Background Serum tumor markers are ubiquitously used in the clinic for cancer screening. However, the mechanisms accounting for the elevated levels of the serum tumor markers remain to be explored.Methods We performed a pan-cancer analysis of serum alpha-fetoprotein (AFP), carcinoembryonic antigen (CEA) and prostate-specific antigen (PSA). The relation between concentration of serum tumor markers and the expression of their coding genes was assessed. Then the expression of AFP and its genomic background in hepatocellular carcinoma (liver cancer) was studied.Results High expression of AFP mRNA was found mainly in liver cancer. In gastric cancer, breast cancer and lung cancer, high AFP mRNA expression was also discovered occasionally. In liver cancer patients, serum AFP levels correlated significantly with AFP mRNA expression in cancer tissues . Whole transcriptome analysis revealed that serum AFP levels clearly separated liver cancer into two classes with distinct expression profiles according to PCA analysis. Gene co-expression analysis revealed that AFP expression was connected to a module enriched with genes accounting for cell cycle and cell proliferation regulation. In addition, high AFP expression was associated with the molecular classification of liver cancer, including iCluster . Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, which was significantly related to AFP mRNA expression. Survival analysis indicated high serum AFP levels was prognostic of poorer survival of the liver cancer patients (Log-rank test: p = 0.046). This was confirmed by an independent dataset in which liver cancer patients with high serum AFP also had poorer survival (Log-rank test: p = 0.024).Conclusion High expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. De-methylation of cytosine from CpG di-nucleotides in AFP promoter may be the cause of AFP re-expression in adult human liver cancer tissue. Serum tumor markers are essential noninvasive tools for the screening and diagnosis of various cancer types. Many serum tumor markers have been studied and approved for use in the clinic. For example, alpha-fetoprotein (AFP) is widely used for the diagnosis of hepatocellular carcinoma (liver cancer). In addition, positive AFP could also be encountered in other cancer typesAFP is the main component of mammalian fetal serum. It is synthesized by visceral endoderm of the yolk sac and by fetal liver. After birth AFP level decreases dramatically in blood. However, AFP synthesis can be reactivated in liver tumors and germinogeneous teratoblastomas. As a result, serum AFP is an important marker for liver tumors and is widely used in clinical practice Carcinoembryonic antigen (CEA) is a glycoprotein of about 200,000 Daltons in molecular weight. It is expressed in significant amounts during embryonic life, especially by the large intestine, and postnatally by carcinomas arising from this site. Many tumors of epithelial origin at other sites may also express CEA and are associated with elevated CEA levels in blood circulation PSA is most frequently detected in prostate cancer. Positive correlation has been confirmed between the PSA level and tumor stage and volumeAlthough serum tumor markers like AFP, CEA and PSA have been extensively studied and used in the clinic, questions regarding the mechanisms leading to their expression in cancer have not been well answered. This is exemplified by AFP, for which the molecular mechanisms leading to re-expression of AFP in adult human liver cancer and other tumor types is still unclearIn this study, we tried to address the questions mentioned above using genomic data from large cohort of cancer patients. We compared the expression of the coding genes of AFP, CEA and PSA, and found that only AFP expression correlated with its serum levels in liver cancer patients. Further analysis revealed aberrant AFP re-expression actually represented a shift of cell transcriptome that involved many genes, especially those related to cell proliferation regulation. We then identified de-methylation of a CpG locus located at the promoter of AFP that may be accountable for the AFP re-activation.Totally 4,666 tumor samples were included in the pan-cancer gene expression analysis of tumor markers. There were 421 liver cancer samples, 326 colon cancer samples and 549 prostate cancer samples. The details of patient and sample information could be found in the publications associated with each studyFor hepatocellular carcinoma dataset from TCGA (The Cancer Genome Atlas) study, all patients received surgical resection of their tumors. No other treatment, for example ablation, chemotherapy, or radiotherapy had been given to the patients before surgery. Surgical specimens of primary hepatocellular carcinoma and matched blood samples were collected for each patient. Totally 371 patients with full genomic data were included in this study. For clinical data analysis, patient information from the TCGA hepatocellular carcinoma publication was used, which contained 196 samplesGenomics data from TCGA project were downloaded using RTCGA package in R. The most recent version of RTCGA dataset was used (2016-01-28). For mRNA sequencing analysis, the RNASeq v2 data was used. For methylation analysis of TCGA data, the beta values of each CpG locus derived from Human Methylation 450 array platform was used. For survival analysis, a recently updated follow-up data processed by Liu J et.al. was usedGene co-expression network analyses was performed using Co-Expression Modules identification Tool (CEMiTool), an R package that can identify and analyze co-expression modules in a fully automated manner. CEMiTool is featured by unsupervised gene filtering, automated parameter selection for identifying modules, enrichment and module functional analyses, as well as integration with interactome data to generate molecular interactionsThe whole genome methylation analysis was performed using Human Methylation 450 array platform. There are 4 probes targeting AFP gene, including one probe mapped onto the promoter region (cg10778295), two probes mapped onto around -5,000 from the transcription start site , and another probe mapped onto the interior of the gene (cg02387745). However, the probe inside AFP has no readings. Pearson correlation analysis was performed to assess relationship between methylation status of each probe with AFP expression.Statistical analysis was performed using R software. Human genome assembly hg19 was used as the reference genome. Liver cancer patients were separated into three groups based on serum AFP levels: high (>= 300 ng/ml), middle , low (< 6 ng/ml). Survival plot was estimated using Kaplan-Meier method and groups were compared with log-rank test. For correlation analysis between the levels of markers in serum and tumor, serum marker levels were added by 1 and then log2 transformed. Pearson correlation analysis was then performed. For comparison of means of gene expression or methylation between two groups, t test was used.To unveil the roots of serum tumor markers, we selected AFP, CEA (encoded by CEACAM5)Next, we asked whether the presence of tumor markers in the bloodstream was resulted from high expression of these markers by tumors. We compared the expression of CEA, AFP and PSA in tumor tissue with their serum levels. In liver cancer, a strong correlation between AFP gene expression and serum levels was observed   . In addiPrincipal component analysis (PCA) was performed to assess the inner structure of liver cancer expression data. The distribution of liver cancer samples was plotted using the top three principal components and patients are colored by their serum AFP levels. A clear separation between high and low serum AFP patients could be seen Figure A. This dTo identify key genomic modules co-regulated with AFP, we performed gene co-expression analysis using mRNA sequencing data of liver cancer. Five gene modules were revealed for liver cancer and AFP belonged to M4 module. M4 and M5 module were significantly related to AFP high expressing liver cancer   Figure . To furtRecent high throughput genomic studies classified liver cancer into several molecularly distinct subtypes. We thus asked whether AFP activation is related to the molecular classification of liver cancer. Higher serum AFP level was significantly associated with iCluster  of liver cancer. The iCluster clustering of liver cancer was derived by integrating multiple whole genome platforms, which is supposed to be the most comprehensive and unbiased classification of cancer Aiming at identifying the molecular mechanisms underlying the elevated levels of the serum tumor markers, we performed a pan-cancer analysis of AFP, CEA and PSA to assess the relationship between concentration of serum tumor markers and the expression of their coding genes. Only AFP expression in tumor tissue correlated with its serum levels. In addition, high expression of AFP defined a subtype of liver cancer with distinct gene expression profiles and clinical features. Methylation analysis revealed de-methylation of AFP promoter occurred in some liver cancer tissues, and was significantly related to AFP mRNA expression.Previous studies suggested that serum AFP levels are mainly controlled at transcriptional level in fetal liver. For example, in normal development of mouse liver, a parallel accumulation of both AFP and albumin mRNAs before birth, followed by a selective nonreciprocal decrease in AFP mRNA after birth, was observedLiver cancer is a heterogeneous disease. Many molecular subtypes have been proposed for liver cancer Most previous studies investigated AFP alone. What we found in this study suggested aberrant activation of AFP was not an isolated event. It was actually part of the systematic diversion of the transcriptome in the liver cancer cells. More importantly, this diversion in transcription also has clinical significance. The most obvious features of AFP high tumors is its poorer prognosis compared with serum AFP normal tumors. Actually, the inferior prognosis in serum AFP positive tumors has been reported by many other studies alreadyIn vivo experimental using mouse models revealed that a 7 kb regulatory region upstream of AFP gene was related to the regulation of AFP expression Although the transcriptional control of AFP expression is evident, it's unclear how liver cell cease expressing AFP after birth, and how AFP expression is re-activated in liver cancer. 2+ influx, prompting DNA synthesis and enhancing tumor cell proliferation Evidence suggests that AFP may not only be a biomarker for cancer diagnosis, but also play functional roles in tumorigenesis. AFP can promote cancer cell proliferation through binding AFP receptor (AFPR), activating PI3K/AKT and many other cancer related genes In conclusion, this study indicates that AFP re-activation is a result of the systematic transcriptome change, which collectively define a molecular subtype of liver cancer. More importantly, high AFP expression is associated with over activation of cell growth or cell cycle control genes. In addition, high AFP expression is related to poor survival in the patients. These data highlights AFP as a biomarker for both liver cancer classification and prognosis.Supplementary figures and tables.Click here for additional data file.


Empirical evidence supports positive associations between social support, interpersonal connections, and health as people age. This symposium addresses how human-animal interaction may facilitate connection throughout later life. Each talk presents unique ways pets: fit into social networks; expand interpersonal connections; and thereby, impact health and wellbeing. The first talk presents longitudinal associations of a history of pet ownership and marital status on health, in particular cognitive functioning, over time. The second talk presents qualitative evidence for how pets fit into older adults’ social network and quantitative evidence for the impact of animal and interpersonal companionship on overall and functional health. The third talk builds upon the literature linking dog walking with older adults’ physical health, by providing evidence for the positive impact of dog walking improving interpersonal connections with neighbors. The fourth talk discusses the influence of a unique intergenerational human-animal interaction service-learning course on university students’ attitudes towards older adults and those with disabilities. Enrolled students provide pet care  to low-income pet owners ages 60 and older and disabled adults. Students reported decreased biases towards older adults and those with disabilities after completing the course. The final talk is the first study to focus on the influence of pets in LGBTQ older adults living in rural southern Appalachia. Identifying as a LGBTQ person and living in a rural environment can present unique challenges and these qualitative results provide insight into pets’ influence on aging in this understudied population.


For older adults living with dementia, social network quality influences health outcomes. However, current social network measurement methods are time consuming and mentally draining for people living with dementia. This study aimed to accurately measure social networks using sensor technology. Bluetooth and radio-frequency identification (RFID) sensors were used to collect social network data in a simulation of a falling nursing home resident living with dementia. Participants wore sensors on their clothing, and video recordings were compared to sensor data. Bluetooth data reflected general direction of movement and instances of idling but were neither precise or accurate. RFID data was accurate after applying data filters. Both systems detected multiple sensors simultaneously. The Bluetooth system is not feasible for clinical use, but the RFID system shows potential for clinical application and accurate measurement of social network factors as interaction frequency and duration.


Following stroke, the leading cause of disability in the United States, muscle alterations commonly occur. These alterations include gross atrophy and shift in fiber type, particularly in the paretic limb, which have lasting implications on gait ability. We will discuss the current evidence supporting a mechanism for these changes  and how these factors differ between the paretic and non-paretic limbs. Further, we will discuss how various therapeutic exercise modalities can be used to modify or reverse skeletal muscle abnormalities and alter physical functioning post-stroke.


Mycobacterium tuberculosis - a global threat, the recent breakout in MDR-TB and XDR-TB has challenged researchers in diagnosis to provideeffective treatment. The main objective to combat drug resistance is to provide rapid, reliable and sensitive diagnostic methods in healthcare centres. This study focuses on development of an effective pipeline to identify drug resistance mutations in whole genome data ofMycobacterium tuberculosis utilizing the Next Generation Sequencing approach and classification of drug resistance strains based on geneticmarkers obtained from TGS-TB, tbvar and TBDReamDB. 74 isolates are characterized into 20 DR-TB, 16 MDR-TB, 16 XDR-TB and 6 nonresistantstrains based on known drug resistance genetic markers. Results provide mutation pattern for each of the classified strains andprofiling of drug resistance to the group of anti-TB drugs. The presence of specific mutation causing resistance to a drug will help set thedosage levels which play an important role in the treatment. Findings on amino acid changes and its respective codon positions incandidate genes will provide insights in drug sensitivity and a way for discovery of potent drugs. The implementation of these approachesin clinical setting provides rapid and sensitive diagnostics to combat the emerging drug resistance. Mycobacteriumtuberculosis and has plagued humans since antiquity. The discoveryof antibiotics brought a revolution in Tuberculosis Chemotherapy,which started, in 1943with Streptomycin, followed by advent ofmany potent anti-TB drugs. The implementation of these drugs intuberculosis therapy immediately resulted in a drastic reduction ofTB incidence all over the world. TB was considered to be no longera public health concern in many developed countries until theoutbreaks of multidrug resistant strains in 1980s Tuberculosis (TB) is an infectious disease caused by M. tuberculosis has evolved to emerge as drug resistant strain thathas resulted in the restriction of TB chemotherapy which pose anurgent public health problem and requires rapid intervention. Thestrains were initially resistant to single drugs, have now evolvedwith sequential accumulation of resistance mutations which hasled to the emergence of Multi-Drug Resistance strain (MDR-TB),Extensively Drug Resistance (XDR-TB) and most recently, totallydrug resistant (TDR) strains. First-line drugs, which are commonlyused for treating tuberculosis such as Rifampicin, Isoniazid,Pyrazinamide and Ethambutol, are becoming ineffective due tomutations in certain genes. These genetic markers are essential forthe identification and classification of drug-resistant strains andmost importantly give scientists an opportunity to design drugs,which counteract the effects of these mutations. MDR-TB showsresistance to at least one of the two most potent drugs: isoniazid(INH) and rifampicin (RIF). The emergence of XDR-TB resistanceis due to having developed resistance to both rifampicin andisoniazid, as well as to fluoroquinolones and at least one of thesecond-line drugs The NGS whole genome sequencing paired-end data ofMycobacterium tuberculosis was procured from NCBI-SRA database.The data isfreely accessible, and the datasets accession numbers arelisted in the supplementary data. The reference genome sequenceH37Rv was retrieved from Genbank database.NGS data may encompass sequence artefacts which include poorquality reads, read errors, duplication and adapter/primercontamination which will have an impact on downstream analysis.Therefore, the quality of the data is crucial in distinguishing thetrue mutations from the sequencing errors otherwise they may leadto wrong conclusions. Pre-Processing of the data was executedusing FastQC tool kit to assess the read quality  For mapping of raw reads versus Mycobacterium tuberculosis h37rvcomplete genome, BWA-MEM algorithm was used The variants were identified using Genome Analysis Toolkitvariant calling best practice workflow including indel realignmentand base recalibration The annotated VCF files generated from SNPeff were combinedusing VCFcombine tool from Galaxy web-based platform, whichcombines all the VCF, files positionally when sites and alleles areidentical  Out of screening 480 entries in the SRA database search formycobacterium whole genome data, 74 isolates were selected basedon quality control and genome coverage. These samples werefurther processed for variant calling and the generated VCF fileswere combined to obtain the union list of mutations positionally.This resulted in identification of 11,130 variants of which 8554(76.85%) were SNPs, 776 (6.97%) were insertions and 1024 (9.2%)were deletions. These mutations were mapped to the known drugresistant mutations obtained from various databases includingTGS-TB, tbvar and TBDReamDB to generate the resistance profilingof each isolate. Further annotation was performed using SNPefftopredict the effects of variants, gene annotation, codon change andits impact for all the variants called. The number of SNPs annotatedfrom various databases arelisted in the Antimicrobial resistance pattern was determined based onmutations conferring drug resistance to anti-TB drugs. Thedetermined resistance pattern for XDR, MDR and DR strains areillustrated in The annotated SNPs of the predicted resistant types were combinedto obtain the list of mutations specific to each resistant type. Pythonscript was written to read the annotated VCF files and to count thefrequency of synonymous and missense mutation across thegenome to derive the mutation pattern which is represented inIdentification of amino acid changes is crucial to understand theassociation of resistance with drugs. Python script was written togenerate the pattern of codon variations in 25 candidate drugresistant genes The present study explains the classification of drug resistant strains basedon the known drug resistance mutations obtained from various TB mutationdatabases. The mutation pattern generated for the classified strains helps tounderstand the distribution of the SNPs in certain genomic regions resultingfrom the drug selection pressures, thus providing the information onevolutionary targets of drug resistance mechanism. Profiling resistance tovarious TB drugs is important to decide the drug regimen. Otherwise, afaulty diagnosis leading to the ineffective regimen will further increase thedevelopment of Antimicrobial Resistance. The schematic representation ofcodon variations gives overall picture of resistance regions in the candidategenes. The hot spot regions will serve as diagnostic tool for screeningresistance and non-drug resistant regions can be alternative drug targets tocombat resistance. Rapid and accurate prediction of drug resistance throughmolecular diagnostics promise to improve patient's treatment outcome. Infuture directions, implementation of molecular based diagnosis in theclinical setting will help in timely diagnosis and efficient treatment of TBpatients will reduce the development of AMR.Authors declare no conflict of interest.


Until recently, consumers have had limited resources to assess quality of hospices agencies, contributing to growing numbers of consumers turning to online review sites, such as Yelp. Yet little is known about the content of hospice Yelp reviews and how these relate to recently available Center for Medicare and Medicaid Services’ Hospice Compare site data. No study has examined Yelp hospice reviews and compared the themes identified in Yelp reviews to the topics addressed by CMS’s HC measures. To better understand how consumers perceive hospice care, we drew a purposeful sample of 67 hospices in California. Researchers used grounded theory to identify themes and categories within the hospice reviews. Each of two teams of two researchers independently coded the reviews and then met to compare coding and reconcile discrepancies until 100% consensus was reached. We coded a total of 692 consumer Yelp reviews, identifying 15 themes and grouping them under five overarching thematic categories: patient/caregiver-provider relationship; clinical care; agency competency; staff professionalism; and medical equipment and supplies. We found that overall Yelp comments were positive. The most frequently mentioned Yelp themes in hospice reviews were compassionate, caring staff; patient/family gratitude; and staff responsiveness. There was considerable overlap between the themes captured in HC caregivers survey items and Yelp. However, Yelp reviews cover a greater number and more diverse themes than those measures reported on the CMS Hospice Compare site. We recommend that consumers consider both HC and online review sites such as Yelp when evaluating a hospice.


Globally, neonatal mortality rates remain relatively stagnant despite overall progress in reducing under-5 mortality . In regiSignificant gaps exist in infection prevention and control (IPC) practices in maternal-neonatal care settings, resulting in increased risk of health care-associated infections (HAI) for both mother and baby . HealthcAcinetobacter species (spp) and Klebsiella spp [In many resource-limited settings, neonatal sepsis is predominantly caused by Gram-negative organisms, with high prevalence of antimicrobial resistance ,5. A recella spp .As contributors to HAI risk are variable and IPC resources are limited, standardized assessments linked to improvement strategies are essential to guide health care facilities in LMIC to prioritize high-impact strategies to reduce neonatal HAI and death. The WHO has designed several tools to assess hospital-wide IPC practices, including the Hand Hygiene Self-Assessment Framework and the Infection Prevention and Control Assessment Framework at the Facility Level (IPCAF) ,8. StrenThe United States Agency for International Development (USAID) sponsored Infection Control Assessment Tool (ICAT) is a more comprehensive tool designed to assess IPC practices across acute care hospitals. It includes 22 modules as well as checklists for direct observation of several key practices . StrengtThese findings suggest that an assessment tool targeting facility-based maternal and neonatal IPC practices is needed and should address several key factors. First, an assessment tool must cover the wide spectrum of care provided for mothers and neonates in LMICs. Fundamental elements of IPC practice, such as hand hygiene, must be incorporated, but advanced care content, such as IPC related to the use of invasive devices and prolonged supportive care in neonates, should also be included for use by sites where these interventions are provided. Components of the tool focusing on antibiotic administration should also embrace antimicrobial stewardship principals targeting areas with high endemic rates of antimicrobial resistance. While self-assessment would facilitate broad uptake in LMICs, direct observation of key IPC practices by a trained assessor, whether internal or external, would ensure observations made had a high probability of guiding true gaps in IPC practice. An assessment tool should highlight strengths and opportunities for improvement, guiding facilities to plan and implement interventions with the ultimate aim of creating a sustained improvement in IPC practices. Linkage to educational materials and implementation tools would strengthen such a tool, providing key recommendations to health care facilities seeking to improve IPC in maternal and neonatal care. Ultimately, a comprehensive assessment tool designed specifically for maternal and neonatal care will allow facilities to most effectively reduce morbidity and mortality due to HAI in this vulnerable population.


Antibody-based therapy has revitalized the world of cancer therapeutics since rituximab was first approved for the treatment of Non-Hodgkin’s Lymphoma. Monoclonal antibodies against cancer antigens have been successful strategies for only a handful of cancer types due to many reasons including lack of antibody specificity and complex nature of tumor milieu which interfere with antibody efficacy. Polyspecific antibodies are promising class of anti-cancer agents which can be directed at multiple tumor antigens to eradicate tumor cells more precisely and effectively. They may overcome some of these limitations and have already changed treatment landscape for some malignancies such as B cell acute lymphoblastic leukemia. Pre-clinical studies and early phase clinical trials have demonstrated that this approach may be an effective strategy even for solid tumors. This review focuses on the development of bispecific and trispecific antibody therapy for the treatment of solid tumor malignancies and highlights the potential they hold for future therapies to come. Cancer remains the second leading cause of death in the United States, with lung cancer being the leading cause of cancer deaths, followed by breast cancer in women and prostate cancer in men Siegel . Over th. Although some of these primitive formats showed appreciable activity against certain malignancies, the vast majority had a dismal therapeutic-risk index. With rapid advances in genetic engineering, the past two decades have seen a dramatic increase in the production of polyspecific antibodies with more than 120 described formats now in clinical use or undergoing evaluation in clinical trials  are genetically engineered proteins that can simultaneously engage two or more different types of epitopes Figs.  and 2 F. They shBispecific antibodies with ability to engage two different antigens are the most commonly used PsMabs. Since the initial experiments to produce BsMabs , tandem single chain variable fragments (taFvs), diabodies (Dbs), single chain diabodies (scDbs), and triplebodies. Due to their small size, these scFV based antibody fragments have high tumor specificity and tumor penetration. However, their small size also limits serum half-lives which could potentially limit efficacy and increase cost by requiring repetitive dosing  into the proximity of the tumor cell to enhance antitumor effect Fig. . This fu. DART bispecific antibodies, created by engineering two Fv fragments with the variable heavy chain portion exchanged with one another, are larger than BITEs and show better serum stability  antibodies, tandem diabodies appear to potently eliminate targets expressing their tumor associated antigen (TAA) in the absence of costimulatory models or IL-2 pre-activated T cells . Blinatumomab is a novel bi-specific T cell engager which binds sites for both CD19  and CD3 T cell receptor complex, leading to T cell proliferation and activation resulting in target cell (lymphoblast) apoptosis. Unlike catumaxomab, which uses large IgG-like bi-specific antibodies with Fc regions, blinatumomab was created by the fusion of two single chain variable fragments (scFv) connected in a flexible manner through a peptide linker , which first allows tumor specific antibodies to distribute to the tumor antigen site followed by the administration of a small radioactive agent with high affinity for the tumor antibody, limits the accumulation of radiation in non-target sites  and histamine- succinyl-glycine (HSG), when used with lutetium-177 labeled peptide for PRIT in prostate cancer demonstrated effective targeting and permeability in mice pre-clinical studies  and radioimmunotherapy (RIT) use the antibody specificity of tumor-based antigens in conjunction with emitted radiation from suitable radioisotopes to image malignancies (RIS) for diagnostic and treatment purposes. The radioantibody is injected intravenously and distributes to the antigen binding site on tumor cells where the radionuclide delivers the tumoricidal dose to the tumor mass  for detection of colonic liver lesions in an orthotopic murine model , breast cancer, uterine, and bladder cancers [NCT02324257], [NCT01284231]  and met gene amplification has been shown to be a major mechanism in which cancers develop resistance to EGFR inhibitors , and also found in breast and lung carcinoma, was recently found to be expressed in glioma stem cell lines , which binds CD3 and targets EpCAM, increased the sensitivity of tumor cells to cytotoxic T cell death in multiple EpCAM positive ovarian and endometrial cancer cell lines including ovarian carcinosarcoma and primary uterine serous papillary carcinoma  or programmed death-1 (PD-1) or its ligand (PD-L1) and transforming growth factor-β (TGF-β), which mediates immune tolerance using a bifunctional antibody-ligand trap was recently reported  and tri-specific killer cell engagers (TriKEs). BiKEs are created by the fusion of a single chain variable fragment (Fv) against CD 16  and a single-chain Fv against a tumor associated antigen  and targets the death receptor 5 , can selectively and potently kill melanoma cells. This approach may prove beneficial in those patients resistant to monoclonal antibody therapy  directed against HER1, HER3, c-MET and IGF1R with enhanced antitumor effects in a preclinical model , there are many new molecules with three or four binding sites. For example, Castoldi et al.Another example of how novel approaches may simplify treatment is a recent preclinical study demonstrating elimination of large tumors by in-vivo production of bispecific antibodies induced by parenterally administered engineered mRNA (Holzinger et al. Advances in antibody directed therapy have simultaneously fostered the development of another form of immunotherapy, CAR-T cell therapy. While an in-depth discussion on this exciting topic is out of scope for this review article which is focused on polyspecific antibodies, we present a brief review on the topic here and compare the two forms of immunotherapy. CAR-T cell therapy consists on removing T cells from patients and modifying ex vivo using gene transfer to enable expression of specific receptors targeting tumor cells through an antibody-derived binding domain. Once the T cells are genetically modified to express the chimeric antigen receptor, they are infused back into the patients to directly kill the cancer cells Fig.  Caruana. CurrentWhile both monoclonal antibody therapy and CAR T-cells are antigen specific immunotherapies, CAR T cells, at present, have to be individually manufactured for each patient resulting in high cost of production. Despite this, CAR T-cells exhibit several qualities that could make them more advantageous than antibody directed tumor therapy. The genetically engineered receptors allow CAR T-cells to recognize tumor cells with low antigen expression and cause direct lysis of tumor cells whereas classical monoclonal antibodies need a high density of tumor antigens to trigger the ADCC or complement cascade (Caruana et al. Antibody-based cancer directed therapy is an exciting and rapidly advancing field. The introduction of monoclonal antibodies such as rituximab revolutionized cancer therapy and have given way to the creation of bi-specific and tri-specific antibodies which work with more precision and efficacy than their predecessors. The one currently approved bi-specific antibody therapy, blinatumomab and catumaxomab, have shown improved survival rates and quality of life for subsets of cancer patients. Multiple agents are currently being evaluated in clinical trials while optimal structures and treatment algorithms are being defined to maximize benefit-risk ratio. Newer approaches concurrently targeting checkpoint molecules and cancer-specific antigens seem promising in preclinical models and may change the landscape of cancer therapeutics (Junttila et al. Several biological parameters are still missing in the understanding of the tumor biology and its complex microenvironment. Engineered polyspecific antibodies will likely play a major role in oncotherapeutics as cancer research continues to climb to new heights.


Dual-plating of the distal femur is required in some cases to achieve stable fixation. The indications of a medial plate in addition to the lateral plate are medial supracondylar bone loss, low trans-condylar bicondylar fractures, medial Hoffa fracture, peri-prosthetic distal femur fractures, non-union after failed fixation with single lateral plate, poor bone quality and comminuted distal femur fractures (AO type C3). We recommend orthogonal plate configuration with locked plates by a single incision or dual incision approach as per surgeon choice. Supracondylar femur fractures are commonly associated with severe comminution and significant soft tissue injury. Distal femoral fractures are mostly caused by high-energy injuries, such as falling injury and traffic accidents, and fractures are often severely comminuted. Despite the recent advances in techniques and implants, the treatment of intra-articular multi-fragmentary distal femoral fractures remains a challenge. Long-term disability can occur in patients with extensive articular cartilage damage and marked comminution. Distal femur fractures in the elderly are complicated by poor bone quality (severe osteoporosis), a distal segment that is too short for adequate fixation, blood loss, malunion and non-union, and increased mortality -4.Locked plating is one of the best and modern options for treating supracondylar femur fractures with relatively low failure rates. Single lateral plating of distal femur fractures was often found to have a relatively higher failure rate .A medial plate in addition to lateral plating reduces the chances of failure of fixation . This arPre-operative planningDecision making before surgical stabilization is important. The treating surgeon should examine the injured limb to check for the soft tissue status and any distal neurovascular deficit. Also, other injuries should be ruled out. Good quality radiographs in two planes are necessary. Computed tomography of the distal femur with coronal and sagittal reformations helps in delineating fracture patterns. Proper pre-operative planning will guide towards the need for dual plating of distal femur fractures .Indications for dual platingSupracondylar femur fractures were previously treated with condylar buttress plates . SubsequMedial Supracondylar Bone LossIn distal femur fractures with extensive metaphyseal comminution, osteopenic bone and in high-energy or open fractures, there is functional loss of medial cortical buttress. In these situations, there is less chance of healing of the medial column. The addition of a medial plate helps in giving additional stability and reduces the chances of implant failure ,14. RajaLow Trans-condylar Bicondylar FracturesHigh energy injuries sometimes lead to a low horizontal trans-condylar fracture pattern which is associated with an intercondylar split. In this fracture pattern, fixation with a single lateral plate may not achieve stable fixation as sufficient screw purchase will not be possible because of the intercondylar notch. A medial buttress plate in addition to the lateral plate is helpful in this situation ,16.Medial Hoffa FractureAnatomical restoration of the articular surface is necessary for comminuted distal femur fractures. In fractures with a large medial Hoffa fragment, the application of a medial neutralization plate is necessary to achieve stable fixation. This fixation provides stability in addition to interfragmentary lag screws .Peri-prosthetic Distal Femur FracturesIn peri-prosthetic fractures of the distal femur, dual plating offers stable fixation, especially in osteoporotic bone. This allows for early mobilization and rehabilitation. Stable fixation of peri-prosthetic fractures is necessary to avoid failures of fixation. Cicek et al. advocated dual locked plate fixation of peri-prosthetic distal femur fractures with osteoporotic bones .Non-union after Failed Fixation with Single Lateral PlateThere is an increased risk of non-union in patients with comminuted distal femur fractures treated with single lateral locking plate . In thesPoor Bone QualityIn patients with distal femur fracture with osteoporotic bone, there is a high incidence of failure of fixation with a single lateral plate due to poor purchase of screw in osteoporotic bone. Metwaly and Zakaria demonstrated that dual plating in osteoporotic distal femur fractures by a single incision offers the stability of fixation with resultant early mobility and accelerated rehabilitation . In the Comminuted Distal Femur Fractures (AO type C3)In patients with AO type C3 distal femoral fractures, dual plating offers a more stable construct. Imam et al. demonstrated that dual plating fixation using anterior approach for type C3 distal femoral fractures is an efficient and safe method of management. It has several advantages such as precise exposure, easy manipulation, anatomical reduction, and stable fixation . SteinbeSurgical techniquePositionThe patient is positioned supine on a radiolucent operating table with the knee flexed at 30 degrees. Tourniquet use depends on the surgeon and may be used in very distal fractures. The use of a lateral femoral distractor with pins placed in the femoral diaphysis and proximal tibia metaphysis facilitates fracture alignment and disimpacts intra-articular fragments. Intra-operative use of C-arm is necessary for proper plate placement and fracture reduction and alignment .ApproachThe choice of approach depends on the surgeon. There are two approaches, the dual incision approach and the single incision approach. The dual incision approach involves placing a medial and lateral incision for exposure of fracture and articular surface . The sinPrecautionsSoft tissue attachments to bone fragments should be preserved to prevent any devascularisation of bone fragments. Soft tissue retractors should be used with care .Choice of ImplantDual 4.5 anatomically contoured locking plates are generally used. The T-buttress plate can also be used for medial condyle fixation. Cancellous screws of 6.5 mm are preferred for intercondylar fragment fixation .Plate ConfigurationOrthogonal dual plate configuration provides more stable fixation and is biomechanically superior to dual adjacent plating for constructs fixed with either standard compression or locking plates .Post-operative careEarly mobilization in a protected hinged knee brace should be done. Weight-bearing is to be allowed according to radiographic and clinical examination findings at the subsequent follow-up visits. Radiographic healing is established by the union of three cortices of the bone on the anteroposterior (AP) and lateral radiographic views of the bone. Clinical healing is confirmed by the absence of pain either with weight-bearing or with the application of stress over the injured area on examination. Malrotation is detected clinically by comparing the injured side to the normal side. Follow-up is to be continued until fracture healing and full weight-bearing .Dual plating of distal femur fractures offers a reliable stable fixation in cases with medial supracondylar bone loss, low trans-condylar bicondylar fractures, medial Hoffa fracture, peri-prosthetic distal femur fractures, non-union after failed fixation with single lateral plate, poor bone quality and comminuted distal femur fractures (AO type C3). Single-incision or dual incision approach may be used. Orthogonal plate configuration with locked plates provides stable fixation and allows for early rehabilitation. Early mobilization is necessary to prevent joint stiffness.


However, recent studies demonstrate the existence of a novel, centrally-derived peripheral glial population called motor exit point (MEP) glia, which myelinate spinal motor root axons in the periphery. Until recently, the boundaries that exist between the CNS and PNS, and the cells permitted to cross them, were mostly described based on fixed histological collections and static lineage tracing. Recent work in zebrafish using  Myelin is a unique plasma membrane extension produced by specialized glial cells that is wrapped around axons and facilitates rapid transmission of electrical impulses over long distances. Although myelin appeared 430 million years ago in the vertebrate lineage  consists of the brain and the spinal cord, while the peripheral nervous system (PNS) consists of neural tissue outside of the CNS, including motor and sensory axons and sensory neurons clustered in ganglia. While many neurons establish circuits within the CNS, some of these cells send their axons  freely across specialized CNS boundaries known as transition zones (TZs) and travel long distances throughout the organism and ultimately make synapses on peripheral tissues, including muscle. By associating tightly with axons to ultimately ensheath and insulate them with fatty membranes called myelin, myelinating cells increase nerve impulse conduction speed and strengthen the function and efficiency of the whole nervous system.In the CNS, oligodendrocytes (OLs), which are derived from neural tube precursors, make myelin in the brain and spinal cord, while Schwann cells (SCs), which originate from the neural crest (NC), myelinate axons of the PNS  and OL lineage cells. After exiting the CNS, MEP glia reside just outside of the ventral spinal cord along spinal motor nerve root axons, occupying axonal territory between SCs in the periphery and OLs in the spinal cord. The pMN domain constitutes the major site of expression of the basic helix-loop-helix (bHLH) transcription factor Olig2. In zebrafish, olig2  mutants, which harbor a mutation in sox10 and lack SCs, have peripheral OPCs that differentiate and myelinate spinal motor nerves, suggesting that sox10 may be required for MEP glial function or survival  transgenic line that faithfully mimics the endogenous expression of foxd3 , a transcription factor expressed by boundary cap (BC) cells that is also required for SC myelination  and MEP TZs, where axons enter and exit the spinal cord, respectively  that are not found all together in any other myelinating glial cell type  and both mbp and transcript and MBP protein can be detected along motor nerve root axons as early as 4 dpf  mutants, where SCs are arrested at the pro-myelinating stage and fail to myelinate peripheral axons, Monk et al. (gpr126 mutants are, in fact, MEP glial myelin sheaths (Figures gpr126 to initiate myelination. And as previously mentioned, these glial cells also do not express Krox20. Therefore, they are a CNS-derived, peripheral glial cell that myelinates peripheral axons, but uses a distinct molecular mechanism to initiate myelination.Fascinatingly, in k et al.  describe Figures . These d+Krox20 BC cells project membrane processes across the MEP TZ into the ventral spinal cord (Radomska and Topilko, + cells residing within the mouse spinal cord give rise to SCs, which are usually NC-derived (Zawadzka et al., Drosophila, zebrafish and mouse (Sepp et al., For years, mammalian BC cells were thought to constrain MN cell bodies to the spinal cord by repulsion from outside the spinal cord (Bron et al., MEP glial development and function raise many new questions. What are the signals mediating OPC-MEP glial interactions across the MEP TZ? Do MEP glia also interact with SCs and via which molecular mechanisms? Does this novel, centrally-derived glial cell population adopt a central-like myelination pattern, involving the extension of multiple membrane processes to wrap more than one axonal segment? Or does it behave more like a Schwann cell, ensheathing a single axonal segment in a truly peripheral-like fashion? Or alternatively, is MEP glial myelin a kind of hybrid myelin featuring both central and peripheral characteristics? How do MEP glia myelinate if they do not require Krox20 or Gpr126? Electron microscopy of the MEP TZ will be needed to examine MEP glial development at the ultrastructural level to characterize their myelin sheaths that connect the CNS and PNS. RNA-sequencing coupled to genome editing tools such as CRISPR/Cas9 will shed light on the molecular mechanisms that drive MEP glial development, their gating function and differentiation into peripheral myelinating glia. Recent studies in zebrafish have uncovered the existence of novel centrally-derived myelinating glia that function in the PNS and are required for nervous system TZ integrity, and future work may change our way of thinking about mammalian myelinating glia as well.LF wrote the manuscript with input from SK.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.


Although a number of new systemic therapeutic options in patients with advanced solid cancers have emerged due to the improved knowledge of molecular dysregulation in cancers, the durable, long-term, objective responses infrequently occur. This editorial article highlights the major limitation of current systemic therapy due to an inefficient drug delivery. While several mechanisms contributing to cancer drug resistance have been described, the common key barrier among solid cancers is the unique tumor microenvironment that causes the high interstitial fluid pressure (IFP). We discussed the mechanism causing an elevated IFP and how it interferes with drug delivery. To target the high IFP, we demonstrated the novel approach using gold nanoparticle carrying recombinant human tumor necrosis factor (TNF), a vascular disrupting agent, that preferentially and specifically targets tumors while the systemic toxicity is markedly reduced. The addition of cytotoxic agent by either directly conjugating to the gold nanoparticle or by systemic administration following gold nanoparticle carrying TNF resulted in significantly reduced tumor burden and increased survival in multiple mouse models with primary and metastatic endocrine cancer and pancreatic ductal carcinoma. A clinical trial in patients with advanced solid cancers is warranted based on the promising results in preclinical studies. In the era of “precision medicine” for cancer, efforts have been made to identify agents that preferentially target expressed molecular pathways specific to the cancer cells. Despite the potential of these new targeted therapies, durable long-term responses rarely occur. A major limitation of current systemically delivered cancer therapies is the failure of these drugs to effectively reach their target, the cancer cells. Because of inefficient systemic drug delivery, high doses of systemically-administered cancer drugs are usually given, which inevitably cause off-target toxicity, to achieve anti-tumor efficacy. Several factors contribute to the failure of systemic cancer treatments to effectively kill cancer cells. These include the ATP-binding cassette (ABC) transporters that can actively pump cytotoxic drugs out of cancer cells  and the Normally, water and molecules transported through convection flow out of capillaries, flow through the interstitial space, and into the lymphatic system and/or the venous drainage system. This transcapillary flow, created by the gradients of hydrostatic and colloid osmotic pressures in capillaries and in the interstitium, is typically outward (capillaries to lymphatic and/or venous system) because of the slightly negative pressure gradients in the normal interstitium . The eleTumor necrosis factor alpha (TNF) is a cytokine involved in systemic inflammatory response. This cytokine also has a potent effect on vascular endothelium, causing vascular leakage. Because of the severe systemic toxicity, the EU-approved clinical role for TNF in cancer treatment is currently limited to a cumbersome but effective surgical procedure that regionally delivers the combination of TNF and a high dose cytotoxic agent to the affected limb for locally advanced melanoma (isolated limb perfusion). To mitigate the systemic toxicity associated with TNF, our group demonstrated in a phase I clinical trial in patients with advanced solid cancers that CYT-6091, a PEGylated colloidal gold nanoparticle carrying recombinant human TNF, preferentially targets tumor tissue and had no dose-limiting toxicity at a dose 3-times higher than previous clinical trials in cancer patients treated with systemically administered recombinant human TNF. Although CYT-6091 was safe, the anti-tumor activity was minimal as only one patient of 27 achieved a partial response . Thus, Cand a paclitaxel prodrug. We studied the effect of CYT-21625 and CYT-6091 in 3 mouse models of thyroid cancer and neuroendocrine tumors. In this recent publication, we performed CT scan, FDG-PET, and histologic analyses showing that CYT-6091 and CYT-21625 specifically and preferentially target tumor tissue without histologic or clinical evidence of toxicity to normal organs. In addition, both nanomedicines caused intratumoral vascular damage and leakage only in tumor tissue. CYT-21625 treatment resulted in statistically significant lower tumor burden in mice with metastatic anaplastic thyroid cancer, poorly differentiated thyroid cancer (PDTC) and in genetically engineered mice that naturally develop pancreatic neuroendocrine tumors. The survival benefit was observed in mice with metastatic PDTC. Histologic analysis showed that CYT-21625 treated xenografts had lower tumor cell proliferation and increased caspase-dependent apoptosis [all mice that received CYT-6091 pretreatment followed by protein-bound paclitaxel survived. None of the mice receiving vehicle control survived at day 42  support this approach as the treatments induced tumor vascular leakage, increased cytotoxic drug accumulation, and improved animal survival. Because tumor vascular architecture in these mice resembles that seen in patients, such promising responses in preclinical studies of nanomedicine targeting tumor microenvironment need to be expanded to patients with advanced solid cancers in clinical trials.


Physical examination revealed a back abrasion, stupor, and spasmodic laughter  is rare.What do we already know about this clinical entity?Malignant catatonia (MC) often leads to fatal consequences. Administration of low-dose lorazepam typically leads to rapid resolution of symptoms; thus, definite diagnosis is crucial.What is the major impact of the image?Because MC resembles tetanus, diagnosis is often difficult and delayed.How might this improve emergency medicine practice?Administration of low-dose benzodiazepines may be warranted when patients presenting with MC symptoms have a history of psychological disorders and normal blood, urine, cerebrospinal fluid testing and imaging.Documented patient informed consent and/or Institutional Review Board approval has been obtained and filed for publication of this case report.


Post-traumatic Stress Disorder (PTSD) is a stress related syndrome. Chronic PTSD has increasingly been associated with poor health outcomes, neurodegeneration and risk for cognitive impairment (CI). However, the biological mechanisms underlying the development and maintenance of symptoms and potential associations in accelerating aging are not well understood. The aim of this study was to evaluate whether specific biomarkers influence functional limitations and cognitive impairment in rescue and recovery workers (i.e. responders) from the attacks on the World Trade Center (WTC) in New York. Plasma biomarkers were collected during annual health and wellness visits at the WTC responder clinic between 2012 and 2014. Short Physical Performance Battery (SPPB) and clinical data were examined with prospective PTSD symptom scores collected during participant’s initial enrollment into the parent study as early as 2002. We examined the relationship between cardiovascular , metabolic  and inflammation markers  with Post-traumatic Stress Disorder (PTSD), cognitive functioning  and frailty  in responders from the World Trade Center (WTC). We first examined correlations between biomarkers, PTSD symptom severity, PTSD dimensions, cognitive functioning and frailty. We then conducted multivariate regression analyses. In models adjusted for potential confounders, among N=1,045 responders, elevated PTSD was strongly associated with increased frailty, cardiovascular dysregulation and mild cognitive impairment. Current work is ongoing to identify trajectories of change in cognition with frailty and biological factors.


We sought to extend recent research that explored model-based approaches for combining clinical and gait measures to determine the most sensitive grouping for retrospectively classifying fallers from non-fallers which resulted in a model with 92% sensitivity and 66% specificity and an overall model of 83%. In the present study, the clinical assessment battery was augmented by incorporating more challenging balance items while removing clinical measures characterized by ceiling effects and restricted range. Thirty-two community-dwelling older adults  completed a battery comprising 76 measures of more challenging clinical measures of mobility and balance, and retained gait (GaitRITE), postural sway and physiological measures. Within each domain, highly collinear and theoretically-redundant measures were removed. Next, a Principal Component Analysis (PCA) identified those clinical and gait variables that accounted for the most unique variance. Finally, a backward stepwise logistic regression was performed on the reduced set of variables from the PCA to develop predictive equations. The current analysis yielded improved specificity of 75%, but slightly lower sensitivity 81%. Interestingly, when the results for the PCA from the previous study were used with the current data, the model classified fallers with 87% sensitivity and 86% specificity and an overall model of 86%. Notably, in all analyses, gait variables were central in identifying fall risk, with single- vs. dual-task difference scores of particular predictive importance. The differences observed between the best-fitting models across the two cohorts implies that modelling methods should accommodate and harness individual differences .


Gastrointestinal stromal tumor (GIST) is the most common malignant neoplasm of mesenchymal origin. Activating mutations in KIT or PDGFRA receptor tyrosine kinases (RTKs) are central to GIST biology and drive GIST growth and progression . This onKIT exon 14 T670I gatekeeper mutation was also suppressed by regorafenib, but not KIT exon 13 V654A resistance mutation, the most common secondary mutation present at the onset of imatinib failure. These results were further corroborated in biopsies from GIST patients treated with regorafenib in the phase II trial, underscoring V654A mutation as the main vulnerability for regorafenib treatment. Remarkably, we found that all TKIs, either approved or investigated in clinical trials, had activity profiles targeting only a subset of KIT secondary mutations  and growth. Together, we established the rationale for a phase I clinical trial that tested, for the first time in cancer, a rapid alternation treatment-schedule using agents with complementary activity against resistant subclones (NCT02164240).In the absence of approved drugs with pan-KIT inhibitory activity, novel therapeutic strategies are urgently needed in order to overcome the inter- and intra-tumor heterogeneity of subclones harboring different KIT secondary mutations. Interestingly, several TKIs had complementary profiles against secondary resistant mutations, including second- and third-line approved agents for advanced GIST, sunitinib and regorafenib, respectively. Combination of these two drugs widens the spectrum of secondary-resistant clones effectively targeted and may augment the magnitude and/or duration of clinical response. However, dose reduction due to overlapping effects might preclude activity in patients. We first established co-cultures of barcoded GIST cell lines containing clinically relevant KIT primary and secondary mutations, thus representing the polyclonal imatinib-resistance heterogeneity observed in many GIST patients. We subsequently modeled preclinically a rapid alternation treatment schedule of sunitinib and regorafenib, to maintain selective pressure against polyclonal secondary-resistance GIST cells, thereby impeding the regrowth of targeted subclones when the relevant drug for those subclones is withheld. Alternation of three days of sunitinib followed by four days of regorafenib was more effective than either drug alone inhibiting cell proliferation of these polyclonal populations and preventing emergence of a single dominant clone. The intrinsic heterogeneity of resistant subpopulations challenges standard management of cancer patients based on the sequential use of single-agent therapies that are discontinued upon progression or unbearable toxicities. Further, although combinations of kinase inhibitors have a biologic rationale highly needed, clinical development has encountered difficulties due to enhanced and/or overlapping toxicities . In this


The discovery of a fossil survival strategy in modern corals explains unexpected recoveries after warming-induced mortalities. Climate change is affecting reef-building corals worldwide, with little hope for recovery. However, coral fossils hint at the existence of environmental stress–triggered survival strategies unreported in extant colonial corals. We document the living evidence and long-term ecological role of such a survival strategy in which isolated polyps from coral colonies affected by warming adopt a transitory resistance phase, in turn expressing a high recovery capacity in dead colony areas. Such processes have been described in fossil corals as rejuvenescence but were previously unknown in extant reef-builder corals. Our results based on 16 years of monitoring show the significance of this process for unexpected recoveries of coral colonies severely affected by warming. These findings provide a link between rejuvenescence in fossil and extant corals and reveal that beyond adaptation and acclimatization processes, modern scleractinian corals show yet undiscovered and highly effective survival strategies that help them withstand and recover from rapid environmental changes. Corals are subjected to climate change–related impacts worldwide, with overwhelming evidence of mass mortalities affecting vast geographical areas in tropical  Mediterranean Sea, Spain]  Red List . Near-full recoveries  are located 30 nautical miles off the nearest coast . A marine reserve encircles the archipelago, covering an area of 5500 hectares. Illa Grossa , the largest of the islets in the Columbretes, is a C-shaped, drowned, Quaternary volcanic caldera. The monitored C. caespitosa colonies was annually monitored in the Columbretes Islands from 2002 to 2017. Each colony was examined after the summer, when mortality-triggering thermal anomalies occur, and the extent of the necrosed surface was recorded with photographs and sketches  recovered from the last major mortality event suffered by each colony to the last annual monitoring.n = 21) from the Columbretes Islands, previously cleared of organic matter, and a corallite sample from a Holocene fossil reef in Menorca  (Samples of rejuvenated corallites (


Despite research documenting gender differences in numerous outcomes in later life, we know little about gender differences in quality of life (QoL) for older adults who receive institutional long-term care. To address this gap, this study examines the relationship between gender and nursing home (NH) residents’ QoL, including possible reasons for differences observed. We used a mixed methods design including surveys with a random sample of Minnesota NH residents using a multidimensional measure of QoL , resident clinical data, facility-level characteristics, and qualitative interviews with NH residents (n=64). We used mixed models and thematic analysis of resident interviews to examine possible differences in resident QoL based on gender. After controlling for individual and facility characteristics, women reported higher overall QoL than men, with men reporting significantly lower QoL in 4 of 8 QoL domains. In interviews, men noted being especially dissatisfied with facility activities, whereas women more frequently described having friends in the facility and relying on family for support. Some women viewed the NH as a place of respite and described wanting to stay long-term, even though their families asked them to return home. In contrast, men more often described the NH as necessary due to physical needs, but undesirable for long-term living. Our findings provide preliminary evidence that men and women experience QoL differently, with men reporting lower QoL in several domains. Tailoring more activities for men and finding ways to strengthen relationships for men within the facility may help reduce the gender disparities in QoL we observed.


Iatrogenic aortocoronary arteriovenous fistula is a very rare complication of coronary artery bypass grafting in which one of the arterial grafts inadvertently forms a fistulous tract with a cardiac vein, shunting blood from the anastomosed coronary artery. We report a patient with an iatrogenic left internal mammary artery graft to cardiac vein fistula presenting with recurrent angina three years after a three-vessel coronary artery bypass grafting. This case of iatrogenic aortocoronary arteriovenous fistula (ACAVF) is interesting because it is a rare but important complication of coronary artery bypass grafting (CABG) which can result in significant clinical consequences like heart failure, tamponade, and death. To the best of our knowledge, only 38 similar cases of ACAVF have been reported in the literature. We have included a brief review of the literature on this rare complication and the various available treatment options.A 61-year-old woman with diabetes mellitus, hypertension, and hyperlipidemia initially presented with unstable angina; a regadenoson stress nuclear myocardial perfusion imaging (MPI) revealed anterolateral wall ischemia. Subsequent coronary angiography demonstrated severe stenoses of the left anterior descending (LAD) artery, left circumflex artery, and right coronary artery. She underwent CABG with a left internal mammary artery (LIMA) graft to the LAD artery and saphenous venous grafts (SVG) to the right posterior descending (RPDA) and obtuse marginal 4 (OM4) arteries. After CABG, the patient was doing well on guideline-directed medical therapy. Three years later, she presented with acute onset of chest pain suggestive of unstable angina. On admission, her heart rate was 80/min, blood pressure was 140/86 mmHg, and her physical exam was unremarkable.Electrocardiogram showed normal sinus rhythm without any evidence of ischemia. Serially monitored cardiac enzymes were within normal limits, and transthoracic echocardiography revealed normal ejection fraction with no distinct regional wall motion abnormalities. Regadenoson stress nuclear MPI showed anterolateral ischemia, a territory which should have been supplied by the LIMA to LAD graft. Diagnostic coronary angiography revealed known severe native, three-vessel coronary artery disease. The native LAD vessel was very small. Proximal LAD was medium sized. Mid LAD had 100% stenosis at the origin of diagonal branch. Distal LAD was not visualized . Graft aThe case was discussed with the cardiac surgical team as well as in a multicenter interventional conference to explore both surgical and percutaneous options. A percutaneous approach of coiling of the fistula is anatomically complex; a surgical approach which would involve ligation of ACAVF and redo CABG, would put the patient at higher risk of perioperative cardiac morbidity and mortality. Because of the coronary arterio-venous fistula with steal, it was unclear whether revascularization of the native LAD would be of any significant benefit to the patient. After full discussion about the risks versus benefits of treatment options with the heart team, the patient elected for medical management and intervention only if she has escalating symptoms. The patient's anti-anginal therapy was optimized with Metoprolol 50 mg daily, which she tolerated well with gradual improvement in her exercise tolerance and resolution of her anginal symptoms. The patient is currently asymptomatic at 1 year follow-up. Repeat cardiac stress testing may be pursued if she has recurrent symptoms. The tentative plan is to offer her interventional coil closure or surgical closure of the ACAVF if she has recurrent angina or heart failure symptoms.Iatrogenic ACAVF is a rare complication of CABG causing significant morbidity. To the best of our knowledge, only 38 cases have been reported . ACAVF c


Gametocyte density and sex ratio can predict the proportion of mosquitoes that will become infected after feeding on blood of patients receiving nongametocytocidal drugs. Because primaquine and methylene blue sterilize gametocytes before affecting their density and sex ratio, mosquito feeding experiments are required to demonstrate their early transmission-blocking effects. Anopheles mosquitoes must ingest at least 1 male and 1 female gametocyte to become infected. The formation of Plasmodium oocysts on the mosquito midgut wall is commonly used as evidence for successful transmission. These oocysts enlarge over time to rupture and release sporozoites that render mosquitoes infectious. In the absence of treatment, infectivity of malaria-infected individuals can be reasonably well predicted by the density of male and female gametocytes in their peripheral blood  = 1.08 ;  density  or sex r density . Infecti density . There wWe found that measures of mRNA gametocyte density do not correlate with infectivity shortly after treatment with gametocytocidal drugs. The major implication of this finding is that studies that examine transmission-blocking effects of drugs and potentially vaccines require mosquito-feeding assays to measure infectivity. Gametocytocidal drugs rapidly clear gametocytes, distort the gametocyte sex ratio , 11, andHere, we present evidence that gametocyte density and sex ratio are unaffected in the first 48 hours after initiation of treatment, despite a near complete prevention of onward transmission to mosquitoes. Nongametocytocidal drugs did not alter the shape of the associations between gametocyte density, sex ratio, and mosquito infection prevalence; gametocytes appeared equally infectious before and after treatment. In contrast, gametocyte density and sex ratio no longer explained transmission after treatment with DP-MB or SP/AQ-PQ; gametocytes persisted with sex ratios similar to those before treatment, but mosquito infections were nearly completely prevented.The mechanism that underlies the early sterilizing effect despite continued presence of gametocyte mRNA transcripts is unclear. While mRNA is unlikely to survive in free-floating form and, also by microscopy, gametocyte densities remain unaffected shortly after treatment , it is pThe molecular mechanisms that underlie the apparent male-biased clearance of gametocytes after MB treatment and female-biased clearance after PQ treatment are currently unclear; however, they likely reflect the sexual dimorphism of gametocyte proteomes. Our findings thus provide evidence for an early sterilizing effect of MB and PQ. Molecular tools to quantify male and female gametocytes cannot replace mosquito-feeding experiments to assess transmission-blocking properties of antimalarials.


Mobility impairments are prevalent in older adults. Whereas walking had traditionally been viewed as an autonomous process, evidence over the last decade has shown that cognitive processes such as attention and executive function have a significant impact on gait function in older adults. However, the exact neural mechanisms underlying difficulties in the control of mobility in older adults remains an open question. We examine the changes in the executive control of mobility in older adults with mobility impairments using functional near-infrared spectroscopy, as operationalized by performance in the community balance and mobility scale (CB&M). We hypothesized that prefrontal cortical (PFC) activity increases would be higher in older adults with mobility impairments, compared with older adults without mobility impairment, as dual-task walking difficulty increased. Older adults with  and without mobility impairment  were recruited from the local community. Dual-task walking was performed at a comfortable pace, while the difficulty of the concurrent cognitive task was increased using the modified Stroop test. PFC activity was measured using measures of oxygenated hemoglobin across the PFC. Older adults with mobility impairments demonstrated disproportionate increases in PFC activity, in comparison to those without mobility impairments, as the difficulty of the concurrent cognitive task increased (P<.001), even after controlling for age. In conclusion, these data suggest that older adults with mobility impairments may require greater attentional resources than those without mobility impairments when concurrently performing thinking and walking tasks.


The effect was not dependent on the method of immortalization as it was seen in both SV40 and E6 KO cell lines. sAC activity was not directly proportional to expression suggesting that additional regulatory pathways exist. Interestingly, targeted delivery of sAC to the mitochondria was not as effective in rescuing glucose sensitivity as untargeted delivery of sAC into all possible microdomains. Therefore, even though mitochondrial sAC is known to influence metabolism, our data suggests that the nonmitochondrial isoform is most important for cancer cell metabolism. Although metabolomics analysis suggested that serine synthetic pathways are activated in sAC null cells, there is no evidence to suggest that serine is required for sAC null cell growth. Neither inhibition of serine synthesis nor serine starvation differentially affected the growth of sAC null cells compared with WT sAC. DISCUSSION/SIGNIFICANCE OF IMPACT: These data suggest that the Warburg metabolic phenotype in sAC null cells is regulated by specific sAC microdomains. By targeting sAC to specific microdomains, we can further distinguish the role of sAC localization in cellular metabolism. Cancer cells have been shown to exhibit altered metabolic circuitry of pathways like glycolysis, which allow them to adapt to increased metabolic demands of cellular proliferation and waning environmental resources. Beyond helping us improve the use of sAC immunolocalization as a cancer diagnostic, a better understanding of sAC microdomains in transformed cells will help us understand how this signaling pathway is important in cancer. Pharmacologic manipulation of sAC signaling may represent a new cancer therapeutic strategy.OBJECTIVES/SPECIFIC AIMS: The soluble adenylyl cyclase (sAC) is a noncanonical source of cAMP in mammalian cells. sAC is an ATP/bicarbonate ion sensor, whose activity responds to intracellular signals such as pH changes and metabolism. Unlike the more traditionally studied transmembrane adenylyl cyclase, sAC is not tethered to the cell membrane and instead is found in subcellular microdomains like the mitochondria and nucleus. In particular, sAC localization in the mitochondria has been implicated in oxidative phosphorylation and mitochondrial metabolism. Specific changes in sAC microdomain localization have diagnostic utility in a wide variety of cancers, namely melanoma. We have recently found that loss of sAC leads to tumorigenesis and a Warburg/cancer-like metabolic phenotype, consisting of an activated flux through glycolysis, increased lactate production, and dependence on glucose metabolism. In addition, computational analysis of the metabolomics profile of sAC null cells suggests an increased flux through serine synthetic pathways. We hypothesized that specific sAC microdomains are responsible for this cancer-like metabolic state. METHODS/STUDY POPULATION: We have established oncogenic SV40 large T antigen and HPV16-E6 expressing mouse embryonic fibroblasts lacking sAC expression . Using these parental lines, we reintroduced sAC by targeting the protein to specific microdomains. sAC was either driven into the mitochondria (mito-sAC) or was driven into all possible microdomains (WT sAC). Single clones were generated and sAC expression was confirmed by Western analysis. Stable cell lines were evaluated for mitochondrial metabolism, glucose sensitivity, and serine sensitivity. RESULTS/ANTICIPATED RESULTS: We found that reintroduction of WT sAC into sAC null cells rescued sensitivity to glycolytic inhibition compared with control cells (


The comorbidity between alcoholism and eating disorders, especially in young women, is well documented. Alcohol and other drug (AOD)-use disorders are particularly common in women with bulimia nervosa. Although the mechanisms underlying the coexistence of these disorders remain unknown, recent family epidemiology studies suggest that bulimia nervosa and AOD dependence are transmitted independently in families. Furthermore, bulimia nervosa generally develops before the onset of AOD dependence. Thus, factors other than addictive behavior may contribute to the development of bulimia nervosa in a substantial proportion of women. The comorbidity of AOD-use disorders with eating disorders has implications for the treatment of the affected patients. Clinicians working with either alcoholic patients or patients with eating disorders have observed that both types of disorders frequently co-occur. Only recently, however, have researchers begun to investigate the reasons for this comorbidity. This article describes some characteristics of the most common eating disorders and reviews studies examining their comorbidity with alcoholism and other drug-use disorders.The two most common eating disorders are bulimia nervosa and anorexia nervosa. Both disorders primarily affect young women, with the usual ages of onset being between early and late adolescence for anorexia nervosa and between adolescence and early adulthood for bulimia nervosa. Only approximately 10 percent of all eating disorder cases occur in men. Because of this gender distribution, the vast majority of studies have investigated eating disorders only in women. Therefore, this review also focuses mainly on studies of women with eating disorders. Clinically diagnosable eating disorders are relatively rare in the general population. The lifetime prevalence rates are 1 to 3 percent for bulimia nervosa and 0.1 to 1 percent for anorexia nervosa .Bulimia nervosa is characterized by lack of control over food intake, leading to the recurrent consumption of large amounts of food in short periods of time . These binge-eating episodes are interspersed with recurrent compensatory purging behavior(s), such as vomiting or laxative abuse, to prevent weight gain. In addition, the patients’ self-evaluations are unduly influenced by their body shape and weight .Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM–IV), two types of anorexia nervosa exist: a restricting type and a binge-eating/purging type. Patients with restricting anorexia nervosa lose weight primarily by extremely restricting their food intake. Patients with binge-eating/purging anorexia nervosa achieve or maintain a subnormal weight by regularly engaging in binge-eating and purging behavior in addition to restricting their food intake. Thus, binge-eating/ purging anorexia nervosa differs from bulimia nervosa in that the anorexic is severely underweight and amenorrheic, whereas the bulimic typically is of normal weight. These distinctions are important, because the rates of alcohol-use disorders vary among women with different eating disorders.Anorexia nervosa is characterized by the relentless pursuit of thinness, intense fears of becoming fat, and a distorted body image. People with anorexia nervosa experience substantial weight loss. In female patients, the resulting changes in the hormonal system also lead to the absence of menstruation  . AccordiAnother eating disorder described provisionally in the DSM–IV is binge-eating disorder . Like buThe causes and mechanisms  underlying eating disorders remain unknown but most likely include genetic and environmental factors. Twin studies suggest that for bulimia nervosa, approximately 50 percent of the risk is attributable to genetic factors and 50 percent is attributable to the environment . MoreoveNumerous studies have investigated the prevalence of AOD-use disorders among women with eating disorders. A recent review of 51 studies  suggestsA recent survey of AOD-use disorders among women in the general population showed rates of 12 percent for alcohol abuse or dependence and 10 percent for other drug abuse or dependence . TherefoWomen with different eating disorders also differ in their rates of regular alcohol use : These rates were substantially higher among bulimics and binge-eating/purging anorexics (45 percent) than among restricting anorexics (11 percent) . These vThe frequency of eating disorders among alcoholic women has been studied less extensively than the frequency of alcohol-use disorders among eating-disordered women. Several studies have found, however, that the lifetime rates of any comorbid eating disorder among AOD-abusing women are significantly higher than in the general population, ranging from 15 to 32 percent . With reOne study of eating disorders among female and male Japanese alcoholics  in inpatient treatment found that 11 percent of the female alcoholics and 0.2 percent of the male alcoholics had lifetime histories of eating disorders . The verA striking finding emerged when the researchers analyzed different age groups of female alcoholics: Seventy-two percent of all the female alcoholics under the age of 30 had lifetime histories of comorbid eating disorders, compared with 11 percent in the entire sample. Again, the majority of these patients (89 percent) suffered from either bulimia nervosa or binge-eating/ purging anorexia nervosa. Thus, the association between eating disorders with bulimic features and alcohol-use disorders appears to be particularly strong among young women. The reasons for this concentration of eating disorders among young women are unclear. Although bulimia nervosa has been defined only relatively recently , its ratAnother study that examined the rates of eating disorders among female alcohol-dependent inpatients found that 30 percent of these women had lifetime histories of eating disorders . One-thiIn summary, the literature on both eating disorders and AOD-use disorders supports clinical observations of the frequent co-occurrence of both types of disorders. Furthermore, bulimia nervosa and the bulimic  subtype of anorexia nervosa are much more commonly associated with alcohol-use disorders than restricting anorexia nervosa. These findings are consistent with past research that determined behavioral and personality trait differences among patients with different eating disorders. For example, binge-eating/purging anorexics and bulimics share certain traits characteristic of impulsive behavior and mood swings, whereas restricting anorexics consistently have been described as behaviorally restrained and compulsive . Based oAlthough studies have confirmed that eating disorders and AOD-use disorders frequently coexist, the mechanisms underlying this comorbidity have not been elucidated. At least four potential explanations exist for the high rates of co-morbidity :Both disorders are different manifestations of a shared underlying etiology.The two disorders have different causes, but the presence of one disorder may increase a person’s chances of developing the other.An independent disorder causes both disorders.The two disorders have some risk factors in common, whereas other risk factors are specific to each disorder.The first hypothesis of a common etiology has been studied most extensively. Supporters of this hypothesis believe that both eating disorders and AOD-use disorders may be manifestations of an underlying predisposition toward impulsivity or may result from a common mechanism involving endogenous opioids . EndogenVery few studies have investigated the possible roles of transmissible genetic or environmental familial factors in the comorbidity of eating disorders and alcohol-use disorders. In a recent family study, Accordingly, the researchers divided the bulimic subjects into two groups: those with and those without lifetime histories of comorbid AOD dependence. When the rates of AOD dependence were examined in the first-degree relatives of both groups, the prevalence was elevated only among the relatives of bulimics with comorbid AOD dependence but not among the relatives of non-AOD-dependent bulimics. The analyses produced similar, though less robust, results when the rates of not only AOD dependence but also AOD abuse and dependence were evaluated. These findings refute the hypothesis that eating disorders and AOD-use disorders are different manifestations of a shared underlying etiology and indicate instead that both disorders are attributable to independent transmissible factors.not exhibit familial vulnerability to AOD-use problems, factors other than addictions may contribute to the development of bulimia nervosa in a substantial proportion of women. These findings raise the possibility that two bulimic subtypes exist. The first type would represent a “multi-impulsive” subtype, with a familial and personal history of AOD-use problems. The second type may best be described as an “anorexic-like” subtype, with personality and behavioral traits similar to restricting anorexics . Similar to restricting anorexics, these bulimics have no extensive personal or family histories of AOD-use problems.If many bulimic women do Other recently published studies also suggest that alcoholism and bulimia nervosa do not share a common etiology. For example, Genetic analyses of six major psychiatric disorders in women, including bulimia nervosa and alcoholism, supported the existence of separate genetic liabilities for eating disorders and alcoholism . The stuThus, the three epidemiological studies described here suggest that although bulimia nervosa and alcoholism frequently coexist, they apparently do not share an underlying familial or genetic liability. Instead, the two disorders are likely to result from independent causal factors.The other three potential explanations for the high rates of comorbidity between alcoholism and eating disorders have been examined less thoroughly. Most studies investigating the hypothesis that the presence of one disorder may increase the chances of developing the other disorder found that the onset of bulimia nervosa generally preceded the onset of alcohol dependence see . AlthougThe theory that an independent disorder can cause both eating disorders and alcoholism also has not been well studied. One potentially fruitful line of research would be to examine the relationship among anxiety disorders, bulimia nervosa, and alcoholism, because anxiety disorders frequently co-occur with both of the other disorders .The most likely—although also not well-investigated—explanation of the frequent comorbidity of eating disorders, particularly bulimia nervosa, and AOD-use disorders may be that people with both types of disorders share some underlying traits, such as periodic behavior disinhibition and difficulty modulating feelings or emotions . In addition to these shared traits, other etiologic factors likely exist that are specific to each disorder. Clearly, more research is needed to further evaluate this hypothesis.Over the past decade, several researchers have hypothesized that bulimia nervosa, like alcoholism, is a type of addictive disorder . Both alThe addiction model of eating disorders  has contIn contrast, other therapies, such as cognitive-behavioral therapy (CBT) and antidepressant medication, have proven useful in treating eating disorders . CBT focThe most effective treatment approaches for alcoholism and eating disorders also will likely differ, because different behaviors must be addressed for both types of disorders. The primary focus in alcoholism treatment is to avoid consuming the substance, whereas the focus in bulimia nervosa treatment is to change the manner in which the substance  is consumed. Many bulimics and binge-eating/purging anorexics have difficulty modulating food intake and often alternate between periods of imposed food restriction and overconsumption combined with purging behaviors. Treatment must take into consideration both these consumption patterns as well as a disturbed body image. Accordingly, cognitive-behavioral approaches addressing all these issues differ greatly from the 12-step programs commonly used to treat alcoholics.Few empirical data exist to help identify and treat patients with coexisting eating disorders and AOD-use disorders. Still, the frequent comorbidity of these disorders underscores the necessity of determining whether eating disorders are present, especially among young, AOD-abusing women entering treatment. Adequate assessment is even more important, because alcoholic, eating-disordered patients also are likely to engage in other behaviors common among “multi-impulsive bulimics,” such as shoplifting, suicide attempts, or self-mutilating behavior . These cAOD-abusing patients with coexisting eating disorders should receive thorough medical assessments and nutritional consultations. The management of these patients should include monitoring their weight, food intake, and purging behavior as well as assessing their cardiac, fluid, and mineral  statuses. The patients should be observed during and after each meal, with supervised bathroom use to minimize purging opportunities. Although monitoring eating-disordered patients in an AOD-abuse treatment facility may be challenging and labor intensive, it is necessary for treatment.Patients with comorbid AOD-use and eating disorders can pose a particular challenge for the individual clinician or the staff of a treatment facility. These patients may represent a group distinct from patients who only have an AOD-use disorder or an eating disorder. They may require different, more varied, and more intensive assessment and treatment approaches. Researchers and clinicians still have not identified the most beneficial treatment approaches for these patients, and future treatment outcome studies must address this difficult patient population.


Chronic sterile inflammation is a pathological feature of Alzheimer’s disease (AD) and other neurodegenerative diseases. The mechanisms that drive neuroinflammation and its impact on AD progression are still incompletely understood. The accumulation of molecular damage in somatic cells can trigger cellular senescence, an irreversible state of cell cycle arrest accompanied by the expression of proinflammatory mediators known collectively as the “senescence-associated secretory phenotype” (SASP). Misfolded tau forms pathogenic soluble aggregates that are released extracellularly and are transmitted trans-neuronally, promoting native tau phosphorylation and aggregation in target cells. We recently showed that, in addition to neurons, pathogenic soluble extracellular tau aggregates propagate to brain microvascular endothelial cells, where microtubule destabilization triggers senescence/SASP. Because astrocytes have a critical role in the regulation of both synaptic function and cerebral blood flow and are directly exposed to tau at its site of release at the tripartite synapse, we conducted studies to define whether soluble aggregated tau propagates to astrocytes, inducing astrocyte senescence/SASP and neuronal dysfunction/damage. Our studies indicate that tau can be propagated transcellularly to astrocytes, triggering cellular senescence/SASP. Our studies suggest that astrocyte senescence is detrimental to dendritic and synaptic structure and density, suggesting that pathogenic soluble tau-induced astrocyte senescence may contribute to synaptic dysfunction and loss in AD. Drugs that eliminate senescent cells are FDA-approved and antibody-based approaches to remove tau from brain are already in clinical trials. Our studies suggest that these interventions could be effective in the treatment of AD and other tauopathies.


Nationally, there is a shortage of geriatric trained healthcare providers caring for older adults. As the population of older adults grows, health care systems and primary care providers struggle to provide high quality, cost effective care for older adults. Time for training is also limited in busy community health centers. The CATCH-ON Learning Communities (LCs) are telehealth educational interventions based on the ECHO model, modified to be less time intensive, thus decreasing cost to participating clinics. In the LC, geriatric specialists provide evidence-based, best practice training utilizing case discussions to illustrate pertinent learning points via monthly one hour video conferences. Practical, specific behavioral recommendations are offered for immediate implementation in each session. LCs are provided to interprofessional primary care teams. The first LC with a federally-qualified health center (FQHC) yielded consistently high satisfaction from participants, along with a 17% decrease in high risk medication prescriptions and 22% increase in falls screenings. Training the primary care workforce in evidence based geriatric interventions can improve the care of all older adults within each health system, improving healthcare access to help mitigate healthcare inequalities, slow adoption of best practices and rising costs of caring for complex older adults. The CATCH-ON Learning Community is an effective, low cost model of training the primary care work force without geographical or financial constraints that frequently limit access to specialized care.


Financial exploitation (FE) in older adults is a significant public health problem linked to outcomes including depression, financial ruin and early mortality. This study applied exploratory data science techniques to a multi-year statewide protective services dataset of over 8,000 elder abuse cases. The goal was to derive data-driven psychosocial profiles of abuse with an emphasis on determining which factors, commonly shared across abuse cases, were most important for determining when elder FE was occurring and whether it was occurring alone or in conjunction with other types of abuse. We found that pronounced psychological distress  was most important for indicating when abuse had occurred and predicted non-FE related abuse. Drug paraphernalia in the home and perpetrator drug/alcohol use were important predictors of FE-related abuse. When differentiating pure FE from hybrid FE, factors indicative of long-term FE occurrence and substantial financial loss were most important . The findings parallel some existing work characterizing pure and hybrid FE, but also highlight new profile factors that may help determine when FE is occurring and when it is less likely. Applying data science approaches to other large protective service datasets and national datasets such as the National Adult Maltreatment Registry could help improve characterization of abuse types such as pure and hybrid FE resulting in better detection, response and prevention.


Hepatitis C virus (HCV)-induced cirrhosis is a major cause of hepatocellular carcinoma (HCC) worldwide. HCC is an aggressive malignancy in which tumor thrombus can invade portal vein, hepatic veins and inferior vena cava (IVC) in the later stages. Our case brings to attention, HCV patient population who might need long-term follow-up to ensure HCV clearance. Physicians should ensure appropriate follow-up after treatment of HCV and should emphasize on the ongoing screening for HCC in patients with cirrhosis or advanced fibrosis, regardless of antiviral treatment outcome. Hepatocellular carcinoma (HCC) is the fourth most common cancer and the third leading cause of cancer-related deaths in the world . HCC is A 58-year-old male presented to the hospital with chief complaints of dyspnea on exertion associated with pleuritic chest pain and fatigue for two weeks prior to presentation. Medical history was significant for hypertension and hepatitis C genotype 1 treated with ledipasvir/sofosbuvir four years ago. HCV was successfully treated with achievement of sustained virologic response four years ago. The patient did not follow-up after treatment completion. On physical examination, mildly distended, non-tender abdomen was noted. Computed tomography (CT) angiogram of chest was done due to an elevated D-Dimer of 1878 ng/ml and the patient was found to have a segmental pulmonary embolism in the right lower lobe of the lung Figure . Tumor tHCV-induced cirrhosis is a major cause of HCC worldwide. The redetection of HCV RNA in our patient can either be explained by ledipasvir-sofosbuvir treatment failure with HCV reactivation, HCV relapse or HCV reinfection. The preferred antiviral regimen for the vast majority of patients with chronic HCV infection was ledipasvir-sofosbuvir when our patient was treated . HCV NS5The diagnosis of HCC is typically made by radiological liver imaging in combination with serum AFP without the need for biopsy especially in patients with cirrhosis . TherefoExtension of IVC thrombus into right atrium (RA) can present as RA mass . Primary.Definitive therapy of pulmonary tumor emboli is directed at treating the primary tumor . SurgicaThe prognosis of HCC patients with tumor thrombi is extremely poor, with median survival of about three months from diagnosis without treatment . The oneIn conclusion, our case is unique as advanced HCC presented as pulmonary tumor embolism after successful treatment of HCV. In patients with HCC, who present with respiratory distress and chest pain, clinicians should have a high index of suspicion for pulmonary tumor embolism. Our case emphasizes the importance of HCC screening in patients treated for hepatitis C and have advanced fibrosis or cirrhosis for early detection and management of hepatocellular carcinoma.