna by changing microbial communities that hosts are exposed to, by altering host physiology, or both . InvasioEucalyptus sp.  resulting in changes in soil microbial communities  and native Quercus agrifolia (Fagaceae) dominated forests in the San Francisco Bay Area. Specifically, we determined whether changes in microbial composition, diversity and stability in both soil and Batrachoseps attenuatus skin were associated with Eucalyptus or Quercus dominated habitat. To evaluate animal health across Eucalyptus and Quercus dominated habitats, we also measured and compared Batrachoseps attenuatus body condition and the presence/absence of the amphibian chytrid fungus Batrachochytrium dendrobatidis, which causes the lethal amphibian disease chytridiomycosis. Our results illustrate a decline in the richness of skin associated microbiota and a decrease in salamander body condition in Eucalyptus forest, illustrating that plant invasions may have consequences for native species.To investigate potential changes induced by invasive vegetation on environmental and host-associated microbial communities, we sampled microhabitat soil and Eucalyptus invasions on native fauna and their microbiotas. The Bay Area is home to numerous seed-producing stands of E. globulus, E. pulchella, and E. viminalis among a mosaic of mixed native evergreen forests and coastal scrublands. The discrete—yet interspersed—distribution of invasive and native vegetation types in the Bay Area make it an ideal location to evaluate vegetation effects on resident host-associated microbiotas while controlling for geography. In addition, multiple ground dwelling amphibians are distributed throughout the Bay Area and may be sensitive to effects of invasive Eucalyptus on the skin microbiome  because of their highly-limited dispersal  as it has been eroded by a nearby stream, and instead chose a new site with similar characteristics.The San Francisco Bay Area (Bay Area) provides an opportunity to test the effect of crobiome . One ampy campus . To miniBatrachoseps attenuatus skin swabs from Quercus and 28 from Eucalyptus dominated habitats . Access to off-campus sampling sites was granted by East Bay Regional Parks under permit # 965. We collected salamanders by hand using gloves through log flip surveys within ~100 m of the location coordinates. New gloves were donned between the handling of each salamander. To avoid resampling individuals and ensure that salamanders were later returned to their original capture site, we marked each capture log with the individual(s) identification number. We rinsed each salamander with 250 mL of sterile water and swabbed the dorsum with a sterile cotton swab 30 times. Following microbiota sampling, we measured each salamanders’ total body length and mass. All salamanders were returned to their location of capture immediately after sampling. To characterize the microhabitat microbiota, we collected ~20 mg of soil or soil swabs directly from under the logs where each salamander was captured after releasing each individual. We collected 22 habitats . All samWe isolated DNA from skin swab samples using the DNeasy PowerSoil DNA Isolation Kit  following the modifications to the manufacturer’s protocol described in We performed a second PCR on microbiota amplicons to ligate dual-index barcodes paired with Illumina sequencing adaptors  to the eBatrachochytrium dendrobatidis infection in our swabbed individuals, we performed real-time quantitative PCR (qPCR) reactions in duplicate following Batrachochytrium dendrobatidis zoospore standard dilution ranging from 100,000 to 0.1 genomic equivalents. These zoospore standards were prepared using the Bd-GPL strain CJB7–originally isolated from Kings Canyon, CA. At least three reactions per 96-well plate were designated as negative controls, with each receiving five µL of water in lieu of template DNA. To reduce the risk of laboratory contamination we set up qPCR reactions in a laminar flow hood. We ran all qPCR reactions on an Applied Biosystems StepOnePlus Real-Time PCR System , and used the manufacturer’s software for standard curve analysis. We considered an average qPCR quantification of less than one genomic equivalent per swab to be negative for Batrachochytrium dendrobatidis infection.To detect and quantify We processed raw sequencing reads using Trimmomatic  to removPRJNA574188).Our microbiota sequence analysis consisted of established sequence read processing pipelines to filter erroneous reads, generate an amplicon sequence variant  table, create a representative sequence phylogeny and assign taxonomy to ASVs. We chose to use ASVs rather than operational taxonomic units (OTUs), because ASVs provide greater resolution in amplicon differentiation . ASV varvegan and picante: community richness , evenness  and phylogenetic diversity . We calculated these metrics in order to evaluate differences in the number of ASVs (community richness), distribution of ASV frequencies within samples (Shannon diversity index), and phylogenetic representation (Faith’s phylogenetic diversity) across sample groups. To assess differences in community composition across samples, we applied the R packages GuniFrac and vegan to calculate three separate beta diversity metrics: pairwise unweighted/weighted UniFrac distances and Bray–Curtis dissimilarities. We chose to include these beta diversity metrics as they account for differences in presence/absence of phylogenetic lineages among samples (unweighted UniFrac), abundance-based differences in phylogenetic lineages among samples (weighted UniFrac), and non-phylogenetic abundance-based differences among samples (Bray–Curtis). In addition, we computed the core microbiomes  of Eucalyptus soil, Eucalyptus salamander skin, Quercus soil and Quercus salamander skin samples.We transferred the rarefied ASV table and Newick phylogeny to R (version 3.5.1) for further analyses. A Shapiro–Wilk test in R was implemented on all univariate dependent variables to evaluate normality prior to statistical model selection. We calculated three distinct alpha diversity metrics using the R packages Effects of Eucalyptus invasion on soil bacterial composition, diversity, and stability: We evaluated differences in soil community diversity, composition and community homogeneity between Quercus and Eucalyptus dominated habitats. To evaluate differences in alpha diversity between soil communities sampled in Quercus and Eucalyptus dominated habitats, we implemented community richness, Shannon diversity indices and phylogenetic diversity as dependent variables, habitat type as a fixed variable and site identity as a random variable in linear mixed models . The significance of the predictor variable was calculated with likelihood ratio tests (LRT). To characterize the strength and significance of soil community compositional and structural differentiation among habitat types, we implemented three PERMANOVA tests (R package vegan) using weighted UniFrac, unweighted UniFrac, and Bray–Curtis dissimilarity matrices as dependent variables and site identity as a random variable. We produced NMDS plots using the three dissimilarity matrices to visualize clustering of samples by habitat and site identity using the R package phyloseq. To assess whether habitat type influenced variation in soil community structure, we performed three separate multivariate of homogeneity of group dispersions analyses (R package vegan) using the beta diversity metrics. For each beta diversity metric, we used a one-way ANOVA to test differences in point-to-centroid distances between soil samples obtained from Eucalyptus and Quercus dominated habitats. We implemented an indicator species analysis using the R package indicspecies to identify ASVs whose relative abundance differs between soil samples collected in Eucalyptus and Quercus dominated habitats.Effects of Eucalyptus invasion on Batrachoseps attenuatus bacterial composition, diversity and stability: To assess whether salamander skin microbiota sampled in Quercus or Eucalyptus dominated habitat differ in their overlap with microhabitat microbiota, we calculated average unweighted UniFrac, weighted UniFrac, and Bray–Curtis dissimilarity values between every salamander skin sample and all environmental samples in its corresponding site. We used these dissimilarities as dependent variables in a generalized linear mixed model using a logit distribution with habitat type as a fixed variable and site as a random variable. We also evaluated whether skin microbial community diversity, composition and heterogeneity differed between Batrachoseps attenuatus sampled in Quercus and Eucalyptus dominated habitats. We assessed differences in community richness, Shannon diversity indices, and phylogenetic diversity between salamander skin communities sampled in Quercus and Eucalyptus dominated habitats using linear mixed models as described above. We ran PERMANOVA tests using weighted UniFrac, unweighted UniFrac, and Bray–Curtis dissimilarities as dependent variables, habitat type as a fixed variable and site identity as a random variable to evaluate variation in community composition and structure. We produced NMDS plots using the three dissimilarity matrices to visualize clustering of skin samples by habitat and site identity. We also performed three separate multivariate of homogeneity of group dispersions analyses to evaluate how habitat type influenced variation in community structure among individuals in the same group. For each beta diversity metric, we used a one-way ANOVA to test differences in point-to-centroid distances between Eucalyptus and Quercus salamander skin microbial communities. We implemented an indicator species analysis using the R package indicspecies to identify ASVs whose relative abundance differs between salamander skin samples collected in Eucalyptus and Quercus dominated habitats. Lastly, we assessed patterns of isolation by distance (IBD) by comparing our three dissimilarity matrices of community composition to a Euclidean geographic distance matrix between sampling locations. We tested for significance of IBD through mantel tests using R package ade4  with site identity as a random factor. Lastly, we evaluated whether there were correlations between skin alpha diversity metrics  and body condition using Pearson correlation tests.tebrates . We omitEucalyptus and Quercus dominated habitats . The core microbial communities of Eucalyptus dominated habitat soil samples (16 ASVs) were composed of ASV’s characterized as Actinobacteria  and Proteobacteria . In contrast, the core microbiome of Quercus dominated habitat soil samples was composed of eight ASV’s characterized as Actinobacteria , Bacteroidetes , Proteobacteria , and Verrucomicrobia . The indicator species analysis identified 216 ASVs that differed significantly between habitat types with 122 associated with Eucalytpus soil samples and 94 associated with Quercus soil samples , weighted UniFrac , or Bray–Curtis dissimilarities . Microbial community richness and phylogenetic diversity were significantly lower for salamanders in Eucalyptus dominated habitat compared to salamanders sampled in Quercus habitats  but not for Bray–Curtis dissimilarities  but no patterns of IBD with both our weighted and unweighted UniFrac matrices .We did not observe differences in composition and structure between skin and corresponding soil samples among Eucalyptus dominated habitat was comprised entirely of ASVs assigned to the phylum Proteobacteria . The core microbiota of salamander skin samples collected in Quercus dominated habitat was richer in that it possessed 32 ASVs assigned to the phyla Actinobacteria , Chloroflexi , Proteobacteria , and Verrucomicrobia . As observed in the soil core microbial communities, salamander skin core ASVs consisted mostly of rare taxa . However, we found one skin ASV identified as Bordetella petrii to dominate skin communities in Eucalyptus (29.81%) and Quercus (20.45%) dominated habitats. The indicator species analysis identified 294 ASVs that differed significantly between habitat types with 36 associated with Eucalyptus salamander skin samples and 258 associated with Quercus salamander skin samples  compared to individuals collected in Quercus dominated habitats .The core microbiota of salamander skin samples collected in  samples . As obseEucalyptus and Quercus dominated habitats . Salamanders sampled in Quercus dominated habitat possessed higher body condition indices than those sampled from the Eucalyptus dominated habitat , Shannon diversity index , or Faith’s phylogenetic diversity . One salamander (OHG-47_S202) tested positive for Batrachochytrium dendrobatidis with a low average infection load of 41.59 zoospore equivalents .Body condition indices differed significantly between salamanders sampled in  habitat . We did ivalents . The preEucalyptus and Quercus dominated sites. Thus, the filter acting on microbial richness is likely operating at the host level, rather than the passive uptake of different soil microbial communities. At the individual level, we found differences in native salamander skin microbial diversity and body condition associated with Eucalyptus invasion. We also observed higher salamander skin microbial composition heterogeneity and relative abundances of an ASV identified to the family Chlamydiaceae in salamanders inhabiting Eucalyptus dominated habitats.We observed no differences in richness, little variation in community composition and structure, and similar differentiation between soil and skin samples across Eucalyptus sites. In addition, a small fraction of the variation in community composition among soil samples was explained by vegetation type. This finding is surprising given the documented shifts in soil microbiomes following plant invasions –in the Eucalyptus samples. While we cannot differentiate among these two possibilities using 16S rRNA amplicon sequencing alone, this pattern could reflect microbial community changes due to environmental filters present in the Eucalyptus dominated habitat. Changes in the relative abundance of core bacteria and alpha diversity have been documented in previous studies assessing the effects of environmental changes  on the skin microbiota of amphibians  has not been established . Additionally, Batrachoseps attenuatus’ high site fidelity, relatively short dispersal distances and association with fallen logs may decrease differences compared to surrounding leaf litter, which may show greater microbial composition differences between sites  possess distinct skin microbial communities  and biotic factors  may have disproportionate effects on the persistence of distinct rare bacteria in these salamanders. The loss of bacterial species in salamanders inhabiting Eucalyptus habitat may vary by individual- and site-specific factors that were not measured in the current study. Heterogeneous responses of microbial communities have been demonstrated for soil microbes in response to silviculture and agricultural practices , it is possible that an increase in Chlamydiaceae in the skin of salamanders results from microbial dysbiosis  than those in native Quercus woodland . Interestingly, we found differences in the skin microbial community of the native salamander Batrachoseps attenuatus, but no differences in soil microbial communities between Eucalyptus and Quercus habitats. We also found decreased body condition of this native salamander in Eucalyptus dominated habitats. Our findings prompt further experimental work to determine the mechanisms causing these microbial changes and their potential effect on the fitness of native fauna following invasion.To our knowledge, our study is the first to demonstrate changes in the microbial communities of native hosts associated with plant invasion (10.7717/peerj.8549/supp-1Supplemental Information 1Click here for additional data file.


Neoadjuvant therapy with conventional chemotherapies have visibly improved the prognosis of locally advanced pancreatic cancer (PCa). However, molecular targeted therapies that have provided durable responses in other tumor entities, have not yet found access into neoadjuvant therapy of PCa. In fact, due to the presence of the tumor burden serving as an antigen source for T cell priming, neoadjuvant chemotherapy may unleash a more potent antitumoral immune response than adjuvant or palliative chemotherapy. Despite tremendous efforts, successful therapy of pancreatic cancer (PCa) remains a major challenge . FindingCancer immunotherapy, led by immune checkpoint inhibitors (ICI) and cancer vaccines have shown notable long-term efficacy in many solid malignancies . The limAdoptive immunotherapy involves injecting antitumor-programmed immune cells into the patient. New directions are pointing to tumor lysate-pulsed dendritic cells , 12 or tThe failure of immunotherapy in PCa may be partly due to the exclusion of T cells by cancer-associated fibroblasts (CAF) and the impaired drug delivery caused by increased hydrostatic pressure and the poor vascularization in the highly fibrotic pancreatic stroma . Exploitin vitro and in the in vivo murine xenograft model and inhibited PCa growth [While metabolic plasticity has long been recognized as a hallmark of cancer, we have only recently started to exploit the differences between cancer cell and normal cell metabolism . Metabola growth .Our growing understanding of the PCa biology has led to the development of novel immunotherapies as well as drugs targeting key regulators of the stromal and tumor metabolism. However, the full potential of these agents has been hampered by the presence of therapeutic resistance, resulting from intrinsic compensatory signalling pathways and mutagenic evolution . Only co


Older residents often experience disruption in family relationships and social networks due to isolation once they move into public housing communities. While the need for social contact continues, the opportunity may diminish. Older African-American women living in one housing community attempted to cope with their personal safety fears through social isolation . Women in the study (N = 25) were survivors of one or more forms of interpersonal trauma, including childhood abuse, sexual assault and domestic violence. In contrast, a few women in the same sample spontaneously formed social networks within the community. This qualitative investigation will examine how the women adapted to an isolating and unsafe environment by developing social connections. As a social determinant of health, developing healthy social networks inside a housing community can reduce fear and improve well-being and quality of life for low-income older residents who are aging-in-place.


Methamphetamines are commonly abused drugs for their stimulant and euphoric effects. Inhaled and intravenous use may cause damage to the respiratory system. Spontaneous pneumomediastinum is a condition where changes in intrathoracic pressure leads to alveolar rupture and dissection of air along the tracheobronchial tree. Massive subcutaneous emphysema may result from pneumomediastinum which may compromise the central airway. In this case report, we present an unusual case of spontaneous pneumomediastinum and severe subcutaneous emphysema following inhalation of methamphetamine. This case emphasizes the rising concern on the acute respiratory complications of methamphetamine use. Inhaled and intravenous use of stimulants may cause a variety of respiratory injuries. These injuries include but are not limited to nasal septum perforation, pulmonary vascular disease, pulmonary hemorrhage, thermal injury, pulmonary edema, and pneumothorax . SpontanA twenty-two-year-old previously healthy male presented to the emergency department for worsening facial and neck swelling. He noticed worsening dyspnea accompanied by facial swelling a few hours after smoking methamphetamine. Within a few minutes in the emergency room, the patient's mental status declined with more labored breathing; thus, the patient was electively intubated for airway protection. Differential diagnosis was acute allergic reaction to illicit drugs causing upper airway compromise versus acute inhalational injury. Initial chest computed tomography (CT) showed extensive pneumomediastinum with air dissecting to the peribronchovascular interstitial sheaths, interlobular septa, and visceral pleura Figures . There wMechanical ventilation was adjusted having very minimal to no positive expiratory pressure (PEEP) and prolonged expiratory phase. Placement of chest blow holes was not pursued as swelling on the face and neck improved after a few hours. The suspicion for tracheobronchial tree injury was low; thus, we did not perform bronchoscopic surveillance of the airway. Patient received empiric antibiotic treatment with ampicillin sulbactam. The patient was extubated in less than 24 hours after the improvement of peak inspiratory and plateau pressures with the positive cuff leak test. Repeat chest imaging showed decreased subcutaneous emphysema and resolution of pneumomediastinum. No dietary restriction was recommended after extubation as there was no evidence of aerodigestive organ injury. The patient was discharged after 72 hours with improved symptoms.Pulmonary complications have been reported with the use of illicit stimulants. Some recognized respiratory complications are nasal septum perforation, pulmonary vascular disease, pulmonary hemorrhage, pulmonary edema, and pneumothorax . Our casPlain chest X-ray including computed tomography (CT) is an adequate evaluation procedure after a thorough history and physical examination to exclude secondary pneumomediastinum . In one Spontaneous pneumomediastinum is often a self-limiting disease; however, due to concerns for the integrity of the aerodigestive tract, this finding usually results to unnecessary radiological investigations and antibiotic use. In one case series, spontaneous pneumomediastinum is overinvestigated and overtreated; thus, clinicians need to be more judicious with the use of hospital resources in managing patients with spontaneous pneumomediastinum . For thi


Chronic traumatic encephalopathy (CTE) is a neurodegenerative condition associated with significant mortality and morbidity. The central pathophysiological mechanisms by which repetitive cranial injury results in the neurodegeneration of CTE are poorly understood. Current well-established working models emphasize a central role for trauma-induced excessive phosphorylation and accumulation of insoluble tangles of Tau protein. In this review, we summarize recent data from preclinical animal models of CTE where a series of candidate treatments have been carefully evaluated, including kinase inhibitors, antibody therapy, and anti-inflammatory therapies. We discuss the overall translational potential of these approaches and provide recommendations for future bench-to-bedside treatment strategies. Initial symptoms manifest as non-specific cognitive and neuropsychiatric impairments, including depression and heightened aggression, and eventually progress to include a variety of motor impairments and cognitive decline . While tlistica) , it has listica) . In a relistica) . Militarlistica) . Aside fcted CTE .The initial symptoms of CTE may not occur until years or even decades after rmTBI and may affect cognitive and/or emotional domains. By one classification system, symptoms occurring in more than 50% of “mild” CTE (Stages 1 or 2) include impulsivity, depression, physical and verbal violence, memory loss, and suicidality. Severe CTE (Stages 3 or 4) is characterized by additional symptoms such as language impairments, visuospatial deficits, parkinsonism, and dementia-like deficits . CTE is While there remain many unknowns about the molecular and cellular pathological changes that are presumably incited by repeated cranial impact, a strong consensus has unified around the pathophysiological role of hyperphosphorylated tau (“p-tau”) accumulation and neurofibrillary tangle (NFT) formation . Thus, Cin vivo premortem diagnostic markers. In particular, PET imaging with radiotracers such as [F-18]FDDNP (which binds insoluble protein aggregates) has been used to identify tau and beta-amyloid patterns consistent with CTE  and CTE remains somewhat enigmatic. Both tauopathies share a series of culprit tau phosphorylation sites  and TBI Given the major knowledge gaps in our understanding of CTE pathogenesis, as well as limitations in available premortem diagnostic biomarkers, it is not surprising that there are currently no ongoing clinical trials for the treatment of CTE. However, in light of the proposed pathophysiological overlaps between AD and CTE, several therapies that have demonstrated preclinical success in AD models have now been applied to CTE models. This review summarizes key recent findings within this body of literature which have focused on accumulations of hyperphosphorylated tau aggregates as both a direct mediator of neuronal injury and a histological biomarker of disease severity.By definition, the vast majority of CTE diagnoses occur in individuals with a self-reported or witnessed history of contact-sport-related head injuries or military-related blast exposure . AccordiThis approach does have drawbacks: secondary injuries such as cranial fracture or intracranial hemorrhage do occur at some measurable rate . AdditioWhile the more nuanced aspects of CTE-related cellular and molecular derangements remain an active area of research, most agree that a valid preclinical model of CTE should demonstrate evidence of a phosphorylated tauopathy in response to rmTBI. In this regard, insights into CTE pathophysiology may be borrowed from transgenic Alzheimer’s disease models such as TauP301L and 3xTg-AD, with the caveat that these mice develop amyloid and tau pathology even in the absence of rmTBI . Other myears of participation in a contact sport and include individuals who have only received sub-concussive impacts  permeability is one of the main factors limiting the efficacy of antibody treatment in CTE and other neurological diseases. Recent advances in ultrasound technology may be used to aid immune response or drug delivery across the BBB. Unilateral focused ultrasound (FUS) has been a candidate method used to increase BBB permeability by producing transient openings in endothelial tight junctions . Recentl the BBB . In an A the BBB . In conjrvention . While trvention . Low-intrvention  and AD  are also involved in pathological tau hyperphosphorylation. The potent CDK inhibitor roscovitine has been studied in models of TBI and demonstrated attenuation of neurodegeneration in a model of controlled cortical impact in mice . CombiniBeyond tau hyperphosphorylation, the progression of CTE is thought to include a complex cascade of secondary inflammatory and metabolic changes that may also represent potential targets for therapeutic intervention . Ionic iThe production of reactive oxidative species and mitochondrial stress likely plays a key role in driving neuronal ischemia in CTE . These pSadly, despite increasing recognition among athletes and military personnel, there are currently no available treatments for CTE or practical clinical diagnostic markers to identify at-risk individuals. Fortunately, with a detailed neuropathological description from postmortem samples combined with preclinical models that have been inspired by the Alzheimer’s field, we are closer to obtaining a comprehensive pathophysiological understanding of CTE. Like AD, CTE is a progressive neurodegenerative disease that appears to propagate via tau phosphorylation and subsequent aggregation into neurofibrillary tangles. At the same time, trauma-induced changes in circuit function may borrow from prior research in severe traumatic brain injury. While research on these related conditions may shed light on CTE pathology, it also warns of potential pitfalls. In particular, both AD and severe TBI  have suftrans to pathogenic cis form has driven the development of isoform-specific phosphorylated tau monoclonal antibodies. The use of immunotherapy is one of the most promising strategies to treat CTE and other neurodegenerative diseases but suffers from poor translational efficiency. Techniques such as FUS/LIPUS may be used in conjunction with antibody treatment to improve the delivery of cis p-tau antibodies and immune agents across the blood–brain barrier.Perhaps the most intuitive way to halt the progress of CTE is to inhibit processes directly affecting tau phosphorylation and aggregation. Given tau’s multiple physiological functions, therapies must selectively inhibit formation and spreading of pathogenic tau. A profile of kinases directly phosphorylating tau in CTE has been developed and opened the door to a number of kinase inhibitors such as roscovitine and lithium which have shown promising preclinical results. The recent finding that tau is converted from a functional As these candidate therapies move forward to clinical phases, researchers should note the failure of dementia research to produce successful clinical trials . Why do PB and VK played significant roles in the initial manuscript drafts and subsequent revisions.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The potential importance of germline genetic variation for identifying men at increased risk of prostate cancer has become increasingly recognised in recent years. We present an extensive review of the major developments in the identification of genetic loci, genes and individual variants associated with greater risk of prostate cancer, and what is currently known regarding whether these heritable prostate cancer risk factors can also inform likelihood of experiencing clinically significant rather than indolent forms of the disease. We finally discuss how these research discoveries might serve to inform clinical germline genetic testing guidelines and treatment options for prostate cancer in the future.Prostate cancer (PrCa) is a heterogeneous disease, which presents in individual patients across a diverse phenotypic spectrum ranging from indolent to fatal forms. No robust biomarkers are currently available to enable routine screening for PrCa or to distinguish clinically significant forms, therefore late stage identification of advanced disease and overdiagnosis plus overtreatment of insignificant disease both remain areas of concern in healthcare provision. PrCa has a substantial heritable component, and technological advances since the completion of the Human Genome Project have facilitated improved identification of inherited genetic factors influencing susceptibility to development of the disease within families and populations. These genetic markers hold promise to enable improved understanding of the biological mechanisms underpinning PrCa development, facilitate genetically informed PrCa screening programmes and guide appropriate treatment provision. However, insight remains largely lacking regarding many aspects of their manifestation; especially in relation to genes associated with aggressive phenotypes, risk factors in non-European populations and appropriate approaches to enable accurate stratification of higher and lower risk individuals. This review discusses the methodology used in the elucidation of genetic loci, genes and individual causal variants responsible for modulating PrCa susceptibility; the current state of understanding of the allelic spectrum contributing to PrCa risk; and prospective future translational applications of these discoveries in the developing eras of genomics and personalised medicine. Prostate cancer (PrCa) is the most frequently diagnosed cancer in males in Europe and North America and second most common worldwide, with over 1.4 million diagnoses recorded in 2020 ,4.Although several promising molecular and genomic biomarkers for PrCa diagnosis or management have been identified in recent years , prostatNo consistent, consensus definition of aggressive PrCa has thus far been adopted within the research or clinical settings, which can hinder comparability of studies to identify risk factors and uniformity of clinical treatment application. Prior to the advent of PSA testing, aggressive PrCa had been considered to encompass only cancers which had advanced beyond the prostate itself . More reThe most clearly established risk factors for PrCa are increased age, ethnicity and family history of PrCa and certain other cancers. Familial aggregation of PrCa is one of the strongest risk factors, and provided support for the likely existence of genetic risk factors shared among families. Men with one male first-degree relative  diagnosed with PrCa themselves have an estimated relative risk of approximately 2.5, and risk of diagnosis with PrCa further increases for men with multiple affected FDRs and lower ages at their diagnoses ,14,15. REvidence has also been presented for clustering of aggressive clinical presentation of PrCa within families, suggestive for heritability of aggressive PrCa phenotypes. A number of studies from the Swedish population have demonstrated increased risk of high grade PrCa observed among brothers of cases with high grade disease , with grBRCA1 and BRCA2 genes, whilst Lynch syndrome is categorised by germline mutations in DNA mismatch repair genes. A strong family history of PrCa remains a more effective indicator of PrCa risk than family history of other cancer types however, especially with respect to early-onset and lethal disease . This is consistent with previous reports that the KLK3 GWAS SNP rs2735839 is associated with Gleason score in addition to overall disease risk  or remained associated with aggressive status among only patients with low PSA levels from two separate ancestral populations [KLK3 variation in PrCa susceptibility, risk of aggressive disease and serum PSA levels may therefore warrant more extensive investigation, especially in prospective or PSA naïve cohorts, and may have the potential to enable the identification of a subset of individuals at lower risk of poor prognosis disease who could benefit from less interventionist treatment options.Case-only GWAS have to date reported at a genome-wide significant threshold two loci associated with Gleason score , one wit of PrCa , whilst  of PrCa ,242. Thease risk ,246,247.ulations . The fulWhilst these initial case-only reports imply that caution is warranted regarding the potential for GWAS loci to be able to accurately stratify PrCa patients more likely to develop clinically significant disease, increasing evidence supports the improving ability of genetic risk scores  incorporating ever larger numbers of established susceptibility variants to identify a population subset at greater lifetime risk of diagnosis with PrCa of any severity ,256,257.Although the ability of GRS to predict disease status within cohort studies has been demonstrated for various traits, their potential clinical utility to inform screening decisions for individual members of the population does however largely remain to be established at this point in time. Their potential consideration for implementation as a prospective risk-profiling tool prior to screening for PrCa may, however, soon become warranted. A polygenic hazard score (PHS) has demonstrated initial promise for the detection of clinically significant PrCa at younger age among higher PHS percentiles ,264, incAlthough many common loci have been identified which contribute substantially towards PrCa risk, rare variation is also estimated to play an important role in PrCa heritability , especiaBRCA2 gene, confirming earlier observations linking BRCA2 mutation carriers to more aggressive phenotypes through other approaches [ATM, BRCA1 and PALB2  and HOXB13. The latest National Comprehensive Cancer Network (NCCN) guidelines for germline testing also propose screening CHEK2 and PALB2 as part of their minimum recommended predisposition gene panel [TP53 plus additional DNA repair genes including BRIP1 and NBN have also been proposed for inclusion on screening panels, but await more definitive evidence to achieve consensus of utility [ATM, BRCA1, BRCA2 and potentially other DNA repair genes may inform response to PARP inhibitors [BRCA1, BRCA2 and other DNA repair genes sensitivity to platinum chemotherapy [Germline testing for rare moderate penetrance pathogenic variants in specific genes is becoming an increasingly important focus of PrCa management and treatment, with the additional promise of guiding tailored therapeutic interventions appropriate for targeting specific molecular vulnerabilities in individual patients’ tumours. Although few genes have been conclusively identified to date in which rare variants confer higher risk of developing aggressive PrCa, as further larger, cross population sequencing studies and meta-analyses are performed, additional genes for which mutation carriers experience greater risk of aggressive disease and/or more favourable response to particular treatment options are likely to be established . At presne panel . The tum utility . In patihibitors ,305,306,otherapy ,308, andotherapy ,310. InvAlthough family history of the disease is usually the main reason for genetic testing of men without a diagnosis of PrCa, an appreciable proportion of PrCa patients without a family history sufficient to meet NCCN guidelines for germline genetic testing have also been demonstrated to carry rare germline putative PrCa susceptibility variants . Even grThe majority of samples included in studies investigating risk factors for PrCa to date have been from populations of European ancestry. However, given differing allelic architecture and frequencies of both rare and common variants between populations, in addition to the higher incidence and poorer prognosis of PrCa among men of African descent, reducing under-representation of additional ethnicities in PrCa research remains an unmet requirement in order to ensure applicability of discoveries across populations and pan-ethnic access to healthcare improvements ,312,313.


On July 28, the correctional officer had multiplebrief encounters with six incarcerated or detained persons (IDPs)Subsequently, VDH and facility staff members reviewed July 28 quarantine unit videosurveillance footage and standard correctional officer shift duty responsibilities toapproximate the frequency and duration of interactions between the correctional officerand infectious IDPs during the work shift . AlthougThe correctional officer reported no other known close contact exposures to persons withCOVID-19 outside work and no travel outside Vermont during the 14 days preceding illnessonset. COVID-19 cumulative incidence in his county of residence and where thecorrectional facility is located was relatively low at the time of the investigation , suggesting that his most likely exposures occurred in thecorrectional facility through multiple brief encounters  with IDPs who later received apositive SARS-CoV-2 test result.Among seven employees with exposures to the infectious IDPs that did meet the VDH closecontact definition, one person received a positive test result. Among thirteen employees with exposures to the infectious IDPs that did notmeet the VDH close contact definition during contact tracing, only the correctionalofficer received a positive SARS-CoV-2 test result.Data are limited to precisely define “close contact”; however, 15 minutesof close exposure is used as an operational definition for contact tracinginvestigations in many settings. Additional factors to consider when defining closecontact include proximity, the duration of exposure, whether the infected person hassymptoms, whether the infected person was likely to generate respiratory aerosols, andenvironmental factors such as adequacy of ventilation and crowding. A primary purpose ofcontact tracing is to identify persons with higher risk exposures and therefore higherprobabilities of developing infection, which can guide decisions on quarantining andwork restrictions. Although the initial assessment did not suggest that the officer hadclose contact exposures, detailed review of video footage identified that the cumulativeduration of exposures exceeded 15 minutes. In correctional settings, frequent encountersof ≤6 feet between IDPs and facility staff members are necessary; public healthofficials should consider transmission-risk implications of cumulative exposure timewithin such settings.


With advancing age, the incidence rate of Alzheimer’s disease and dementia gradually increases, and mortality from either Alzheimer’s disease or dementia has increased in recent decades . RecentlPostmenopausal women experience a dramatic decrease in circulating estrogen level. Due to the cardio-protective effect of estrogen, premenopausal women are exposed to a lower risk of cardiovascular disease compared to postmenopausal women. Elastic conduit arteries including the aorta are more vulnerable to either internal or external stimulation than smaller muscular vasculatures because of their anatomical characteristics. Thus, central artery stiffness measures such as pulse wave analysis (augmentation index) and aortic pulse wave velocity are used as validated surrogate markers to predict future cardiovascular morbidity and mortality. Elastic central arteries in postmenopausal women older than 60 yr of age are in particular stiffer than pre- or postmenopausal women under 60 yr of age . In a reRegular physical activity including aerobic and resistance exercise is recommended for postmenopausal women to improve not only musculoskeletal and cardiovascular function, but also cognitive function. Three months of combined circuit exercise reduce arterial stiffness and other cardiovascular disease risks in hypertensive postmenopausal women. FurtherCompared to continuous exercise, high-intensity interval exercise can be more beneficial in enhancing cognitive function via not only decreased central artery stiffness but also facilitated neurotrophic factors production and increased neurotrophic factor bioavailability in postmenopausal women. The hypoxia state in high-intensity aerobic exercise increases VEGF production. In particular, intermittent hypoxia for high-intensity interval exercise facilitates the generation of BDNF, the most important neuroplasticity marker, in the cerebrovascular endothelium. Furthermore, lactate, a byproduct of high-intensity exercise, can be used to facilitate BDNF and VEGF generation in peripheral tissues and is an additional energy resource for brain neuron activity. Both the BDNF and VEGF produced in peripheral tissues can directly facilitate neuroplasticity in the central nervous system after passing through the blood brain barrier.Future studies are warranted to comprehensively investigate the effects of high-intensity interval training on central artery stiffness, neuroplasticity, and cognitive function, and elucidate the associated physiological mechanisms in postmenopausal women, the population most vulnerable to cardiovascular events and cognitive impairment.


TERT promoter mutations are the most common somatic alteration identified in UBC. In this study, we analyzed different histological tissues from whole-organ mapping bladder cancer specimens to reveal TERT mutational status, as well as to discern how tumors develop. Methods: Up to 23 tissues from nine whole-organ mapping bladder tumor specimens, were tested for TERT promoter mutations including tumor associated normal urothelium, non-invasive urothelial lesions , carcinoma in situ (CIS) and different areas of muscle invasive bladder cancers (MIBC). The mutational DNA hotspot region within the TERT promoter was analyzed by SNaPshot analysis including three hot spot regions . Telomere length was measured by the Relative Human Telomere Length Quantification qPCR Assay Kit. Results: TERT promoter mutations were identified in tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC. Analysis of separate regions of the MIBC showed 100% concordance of TERT promoter mutations within a respective whole-organ bladder specimen. Polyclonal events were observed in five out of nine whole-organ mapping bladder cancers housing tumor associated normal urothelium, non-invasive urothelial lesions and CIS where different TERT promoter mutations were found compared to MIBC. The remaining four whole-organ mapping bladders were monoclonal for TERT mutations. No significant differences of telomere length were observed. Conclusions: Examining multiple whole-organ mapping bladders we conclude that TERT promoter mutations may be an early step in bladder cancer carcinogenesis as supported by TERT mutations detected in tumor associated normal urothelium as well as non-invasive urothelial lesions. Since mutated TERT promoter regions within non-invasive urothelial lesions are not sufficient alone for the establishment of cancerous growth, this points to the contribution of other gene mutations as a requirement for tumor development.Background: Multifocal occurrence is a main characteristic of urothelial bladder cancer (UBC). Whether urothelial transformation is caused by monoclonal events within the urothelium, or by polyclonal unrelated events resulting in several tumor clones is still under debate.  TERT) promoter mutations occur in 60–80% of all urothelial bladder cancers (UBC) independent of tumor stage and grading thus, represent the most frequent alteration in this tumor entity [TERT [TERT promoter mutations in UBC are found in 99% of tissue samples at position −124 and −146 base pairs upstream from the ATG transcriptional start site position and are responsible for aberrant telomerase activity [TERT mutational incidence rates in UBC several studies proposed a possible role implementing these alterations in urinary testing and as a follow-up diagnostic tool [Telomerase reverse transcriptase  and CIS as well as the tumor mass [Archival material of the Institute of Pathology, Erlangen was retrospectively evaluated and available bladder cancer specimens diagnosed as MIBC were screened for mor mass . All themor mass . A schemmor mass . PatholoTERT promoter mutated tumor associated normal urothelium as well as non-invasive urothelial lesions from the whole-organ mapping bladder specimens were immunohistochemically evaluated for CK20, CD44, TP53 and MIB1 staining. CK20 and CD44 were chosen as differentiation markers, which show distinct staining patterns among normal urothelium as well as for non-invasive urothelial lesions thus, are used for routine diagnostic evaluation. P53 evaluation as well as MIB1 staining is also used for evaluation of distinguishing normal urothelium as well as for non-invasive urothelial lesions [TERT promoter mutations and used for immunohistochemistry as preformed with a Ventana BenchMark Ultra  and a Dako Link 48  autostainer accreditated by the German Accreditation Office (DAKKs) according to DIN EN ISO/IEC 17020. Detail information of the used antibodies are displayed in All  lesions . Whole t® 16 System, Promega, Mannheim, Germany) according to the manufacturer’s instructions. The tissue component from each tumor associated normal urothelium as well as non-invasive urothelial lesions, CIS and MIBC was manually microdissected from marked areas on each consecutive tissue slide derived from its corresponding tissue block in order to achieve at least 80% purity. DNA isolation was performed using the DNA preparation kit . The usage of labelled dideoxynucleotides enables the identification of the nucleotide base at the site of interest . After a denaturation step at 90 °C for five minutes the detection was performed with capillary electrophoresis using an ABI 3500 Genetic analyzer .The digestion of the remaining primers and free deoxynucleotides after PCR amplification was performed with alkaline phosphatase  and an exonuclease . . The mulinterest . Two difTelomere length was analyzed by Relative Human Telomere Length Quantification qPCR Assay Kit  according to the Manufacturer’s instruction. Telomere length is recognized and amplified by comparing samples to reference genomic DNA containing a 100-base pair (bp) telomere sequence located on human chromosome 17. The total as well as the average telomere length was then calculated. p-Values < 0.05 represented statistical significance.Descriptive statistical analysis was used to characterize the nominal variables in terms of frequency and percentages. A non-parametric Wilcoxon rank-sum test was used for comparison between continuous variables. All analysis was performed by GraphPad Prism 7.2  and JMP SAS 13.4 (SAS). TERT promoter mutated regions were identified. TERT promoter mutations identified among the different tissue regions within the whole-organ mapping bladder tumor specimens. Results showed that the percentages of mutated samples generally increased in a step-wise manner from 17.24% among tumor associated normal urothelium, 33.3% in hyperplasia, 14.3% in dysplasia to 46.1% of CIS specimens and 100% of all MIBC regions. Representative images of mutated tumor associated normal urothelium as well as CIS are shown in From 149 available tissue samples, 75 (50.33%) TERT promoter mutations within the whole-organ mapping bladder cancer specimens. As shown in TERT promoter mutation compared to the MIBC. Interestingly, in Bladder #9 the CIS housed a TERT −124 mutation, which was also different to the MIBC (−146). Detailed information of the tissue histologies as well as the mutational status for the TERT promoter for the polyclonal events are displayed in TERT promoter mutation compared to the MIBC.One objective of this study was to test for clonality events of TERT promoter mutations and total telomere length, some TERT mutated and wild type tissues as well as TERT mutated MIBC samples were analyzed. None of the determined telomere lengths were significantly different between mutated and wild type tissue samples (data not shown). To determine if there was an association between TERT promoter gene mutations throughout nine whole-organ mapping bladder cancer specimens thus, representing a full spectrum of tumorigenesis. Our results demonstrate that adjacent and non-adjacent tumor associated urothelium, non-invasive urothelium lesions as well as CIS surrounding the tumors are TERT mutated. Additionally, detection of mono- as well as polyclonal mutated specimens with identification of one or several TERT promoter mutations strengthen both clonality hypotheses. In this study, we evaluated the role of TERT promoter mutations have been identified in the vast majority of bladder tumors independent of pathological characteristics. The hot spot mutations detected in UBC and identified among this cohort locate at −57, −124 and −146 base pairs upstream from the ATG site of the TERT gene and generate novel transcription factor binding sites. Similar to the first descriptions of these mutations by Allory et al. the hot spot mutation at the −124 nucleotide position was the most frequent substitution identified in our whole-organ mapping bladder cancer cohort [TERT promoter mutations in systematically collected normal urotheliums locating adjacent to non-invasive bladder tumor tissue. Additionally, even when the tumor was not mutated the associated normal urothelium showed a TERT promoter mutation. Moreover, if TERT mutations were initially observed, positive associations with bladder recurrence after therapy were shown indicating a potential use of TERT promoter gene mutations as a biomarker [TERT promoter mutations in tumor associated normal urothelium but also in non-invasive urothelial lesions adjacent to or non-adjacent to muscle invasive tumors. Considering TERT mutations in bladder tumors, it is interesting to note that we found in contrast to non-invasive tumors described above, all MIBC tissues presented with a specific mutation within a whole-organ mapping bladder specimen. Additionally, this observation also strengthens the fact that TERT promoter mutations seem to be an early and crucial event during bladder tumorigenesis and importantly are independent of pathological, histological and clinical characteristics [Evolution of especially epithelial cancers can be demonstrated by identifying distinct histologies including dysplasia or CIS sharing both mutational backgrounds with the tumor ,10. Due iomarker . In lineeristics ,15. TERT promoter gene were identified. Interestingly, all MIBC samples within its respective bladder specimen showed the same hot spot mutation. However, in contrast to MIBC polyclonal TERT mutations within the same bladder specimens were identified in tumor associated normal urothelium and non-invasive urothelial lesions. This finding supports the widely accepted idea that carcinogens in the urine could damage the urothelial layer and therefore mutational backgrounds could differ. On the other hand, four out of nine analyzed whole-organ mapping bladder tumors were monoclonal for TERT promoter mutations pointing to the fact of a possible seeding or migration of the cells [TERT promoter mutations and how they affect follow-up diagnostic tools has to be investigated in the future [Clonality is widely discussed regarding bladder tumorigenesis with poly- as well as monoclonal observations. In detail, whether the process of tumor formation is due to monoclonal events within the urothelium spreading through the bladder wall or by polyclonal, events resulting in several independent tumor clones is still under debate. Findings for both theories exist and with recent advances in molecular subtyping multifocal tumors and tumor heterogeneity will even be more important in terms of planning neoadjuvant treatment regimens for patients . We demohe cells . To whice future .TERT gene is to maintain and protect the ends of human chromosomes however, as we age they become shorter [TERT promoter mutation, functional investigations are still ongoing. In the study by Borah et al. [TERT mutated as well as wild type urothelial cell lines and observed an increased mRNA level of TERT transcripts, however neither the protein level nor the telomere length showed significant differences thus supporting non-translated mRNA. Additionally, Allory et al. [TERT between mutation carriers and wild types. These observations described above are comparable with our findings where there was no differences in telomere lengths. One further explanation could be that activation of the telomerase via mutations of the TERT promoter could also lead to other functions independent of telomere lengthening. These independent functions could affect many biological processes, including cell survival and apoptosis, DNA damage repair, mitochondrial function and stem cell activity. In addition, evidence exists that activating telomerase could also enable cells to acquire tumor-initiating mutations [TERT promoter mutations ultimately affect the urothelial tumor cells and additionally, implementing TERT promoter mutations as a diagnostic tool needs further investigation. Moreover, it was recently shown that cell lines from solid tumors with somatic TERT promoter mutations showed a significantly shorter telomere length compared to cell lines with a wild type TERT promoter [TERT promoter mutations compared to tumor associated urothelium and non-invasive urothelium as well as CIS possibly indicating a complex interplay between TERT mutational activation, telomere length variation and other cellular processes. The normal function of telomerase encoded by the  shorter . With aph et al.  the authy et al.  observedutations . How TERpromoter . AlthougTERT promoter gene have been analyzed and thereby other TERT promoter alterations could have been missed. Limitations of our study is the retrospective nature as well as the limited, partly heterogenous sampling of the bladder cancer specimens. In addition, only hot spot mutations of the TERT promoter gene mutations occur in tumor associated urothelium, non-invasive urothelial lesions and CIS thus, highlighting a crucial and important role of the TERT gene in the development of bladder tumors. Moreover, the evaluation of distinct promoter mutant positions strengthens both theories of a mono- as well as a polyclonal development of bladder tumors. To our knowledge, we demonstrate for the first time in tissues from whole-organ mapping bladder tumor specimens containing MIBC,


Contrast induced neurotoxicity (CIN) is a rare complication of cardiac catheterization and re-exposure to contrast medium carries the risk of recurrent CIN. We report a case of successful contrast re-challenge in a 60-year-old female patient who developed CIN after her first procedure of coronary angiography (CAG) which resulted in symptoms of disorientation, amnesia and cortical blindness. A non-contrast enhanced CT performed four hours after the CAG was normal, however, her MRI brain scan showed scattered tiny hyper intensities in posterior occipito-temporal and parietal regions suggesting CIN. Patient’s symptoms resolved completely after 72 hours. Two months later, because of persistent exertional angina, patient was successfully re-challenged with lesser amount of contrast medium with administration of hydrocortisone prior to procedure, and PCI to LAD was completed without recurrence of CIN. Contrast induced neurotoxicity in form of fits, confusion, cortical blindness and encephalopathy is very rare complication after angiography of coronary arteries and bypass grafts.A-60-year old woman with history of hypertension, dyslipidemia and paroxysmal AF admitted for acute coronary syndrome and underwent CAG. Her CAG was performed through right radial access with 5F Judkins diagnostic catheters. There was significant tortuosity in her brachiocephalic trunk which resulted in difficult engagement of both left and right coronary systems, hence larger volume (300 ml) of contrast media (Iohexol) was administered during her coronary angiography. Patient did not have a previous history of any procedure with contrast agent exposure. Her CAG showed significant 70% & 90% tubular lesions in proximal and mid segments (respectively) of left anterior descending coronary artery (LAD) requiring intervention. However, patient started to become confused, aggressive and later developed amnesia and cortical blindness. Her neurological examination did not reveal any cranial, sensory or motor nerves abnormality. A non-contrast computerized tomography (CT) scan performed four hours after the start of symptoms showed no acute pathological findings. Her brain magnetic resonance imaging (MRI) demonstrated tiny hyperdensities in the posterior occipito-temporal and parietal regions suggesting contrast induced neurotoxicity . PatientContrast induced neurotoxicity (CIN) following cardiac catheterization is a rare but devastating complication. Its clinical presentation varies from mild symptoms of headache and vomiting to more serious presentation with seizures, hemiparesis, encephalopathy and cortical blindness.The exact mechanism of contrast induced CIN remains unknown. Disruption of blood brain barrier and direct contrast neuronal toxicity mainly in the occipital region of brain haven been postulated as a possible mechanism in many reports.8Contrast media re-challenge has not been widely reported in literature. We identified only three cases where re-challenge of contrast media did not result in recurrence of cortical blindness.9Herein, we propose that re-challenge with minimal amount of contrast medium after pre-treatment with intravenous corticosteroids can be considered in patients with previous history CIN if: i) a second procedure is mandated as was the case in our patient to have persistent angina despite optimal anti-anginal medical therapy ii) CIN resolves completely after the first contrast exposure and iii) larger volume of contrast is associated with CIN.CIN following coronary angiography is an extremely rare but usually reversible complication. Re-exposure of contrast media to patients with history of CIN carries the risk of recurrent CIN, hence it is not well documented. We successfully re-challenged contrast medium in our patient and proposed that contrast rechallenge may be considered in some patients if certain conditions are fulfilled However, it is difficult to conclude whether or not CIN will recur with contrast re-challenge but we are reassured with the fact that CIN is usually transient and resolves completely.MAS & MWA did manuscript writing. MMS edited the manuscriptSKN reviewed the manuscript. HAB gave final approval. MAS responsible and accountable for the accuracy or integrity of this study.


The purpose of this study was to explore demographic differences in health personality. Data consisted of 3,907 participants, 65 years and older. Multivariate analysis of variance with post-hoc testing revealed that women had higher health neuroticism scores than men, but men had higher health extraversion scores than women. Those married reported higher health agreeableness than those not married and young-old participants had higher health extraversion and health openness compared to other age groups. Regional differences included Midwest participants reporting higher health openness but lower health conscientiousness scores when compared to participants from other regions. There were also significant interactions. For example, individuals from geographic areas with predominately White Midwest residents were significantly higher on health neuroticism when compared to Northwest, South, and West regions. The results are helpful for healthcare providers who can tailor intervention approaches to specific populations.


Gs), net assimilation rate (A), and LOX and methanol emissions to varying MeJA concentrations (0.2–50 mM) in cucumber (Cucumis sativus) leaves with partly open stomata and in leaves with reduced Gs due to drought and darkness. Exposure to MeJA led to initial opening of stomata due to an osmotic shock, followed by MeJA concentration-dependent reduction in Gs, whereas A initially decreased, followed by recovery for lower MeJA concentrations and time-dependent decline for higher MeJA concentrations. Methanol and LOX emissions were elicited in a MeJA concentration-dependent manner, whereas the peak methanol emissions (15–20 min after MeJA application) preceded LOX emissions (20–60 min after application). Furthermore, peak methanol emissions occurred earlier in treatments with higher MeJA concentration, while the opposite was observed for LOX emissions. This difference reflected the circumstance where the rise of methanol release partly coincided with MeJA-dependent stomatal opening, while stronger stomatal closure at higher MeJA concentrations progressively delayed peak LOX emissions. We further observed that drought-dependent reduction in Gs ameliorated MeJA effects on foliage physiological characteristics, underscoring that MeJA primarily penetrates through the stomata. However, despite reduced Gs, dark pretreatment amplified stress-volatile release upon MeJA treatment, suggesting that increased leaf oxidative status due to sudden illumination can potentiate the MeJA response. Taken together, these results collectively demonstrate that the MeJA dose response of volatile emission is controlled by stomata that alter MeJA uptake and volatile release kinetics and by leaf oxidative status in a complex manner. Treatment by volatile plant hormone methyl jasmonate (MeJA) leads to release of methanol and volatiles of lipoxygenase pathway (LOX volatiles) in a dose-dependent manner, but how the dose dependence is affected by stomatal openness is poorly known. We studied the rapid (0–60 min after treatment) response of stomatal conductance ( Thexenals . The emiΦM) and the total volatile emission bursts after (IT) during a period of 60 min after MeJA treatment were calculated as our previous report [To study the quantitative emission characteristics of LOX compounds and methanol, the emission maxima   and all statistical effects were considered significant at p < 0.05.All experiments were replicated at least three times with different plants and all data shown are averages ± SE. Effects of MeJA dose on foliage photosynthetic and emission traits were studied by linear or non-linear regressions depending on the shape of the response. Effects of abiotic factors combined with MeJA treatment on Gs that controls MeJA entry into the leaf. This implies that environmental stresses that reduce Gs are expected to reduce the plant sensitivity to airborne MeJA as was confirmed in our study for drought stress. Furthermore, changes in Gs alter the dynamics of water-soluble stress-volatile release from the plants, and this can have significant implications for stress propagation and signaling. A model of the relationships between rapid constitutive emission of volatiles and the role of stomata and cuticle by MeJA treatment interacting with light condition was put forwarded (Our experiments demonstrate that the response to MeJA strongly depends on orwarded . On the


Sadness is often thought of as unpleasant and dysfunctional. Yet, evolutionary-functionalist approaches and discrete emotional aging frameworks suggest that sadness is an emotion that helps us deal with loss and thus may become particularly salient and adaptive in late life. This talk presents findings from a multi-study, multi-method research program using age-diverse samples and experimental and longitudinal study designs. Findings show (1) intact or elevated levels of sadness responding in late life . Moreover, (2) higher levels of sadness responding are linked to adaptive outcomes in late life  with some effects generalizing across age groups . Implications for future research are discussed.


Leishmania genus protozoan parasites. Inoculation by infected Phlebotamine sandflies results in asymptomatic infection or a diverse range of clinical manifestations. Leishmaniasis can present with tegumentary lesions or visceral disease with parasite dissemination and high mortality [Leishmania species cause this spectrum of human disease [Leishmaniasis is a vector-born disease, caused by ortality . The spe disease . HoweverLeishmania parasites encounter diverse environments, genetic adaptations may result in positive or negative trade-offs in other life-cycle stages. In addition, as humans are not the primary vertebrate reservoir, protective or pathologic immune responses may alter disease outcome but not parasite fitness. Thus, understanding how Leishmania genetics influences outcomes of human leishmaniasis requires consideration of selective pressures across life-cycle stages (Leishmania parasites to navigate its evolutionary landscape.Evolutionary biology can be applied to understand the genetic differences among parasites with different disease manifestations. Because e stages . For insLeishmania evolution provide challenges to investigating host range and parasite virulence, they also present opportunities to understand human susceptibility. The range of leishmaniasis is limited by interactions between vectors and animal reservoirs. As their habitat is altered due to climate change and social conflict, ecologic studies informed by evolutionary dynamics could predict changes in leishmaniasis distribution. Human pathogenesis varies with the infecting Leishmania species; however, infection with the same species can result in an appropriate immune response with resolution, impaired response with parasite proliferation, or excessive inflammation with immunopathology [Leishmania parasites encode mechanisms to influence host immunity, understanding molecular pathogenesis requires studies using a diverse collection of parasites. Synthesis of these approaches is needed to understand variation in leishmaniasis outcomes and improve human health.While the complex pressures shaping athology . To elucPlasmodium parasites by treating mosquito nets with anti-malarial compounds [This evolutionary complexity may prove advantageous in developing novel treatments. For example, targeting parasites in vectors and reservoirs can decrease transmission and minimize human toxicity. This strategy has shown promise against ompounds . Furtherompounds  uniquely


Multisite medical data sharing is critical in modern clinical practice and medical research. The challenge is to conduct data sharing that preserves individual privacy and data utility. The shortcomings of traditional privacy-enhancing technologies mean that institutions rely upon bespoke data sharing contracts. The lengthy process and administration induced by these contracts increases the inefficiency of data sharing and may disincentivize important clinical treatment and medical research. This paper provides a synthesis between 2 novel advanced privacy-enhancing technologies—homomorphic encryption and secure multiparty computation (defined together as multiparty homomorphic encryption). These privacy-enhancing technologies provide a mathematical guarantee of privacy, with multiparty homomorphic encryption providing a performance advantage over separately using homomorphic encryption or secure multiparty computation. We argue multiparty homomorphic encryption fulfills legal requirements for medical data sharing under the European Union’s General Data Protection Regulation which has set a global benchmark for data protection. Specifically, the data processed and shared using multiparty homomorphic encryption can be considered anonymized data. We explain how multiparty homomorphic encryption can reduce the reliance upon customized contractual measures between institutions. The proposed approach can accelerate the pace of medical research while offering additional incentives for health care and research institutes to employ common data interoperability standards. The current biomedical research paradigm has been characterized by a shift from intrainstitutional research toward multiple collaborating institutions operating at an interinstitutional, national or international level for multisite research projects; however, despite the apparent breakdown of research barriers, there remain differences between ethical and legal requirements at all jurisdictional levels . There aFor example, the International Cancer Genome Consortium endeavors to amass cancer genomes paired with noncancerous sequences in a cloud environment, known as pancancer analysis of whole genomes. The International Cancer Genome Consortium’s data access compliance office was unable to establish an international cloud under the Pancancer Analysis of Whole Genomes Project because of conflicts between United States and European Union data privacy laws . These cIn this paper, we describe how traditional data-sharing approaches relying upon conventional privacy-enhancing technologies are limited by various regulations governing medical use and data sharing. We describe two novel privacy-enhancing technologies, homomorphic encryption and secure multiparty computation, that extend the capacity of researchers to conduct privacy-preserving multisite research. We then turn to analyze the effects of regulation on using these novel privacy-enhancing technologies for medical and research data sharing. In particular, we argue these privacy-enhancing technologies guarantee anonymity as defined under the EU GDPR and are, therefore, key enablers for medical data sharing. We focus on the GDPR, as it currently represents a global benchmark in data protection regulations. We argue that using these technologies can reduce the reliance upon customized data-sharing contracts. The use of standardized agreements for multiparty processing of data in concert with privacy-enhancing technologies can reduce the bottleneck on research. Finally, we turn to address how these novel privacy-enhancing technologies can be integrated within existing regulatory frameworks to encourage increased data sharing while preserving data privacy.Before examining novel privacy-enhancing technologies, it is necessary to examine the main models for exchanging medical data for research purposes and the limitations of conventional privacy protection mechanisms that are currently used to reduce the risk of reidentification. We synthesize the data-sharing models into three categories and analyze their main technological issues .The centralized model requires medical sites  that are willing to share data with each other to pool their individual-level patient data into a single repository. The data repository is usually hosted by one medical site or by an external third party , playing the trusted dealer role. The main advantage of this model is that the trusted dealer enables authorized investigators to access all the patient-level information needed for data cleaning and for conducting statistical analysis. Moreover, such a data-sharing model minimizes infrastructure costs at medical sites, as data storage and computation are outsourced. However, from a data privacy perspective the centralized model is often difficult to realize, especially when medical and genetic data should be exchanged across different jurisdictions. The central site hosting the data repository represents a single point of failure in the data-sharing process. All participating sites must trust such single entity for protecting their patient-level data .k-anonymity privacy model . Although homomorphic encryption and secure multiparty computation offer privacy guarantees, there is still an orthogonal risk of reidentifying individuals from aggregate-level results that are eventually decrypted and can be exploited by inference attacks [Nevertheless, any standards will need to be continually updated to respond to new technological changes. For example, one of the most significant drawbacks of fully homomorphic encryption is the complexity of computation. This computational complexity makes it hard to predict running times, particularly for low-power devices such as wearables and smartphones. For the foreseeable future, this may limit the devices upon which fully homomorphic encryption can be used . Therefo attacks ,21,27,74A final consideration relates to ethical issues that exist beyond whether homomorphic encryption, multiparty computation, and multiparty homomorphic encryption involve processing anonymized or personal data. First, the act of encrypting personal data constitutes further processing of those data under data protection law. Therefore, health care and research institutions must seek informed consent from patients or research participants . InstituMedical data sharing is essential for modern clinical practice and medical research. However, traditional privacy-preserving technologies based on data perturbation, along with centralized and decentralized data-sharing models, carry inherent privacy risks and may have high impact on data utility. These shortcomings mean that research and health care institutions combine these traditional privacy-preserving technologies with contractual mechanisms to govern data sharing and comply with data protection laws. These contractual mechanisms are context-dependent and require trusted environments between research and health care institutions. Although federated learning models can help alleviate these risks as only aggregate-level data are shared across institutions, there are still orthogonal risks to privacy from indirect reidentification of patients from partial results . Further


Approximately 400 million people throughout the world suffer from a rare disease. Although advances in whole exome and whole genome sequencing have greatly facilitated rare disease diagnosis, overall diagnostic rates remain below 50%. Furthermore, in cases where accurate diagnosis is achieved the process requires an average of 4.8 years. Reducing the time required for disease diagnosis is among the most critical needs of patients impacted by a rare disease. In this perspective we describe current challenges associated with rare disease diagnosis and discuss several cutting-edge functional genomic screening technologies that have the potential to rapidly accelerate the process of distinguishing pathogenic variants that lead to disease. Approximately 400 million individuals worldwide are directly affected by a rare disease  and whole genome sequencing (WGS) in a clinical setting. While the application of these technologies has greatly facilitated the identification of disease-associated genetic variants, the rate of diagnosis for rare disease remains below 50%  over the past several years now provide scalable mechanisms to assign functional properties to large catalogs of variants. These approaches can be used to rapidly distinguish clinically detected variants with an increased likelihood of pathogenicity and facilitate the prioritization of variants that warrant in-depth evaluation.One common experimental approach used to explore the functional consequences of a genetic variant has been the use of plasmid-based reporter assays. These assays can be engineered to harbor specific variant sequences within exons, introns, or even noncoding regulatory regions of a transgenic reporter gene. Individual reporter constructs can be introduced into cultured cells and transgene expression and/or function can be evaluated using relevant methods. In recent years several plasmid-based reporter approaches have been adapted to multiplexed formats that permit the characterization of thousands of genetic variants simultaneously using high-throughput sequencing-based readouts. These massively parallel genomic assays have been utilized to profile published catalogs of disease-associated genetic variants and distinguish variants with functional implications . Distinguishing the functional consequences of these variants may require assays that are capable of profiling cellular phenotypes. Advances in genome editing technology, specifically CRISPR/Cas9, have dramatically improved the ability to engineer cellular models with specific genetic alterations , inhibition (CRISPRi), or activation (CRISPRa) of protein-coding genes  or the repression/activation of targeted genomic regions (CRISPRi/CRISPRa). Consequently, these screens do not perfectly model the impact of clinically detected variants. As CRISPR-based screening methods continue to advance it may become possible to functionally screen large numbers of specific variants through pooled format adaptations of precision editing technologies  (Shen et al. The ability to rapidly assign experimentally determined functional properties to clinically detected genetic variants will have profound impacts on rare disease diagnosis. In addition to existing resources, clinical geneticists will have access to empirical data that will facilitate more informed decisions related to variant pathogenicity. This information will reduce the time required to analyze individual patient genomes, increase patient throughput, and ultimately translate to improved rates of diagnosis. Moreover, the barriers to generating this data are minimal as many high-throughput functional assays do not require modifications to existing laboratory infrastructure nor do they require patient specimens.The experimental strategies we discuss here are intended to complement, not replace, current standard practices in variant interpretation. Moreover, the functional assays we have described are mainly suited for Mendelian diseases. Experienced clinical geneticists will always be needed to critique experimental results and to investigate diseases with more complex genetic contributions. Rare disease diagnosis will remain a constant challenge, but bridging the gap between clinical and functional genomics could provide an accelerated path to diagnosis for many rare disease patients that are still searching for answers.


There is limited literature on formal caregivers’ communication with persons living with dementia (PLWD) in home settings. Most research comes from studies of long-term care home settings or informal home care contexts. Yet, there are expected needs and rising demands for formal caregiver support within home care. The aim of this study was to understand better the lived experiences of personal support workers (PSWs) regarding their communication with PLWD in home settings. A hermeneutic phenomenological approach guided this research. Semi-structured interviews were conducted with 15 PSW participants. Three major themes were identified through thematic analysis: (1) challenged by dementia-related impairments; (2) valuing communication in care; and (3) home is a personal space. PSWs experienced difficulties in their communication with PLWD despite recognizing the importance of communication in providing optimal home care. This suggests that while PSWs possess good intentions, they do not possess the skills necessary to ensure effective interactions. Dementia-specific education and training are recommended to improve PSWs’ communication skills and to enhance quality of care. Findings highlight further the uniqueness of the personal home space itself on PSWs experiences with communication. Aspects of the home care environment can enable, but also complicate, successful communication between PSWs and PLWD. Consequently, findings also have implications for family members of PLWD and home care employers regarding optimizing practice and improving care.


This review enhances the existing literature on relationships between problematic smartphone use (PSU), psychopathology, addictive personality, and online social engagement as regards young adults, giving attention to predictive determinants of addictive behavior in smartphone usage. My article cumulates previous research findings on the psychology of addictive smartphone behavior in terms of problematic use, social anxiety, and depressive stress by focusing on the relationship among mobile social media usage, smartphone addiction risk, mental health issues, and individual well-being. The inspected collected findings prove that depression and social anxiety constitute risk determinants for greater PSU and that particular categories of smartphone applications are positively related to well-being. State anxiety and motivations represent significant predictors of PSU. High PSU affects participation in social engagement. As limitations in the current review, my results point towards relevant avenues of research on social consequences of teenagers’ smartphone problematic use. Future directions should clarify whether compulsive smartphone use adversely affects both mental and physical health in the long run. PSU hasPSU shapes subjective and psychological well-being, and may configure associated anxiety and depression psychopathology. Mental health and somatic symptoms are adversely impacted by PSU leading to impaired socio-emotional functioning and possibly causing psychological distress.Users’ psychological features may not clarify every characteristic of PSU. High PSU affects participation in social engagement. Users’ absence of social networks may hinder agreeable social communications  and emotParental neglect is considerably related to teenagers’ smartphone addiction. In the link between parental neglect and PSU, the former is not relevantly connected with the relational instability with peers, negatively shaping PSU. The relational instability with teachers has a fragmentary mediation impact between parental neglect and PSU . ParentsParenting style and attachment may mediate young adults’ smartphone use, improving interpersonal adaptation and self-control, while articulating family well-being. Young adults’ addictive personality may be shaped by parental mediation practices and self-regulation.Significant research has considered lately the psychology of addictive smartphone behavior in terms of problematic use, social anxiety, and depressive stress. My article extends previous work by focusing on the relationship among mobile social media usage, smartphone addiction risk, mental health issues, and individual well-being. Progressively relevant degrees of smartphone ownership and utilization give rise to the implicit risk for addictive behaviors and adverse health results, shaping subjective and psychological well-being. The conclusions drawn from the above analyses are that depression and anxiety symptoms are associated with PSU severity, generating, among others, emotion dysregulation, psychological distress, poor sleep quality, and diminished academic performance. Personality traits, social-emotional distress, and duration of daily smartphone use constitute antecedents of PSU, impacting subjective and psychological well-being. As limitations in the current review, my results point towards relevant avenues of research on social consequences of young adults’ smartphone addiction. Future directions should clarify whether compulsive smartphone use adversely affects both mental and physical health in the long run.The author confirms being the sole contributor of this work and approved it for publication.The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Pulmonary fibrosis arises from the repeated epithelial mild injuries and insufficient repair lead to over activation of fibroblasts and excessive deposition of extracellular matrix, which result in a mechanical stretched niche. However, increasing mechanical stress likely exists before the establishment of fibrosis since early micro injuries increase local vascular permeability and prompt cytoskeletal remodeling which alter cellular mechanical forces. It is noteworthy that COVID-19 patients with severe hypoxemia will receive mechanical ventilation as supportive treatment and subsequent pathology studies indicate lung fibrosis pattern. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation. Recent pathological studies reported some of the COVID-19 patients with lung fibrotic lung features. Clinically, the main consequence of SARS-CoV-2 infection is cytokine storm, however previous studies indicate that anti inflammation therapy have no effects on pulmonary fibrosis, thus other mechanisms need to be provided to address this issue. Early micro injuries to alveoli increase local vascular permeability which provokes edema accompanied by inflammatory cytokines which prompt cytoskeletal remodeling and alter cellular mechanical forces. If these mild injuries could not be repaired properly, then fibroblasts will be activated and subsequent excessive deposition of extracellular matrix will result in a mechanical stretched niche. At advanced stages, mechanical stress originates mainly from the stiff matrix since boundaries between stiff and compliant parts of the tissue could generate mechanical stress. Therefore, mechanical stress has a significant role in the whole development process of pulmonary fibrosis. The alveoli are covered by abundant capillaries and function as the main gas exchange unit. Constantly subject to variety of damages, the alveolar epithelium injuries were recently recognized to play a vital role in the onset and development of idiopathic pulmonary fibrosis. In this review, we summarize and the literature regarding the effects of mechanical stress on the fundamental cells constituting the alveoli in the process of pulmonary fibrosis, particularly on epithelial cells, capillary endothelial cells, fibroblasts, mast cells, macrophages and stem cells. Finally, we briefly review this issue from a more comprehensive perspective: the metabolic and epigenetic regulation.Pulmonary fibrosis (PF), which constitutes a broad range of heterogeneous end stage interstitial lung diseases, is characterized by excessive deposition of extracellular matrix and destruction of the pulmonary parenchyma  about 50–70 m2 Weibel , 20-time2 Weibel . In the 2 Weibel .Mechanical sensing and regulating of endothelial cells are involved in the process of lung disease (Fang et al. Taken together the mechanical stress exposed to the endothelial cells is translated to different signals for the initiation and progression of lung fibrosis.2+ to interact with specific intracellular target proteins (Donato et al. 2+ influx can be induced by mechanical stretch in human lung fibroblasts (Murata et al. 2+ mediated S1006A stimulation. Taken together, these data indicate that mechanical stress promotes fibrosis by both stimulating the proliferation and migration of fibroblasts.The migratory and proliferative fibroblasts organizing in distinct clusters is called fibroblastic foci and this depicts the typical phenotype of lung fibrosis featured by accumulation of exaggerated amounts of ECM that forms a stiff milieu  where fiMacrophages are involved in the cross-talk between innate and adaptive immunity (Epelman et al. Mast cells, originate from CD34-expressing haematopoietic stem cells in the bone marrow, are best known for their roles in allergic and acute inflammatory diseases (Wernersson and Pejler −/− AECIIs cannot regenerate new alveoli which resulted in sustained elevated mechanical tension that subsequently activates a TGF-β signaling loop in stem-like AECIIs and promote fibrosis (Wu Histologically, PF develops from microscopic fibrotic areas at the very peripheral regions of lung and slowly progress inward (Plantier et al. rosis Wu . Clinicarosis Wu . The lunrosis Wu . This coAccumulating evidence suggests abnormal metabolism in PF (Rowan et al. 6A modifications of pri-miRNA-126 was involved in the process of pulmonary fibrosis (Han The term “epigenetics” describes heritable changes in a cellular phenotype without alterations in the DNA sequence (Berger et al. osis Han . What’s osis Han  which maosis Han . Indeed,osis Han . Thus, uIn this review, we highlight the importance of rigid fibrotic niche in orchestrating the mechanical response of alveolar cells in exacerbating lung fibrosis Fig. . The alvFurthermore, mechanical stress exerts a more comprehensive impact via metabolic and epigenetic regulation, which should be a promising filed for treating PF since rapid advances have been made in developing drugs to adjust metabolic status and target the epigenetic landscape. Therefore, translating these mechanism insights into clinical utilization may enable novel approaches for alleviating lung fibrosis.


Because old age is associated with defects in circadian rhythm, loss of circadian regulation is thought to be pathogenic and contribute to mortality. We show instead that loss of specific circadian clock components Period (Per) and Timeless (Tim) in male Drosophila significantly extends lifespan. This lifespan extension is not mediated by canonical diet-restriction longevity pathways, but is due to altered cellular respiration via increased mitochondrial uncoupling. Lifespan extension of per mutants depends on mitochondrial uncoupling in the intestine. Moreover, up-regulated uncoupling protein UCP4C in intestinal stem cells and enteroblasts is sufficient to extend lifespan and preserve proliferative homeostasis in the gut with age. Consistent with inducing a metabolic state that prevents over-proliferation, mitochondrial uncoupling drugs also extend lifespan and inhibit intestinal stem cell overproliferation due to aging or even tumorigenesis. These results demonstrate that circadian-regulated intestinal mitochondrial uncoupling controls longevity in Drosophila and suggest a new potential anti-aging therapeutic target.


Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.) are responsible for the majority of nosocomial infections  . Another study achieved successful phytomedited synthesis of green TiO2NPs that proved to be effective for treating biofilm-based bacterial and fungal infections .Seven original research articles spanning diverse disciplines describe the development of NATs for clinically-relevant MDR pathogens. One study describes the one-pot synthesis of Ag-ZnO nanoparticles at low temperatures and demonstrated remarkable antimicrobial activity of these nanoparticles against methicillin-resistant Enterobacterales (CPE). The authors showed how antimicrobial combinations synergized against most CPE expressing resistance genes. These antimicrobial combinations may facilitate the successful treatment of patients infected with CPE . Another original research article identified two potent combinations of antibiotics for clinical MRSA infection, both in vitro and in vivo . A separate study found that the compound 2,4-Di-Tert-Butylphenol isolated from an endophytic fungus substantially reduced the secretion of virulence factors and biofilm and its associated factors controlled by quorum sensing in a dose-dependent manner in Pseudomonas aeruginosa .Another research article assessed the therapeutic efficacy of antimicrobial combinations on carbapenemase-producing Streptococcus pneumoniae infections . New putative antimicrobial candidates were reported by Okella et al. They designed an antimicrobial peptide and performed target identification based on a putative antimicrobial peptide motif derived from fish. From all the peptide motifs generated in this work, the authors identified Pleurocidin (secreted by flatfish) as having strong antimicrobial potential.Furthermore, a study tested the anti-virulence activity of potential uridine diphosphate glucose pyrophosphorylase (UDPG:PP) inhibitors and showed that these inhibitors are a potential drug candidates against León-Buitimea et al.). Another review explored the possibility of designing antimicrobial nanoparticle-based devices to exploit the potential of antimicrobial nanoparticles to combat MDR pathogens . Finally, a third review describes the mechanisms associated with drug resistance in pyogenic streptococci and discusses the advantages and limitations of innovative therapeutic strategies such as bacteriocins, bacteriophage, phage lysins, and metal nanoparticles .Three review articles included in this special issue address the use of NATs to face MDR bacteria. A mini-review discusses combination treatments  as a pathway to develop antimicrobial therapeutics with broad-spectrum antibacterial action, bactericidal instead of bacteriostatic activity, and better efficacy against MDR bacteria (In summary, this group of articles contributes to the search for new therapeutic strategies to combat antibacterial resistance. MDR and XDR infections are growing in incidence; the main challenges facing society are now to design, develop, and evaluate new therapeutic strategies that can spearhead the development of alternative therapies against clinically-relevant MDR pathogens.All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.