Search

Objectives The aim of this meta-analysis was to conduct a contemporary systematic review of high quality non-randomised controlled trials to determine the effect of pre-liver transplantation (LT) transarterial chemoembolisation (TACE) on long-term survival and complications of hepatocellular carcinoma (HCC) patients. Background TACE is used as a neoadjuvant therapy to mitigate waitlist drop-out for patients with HCC awaiting LT. Previous studies have conflicting conclusions on the effect of TACE on long-term survival and complications of HCC patients undergoing LT. Methods CINAHL, Cochrane Controlled Register of Trials, Embase, PubMed, and Web of Science were systematically searched. Baseline characteristics included number of patients outside Milan criteria, tumour diameter, MELD score, and time on the waiting list. Primary outcomes included 3- and 5-year overall and disease-free survival. Secondary outcomes included tumour recurrence, 30-day postoperative mortality, and hepatic artery and biliary complications. Results Twenty-one high-quality NRCTs representing 8242 patients were included. Tumour diameter was significantly larger in TACE patients (3.49 cm vs 3.15 cm, P = 0.02) and time on the waiting list was significantly longer in TACE patients (4.87 months vs 3.46 months, P = 0.05), while MELD score was significantly higher in non-TACE patients (10.81 vs 12.35, P = 0.005). All primary and secondary outcomes displayed non-significant differences. Conclusion Patients treated with TACE had similar survival and postoperative outcomes to non-TACE patients, however, they had worse prognostic features compared to non-TACE patients. These findings strongly support the current US and European clinical practice guidelines that neoadjuvant TACE can be used for patients with longer expected waiting list times (specifically >6 months). Randomised controlled trials would be needed to increase the quality of evidence.

Acute upper respiratory tract infections (URTIs) are caused by numerous viruses and bacteria. URTIs can be a cause of morbidity and are among the most common reasons for visiting healthcare practitioners and prescribing antibiotics to children in addition to causing absenteeism from school and work. Oral intake of Lacticaseibacillus rhamnosus GG DSM 33156 has shown beneficial health effects in several clinical trials, primarily relating to immune function and gastrointestinal health in children and adults. It has also been suggested that oral intake of L. rhamnosus GG DSM 33156 can reduce the incidence rate and alleviate symptoms of URTIs in children. We here report the results of a randomised, double-blind, placebo-controlled trial of 619 children aged 2-6 years conducted at a single centre in Scotland. The children, who were in day care or primary school, were followed over a 16-week intervention period with 309 randomised in the active group and 310 in the placebo group. The parents or guardians reported a daily healthcare status and any presumed episodes of URTI, which were subsequently confirmed by a general practitioner. The investigational product was well tolerated in the trial. Although a general trend towards a beneficial effect was observed, this trial did not demonstrate that L. rhamnosus GG DSM 33156 significantly reduced the incidence of URTIs, diagnosed by a general practitioner according to prespecified criteria (primary endpoint). Moreover, none of the secondary efficacy endpoints were met. Applying a Ward’s hierarchical clustering, two separate clusters, focussing on four quality of life-related endpoints, were identified. Cluster 1 was associated with more severe URTI characteristics than cluster 2. Cluster 2 was significantly enriched with children who consumed the product, indicating that the symptoms children experience during an URTI are alleviated by the intake of L. rhamnosus GG DSM 33156. The study is registered at ClinicalTrials.gov ID: NCT03636191.

Microfluidic devices (MFDs) printed in 3-D geometry using digital light projection to polymerize monomers often have surfaces that are not as hydrophobic as MFDs made from polydimethylsiloxane. Droplet microfluidics in these types of devices are subject to droplet adhesion and aqueous spreading on less hydrophobic MFD surfaces. We have developed a post-processing technique using hydrophobic monomers that renders the surfaces of these devices much more hydrophobic. The technique is fast and easy, and involves flowing monomer without initiator into the channels and then exposing the entire device to UV light that generates radicals from the initiator molecules remaining in the original 3-D polymerization. After treatment the channels can be cleared and the surface is more hydrophobic, as evidenced by higher contact angles with aqueous droplets. We hypothesize that radicals generated near the previously printed surfaces initiate polymerization of the hydrophobic monomers on the surfaces without bulk polymerization extending into the channels. The most hydrophobic surfaces were produced by treatment with an alkyl acrylate and a fluorinated acrylate. This technique could be used for surface treatment with other types of monomers to impart unique characteristics to channels in MFDs.

Background: breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. Patients and methods: we included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. Eligibility criteria: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (Results: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10 −5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10 −4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. Conclusions: this is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Health plans develop predictive models to predict key clinical events (eg, admissions, readmissions, emergency department visits). The authors developed predictive models of admissions and readmissions for a quality improvement organization with many large government and private health plan clients. Its membership and authorization data were used to develop models predicting 2019 inpatient stays, and 2019 readmissions following 2019 admissions, based on patients' age and sex, diagnoses identified and procedures requested in 2018 authorizations, and 2018 admission authorizations. In addition to testing multivariate models, risk scores were calculated for admission and readmission for all patients in the model. The admissions model (C = 0.8491) is much more accurate than the readmissions model (C = 0.6237). Measures of risk score central tendency and skewness indicate that the vast majority of members had little risk of hospitalization in 2019; the mean (standard deviation) was 0.042 (0.074), and the median was 0.018. These risk scores can be used to identify members at risk of admission and to support proactive risk management (eg, design of health management programs). Different risk thresholds can be used to identify different subsets of members for follow-up, depending on overall strategy and available resources. This model development project was novel in employing authorization data rather than utilization data. Advantages of authorization data are their timeliness, and the fact that they are sometimes the only data available, but disadvantages of authorization data are that authorized services are not always actually performed, and diagnoses are often "rule out" rather than final diagnoses.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer with a high mortality rate. Epithelial-to-mesenchymal transition (EMT) confers cancer cells with immune evasive ability by modulating the expression of immune checkpoints in many cancers. Thus, the aim of our study is to examine the interplay between EMT and immune checkpoint molecules in HCC. A reversible EMT model was utilised with transforming growth factor (TGF)-β1 as an EMT inducer for HCC cell lines Hep3B and PLC/PRF/5. HCC cells were treated with TGF-β1 for 72 h and the EMT status and immune checkpoint expression were examined. In addition, the migratory ability of HCC cells were examined using wound healing and transwell migration assays in the reversible EMT model. siRNA-mediated knockdown of immune checkpoint molecule, B7-H3, was further utilised to validate the association between TGF-β1-mediated EMT and immune checkpoint expression in HCC. In addition, a web-based platform, SurvExpress, was utilised to evaluate the association between expression of TGF-β1 in combination with immune checkpoint molecules and overall survival in HCC patients. We observed induction of EMT upon treatment of HCC cells with TGF-β1 revealed by reduced expression of epithelial markers along with increased expression of mesenchymal markers. Withdrawal of TGF-β1 reversed the process of EMT with elevated expression of epithelial markers and reduced expression of mesenchymal markers. TGF-β1 treatment elevated the migratory potential of HCC cells which was reversed following reversal assay. Notably, during TGF-β1-induced EMT, there was upregulation of immune checkpoint molecules PD-L1 and B7-H3. However, the reversal of EMT decreased the expression of PD-L1 and B7-H3. In addition, TGF-β1 driven EMT was reversed following knockdown of B7-H3 in both HCC cells further validating the interplay between TGF-β1-mediated EMT and immune checkpoint expression in HCC. Furthermore, the coordinate expression of TGF-β1 with PD-L1 (p=0.01487) and B7-H3 (p=0.009687) was correlated with poor overall survival in 422 HCC patients. Our study has demonstrated a close association between TGF-β1-mediated EMT and regulation of immune checkpoints in HCC.

Loss of physiological microglial function may increase the propagation of neurodegenerative diseases. Cellular senescence is a hallmark of aging; thus, we hypothesized age could be a cause of dystrophic microglia. Stereological counts were done for total microglia, two microglia morphologies (hypertrophic, and dystrophic) across the human lifespan. An age-associated increase in the number of dystrophic microglia was found in the hippocampus and frontal cortex. However, the increase in dystrophic microglia was proportional to the age-related increase in the total number of microglia. Thus, aging alone does not explain the presence of dystrophic microglia. We next tested if dystrophic microglia could be a disease-associated microglia morphology. Compared to controls, the number of dystrophic microglia was greater in cases with either Alzheimer’s disease, dementia with Lewy bodies, or limbic-predominant age-related TDP-43 encephalopathy (LATE). These results demonstrate that microglia dystrophy, and not hypertrophic microglia, are the disease-associated microglia morphology. Finally, we found strong evidence for iron homeostasis changes in dystrophic microglia, providing a possible molecular mechanism driving the degeneration of microglia in neurodegenerative disease.

Post-traumatic stress disorder (PTSD) is associated with extensive physical comorbidities, including lower gastrointestinal symptoms. Diagnostic uncertainty and poor therapeutic responses may result in more frequent colonoscopies than clinically necessary. Polypectomy is standard practice when polyps are identified, and if PTSD is a risk factor for polyp formation, one would expect a higher rate of polyp detection and removal in veterans with PTSD than those without PTSD.To determine the association between PTSD and the rate of colonoscopy and polypectomy in Australian veterans.Diagnostic and therapeutic colonoscopy rates in Australian male Veterans aged ≥50 years were examined by reviewing case records of veterans who accessed Department of Veterans' Affairs funded health services between 1 January 2013 and 31 December 2018.A total of 138 471 veterans was included, of whom 28 018 had a diagnosis of PTSD; 56.4% were aged ≥65 years. Twenty-one percent of the entire cohort underwent at least one colonoscopy during the study period. Increased rates of diagnostic colonoscopy and polypectomy were associated with the presence of PTSD across all age brackets. The effect was empirically large as veterans with PTSD experience colonoscopy rates 76-81% greater than those without PTSD. Similarly, veterans with PTSD experienced polypectomy rates 76-81% greater than veterans without PTSD, and this increase persisted when controlling for the increased number of diagnostic colonoscopies they undergo.The presence of PTSD has a marked impact on colonoscopy rates in Australian veterans. The increased polypectomy rate independent of increased colonoscopy rate suggests that PTSD is a risk factor for colonic polyp formation.

Wereport on the fabrication and measurement of hydrogen-terminated diamond field-effect transistors (FETs) incorporating V2O5 as a surface acceptor material to induce transfer doping. Comparing a range of gate lengths down to 50 nm, we observe inversely scaling peak output current and transconductance. Devices exhibited a peak drain current of ~700 mA/mm and a peak transconductance of ~150 mS/mm, some of the highest reported thus far for a diamond metal semiconductor FET (MESFET). Reduced sheet resistance of the diamond surface after V2O5 deposition was verified by four probe measurement. These results show great potential for improvement of diamond FET devices through scaling of critical dimensions and adoption of robust transition metal oxides such as V2O5.

Introduction: The Diagnostic and Statistical Manual of Mental Disorders (5th ed.; DSM–5) brought a change to the symptom clusters of posttraumatic stress disorder (PTSD). In line with the DSM–5 changes, an updated version of the Clinician-Administered PTSD Scale (CAPS–5) was released. The CAPS–5 is considered to be the gold-standard measure of PTSD; however, examinations of the psychometric properties and optimal factor structure of this scale are underrepresented in PTSD studies. Methods: This study used confirmatory factor analysis (CFA) to assess the factor structure of the CAPS–5 using a sample of 267 male Australian Vietnam Veterans. Models drawn from the PTSD CFA literature were used to test the underlying dimensions of PTSD: the four-factor DSM–5 model, six-factor externalizing behaviour and anhedonia models, and seven-factor hybrid model. Results: The results found that the DSM–5 model showed slightly less than adequate fit (comparative fit index [CFI] = 0.90, Tucker–Lewis index [TLI] = 0.88, root mean square error of approximation [RMSEA] = 0.064), however, other models showed acceptable fit. The anhedonia model provided a significantly better fit than the other models (CFI = 0.92, TLI = 0.90, RMSEA = 0.059). Discussion: Overall, the results supported the anhedonia model. This result may indicate that the underlying dimensions of PTSD in Australian Vietnam Veterans may best be represented by six distinct factors.

Hepatocellular carcinoma (HCC) is the fastest growing cause of cancer‑related deaths globally. Epithelial‑to‑mesenchymal transition (EMT) is a cellular process that confers HCC tumor cells with the ability to evade the immune system. Immune escape in most tumors, including HCC, is controlled by immune checkpoint molecules. The aim of the present study was to investigate the association between EMT and immune checkpoint in HCC, and identify novel therapeutic targets for HCC. An in vitro model of reversible EMT was utilized based on cytokine tumor necrosis factor (TNF)‑α treatment of HCC cell lines Hep3B and PLC/PRF/5. Hep3B and PLC/PRF/5 cells were treated with TNF‑α, and the EMT status and the expression of immune checkpoint molecules was assessed by reverse transcription‑quantitative PCR, western blotting and immunofluorescence. To confirm an association between EMT and immune modulators, cells were exposed to culture medium with TNF‑α for 3 days to induce EMT, following which a reversal assay was performed. The expression of immune modulators and mesenchymal‑to‑epithelial transition (MET) status was investigated upon reversal of EMT. Furthermore, SurvExpress, a web‑based platform was utilized to analyze survival and recurrence in a dataset of patients with HCC. TNF‑α treatment for 3 days induced EMT in Hep3B and PLC/PRF/5 cells, as demonstrated by the downregulation of epithelial markers along with upregulation in mesenchymal markers. An EMT reversal assay was able to induce MET by increasing epithelial markers and decreasing mesenchymal markers. TNF‑α‑induced EMT led to the upregulation of immune modulators, including programmed death receptor ligand (PD‑L)1, PD‑L2, CD73 and B7‑H3. In contrast, reversal of EMT suppressed the expression of PD‑L1, PD‑L2, CD73 and B7‑H3. In addition, high expression of TNF‑α and PD‑L1 in 422 patients with HCC was associated with poor overall survival. The coordinate expression of TNF‑α with PD‑L2 in this patient cohort was associated with increased HCC recurrence. In conclusion, the present study demonstrated a close association between immune modulator expression and EMT induction/reversal driven by TNF‑α.

Gallbladder cancer (GBC) is one of the most common and aggressive biliary tract cancers with a dismal prognosis. Ongoing clinical trials are evaluating a few selected immune checkpoint inhibitors (ICIs) as monotherapy for the treatment of GBC patients. However, only a subset of patients benefits from these treatments. To improve ICI therapy response, molecular mechanisms that confer resistance to immune checkpoint (IC) blockade needs to be explored. Epithelial-to-mesenchymal transition (EMT) program and cancer stem cells (CSCs) have been implicated as key processes that confer ICI treatment resistance. However, in GBC the EMT-CSC-IC axis has not yet been clearly elucidated. This study aims to examine the aberrant expression of ICs associated with CSC and EMT. We successfully enriched CSCs by utilizing a 3-dimensional culture system and established a reversible EMT model with human GBC NOZ cell line. Notably, ICs CD73 and PD-L1 were closely associated with both CSC and EMT phenotypes. Knockdown of CD73 or PD-L1 reduced the proliferative and motile abilities of both adherent monolayers and anchorage-free spheroids. In conclusion, blocking CD73 and PD-L1 offer a promising therapeutic strategy for targeting highly aggressive populations with CSC and EMT phenotype to improve GBC patient prognosis.

Sorafenib, an oral multi-tyrosine kinase inhibitor, has been the first-line therapy for the treatment of patients with advanced HCC, providing a survival benefit of only three months in approximately 30% of patients. Cancer stem cells (CSCs) are a rare tumour subpopulation with self-renewal and differentiation capabilities, and have been implicated in tumour growth, recurrence and drug resistance. The process of epithelial-to-mesenchymal transition (EMT) contributes to the generation and maintenance of the CSC population, resulting in immune evasion and therapy resistance in several cancers, including HCC. The aim of this study is to target the chemoresistant CSC population in HCC by assessing the effectiveness of a combination treatment approach with Sorafenib, an EMT inhibitor and an immune checkpoint inhibitor (ICI). A stem-cell-conditioned serum-free medium was utilised to enrich the CSC population from the human HCC cell lines Hep3B, PLC/PRF/5 and HepG2. The anchorage independent spheres were characterised for CSC features. The human HCC-derived spheres were assessed for EMT status and expression of immune checkpoint molecules. The effect of combination treatment with SB431542, an EMT inhibitor, and siRNA-mediated knockdown of programmed cell death protein ligand-1 (PD-L1) or CD73 along with Sorafenib on human HCC-derived CSCs was examined with cell viability and apoptosis assays. The three-dimensional spheres enriched from human HCC cell lines demonstrated CSC-like features. The human HCC-derived CSCs also exhibited the EMT phenotype along with the upregulation of immune checkpoint molecules. The combined treatment with SB431542 and siRNA-mediated PD-L1 or CD73 knockdown effectively enhanced the cytotoxicity of Sorafenib against the CSC population compared to Sorafenib alone, as evidenced by the reduced size and proliferation of spheres. Furthermore, the combination treatment of Sorafenib with SB431542 and PD-L1 or CD73 siRNA resulted in an increased proportion of an apoptotic population, as evidenced by flow cytometry analysis. In conclusion, the combined targeting of EMT and immune checkpoint molecules with Sorafenib can effectively target the CSC tumour subpopulation.

This article demonstrates effects on utilization of a clinical transformation: changing locus of care from a dedicated sickle cell day unit to an approach that “fast-tracks” patients through the emergency department (ED) into an observation unit with 24/7 access. Retrospective quantitative analyses of claims and Epic electronic medical record data for patients with sickle cell disease treated at Thomas Jefferson University (inpatient and ED) assessed effects of the clinical transformation. Additionally, case studies were conducted to confirm and deepen the quantitative analyses. This study was approved by the Thomas Jefferson University Institutional Review Board. The quantitative analyses show significant decreases in ED and inpatient utilization following the transformation. These effects likely were facilitated by increased observation stays. This study demonstrated the impact on utilization of transformation in care (from dedicated day unit to an approach that fast-tracks patients into an observation unit). Additional case studies support the quantitative findings.

The US health care system faces rising costs related to population aging, among other factors. One aspect of the high costs related to aging is Medicare outpatient therapy expenditures, which in 2010 totaled $5.642B for ∼4.7 million beneficiaries. Given the magnitude of these costs and the need to maximize value, this study developed and tested a predictive model of outpatient therapy costs. Retrospective analysis was performed on electronic medical record data from October 31, 2014-September 30, 2016 for 15,468 Medicare cases treated by physical therapists associated with a large, national rehabilitation provider. The analysis was a multiple linear regression of cost per case by 27 predictor variables: age group, sex, recent hospitalization, community vs. facility residence, the 10 states served, time from admission to initial evaluation, initial functional limitation reporting level, functional limitation reporting category, and 9 chronic conditions. The model was designed to be predictive and includes only variables available at the start of a case. The model was statistically significant (P .0001) but explained only 7.4% of the variance in cost. Of the predictor variables, 16 had statistically significant effects. Those most highly predictive included state in which service was provided (8 of the 16 effects), and 3 variables indicating physical functioning at initial evaluation (initial functional limitation category and level, and residence in community vs. facility). There is need for more research focusing on the effects of specific types of treatment, and also for a more proactive model for outpatient therapy reimbursement that emphasizes prevention as well as treatment.

We study scalable approximation algorithms for the k-cycle transversal problem, which is to find a minimum-size set of edges that intersects all simple cycles of length k in a network. This problem is relevant to network reliability through the important metric of network clustering coefficient of order k. We formulate two algorithms to be both scalable and have good solution quality in practice: CARL and DARC. DARC is able to efficiently update its solution under dynamic node and edge insertion and removal to the network. In our experimental evaluation, we demonstrate that DARC is able to run on networks with billions of 3-cycles within 2 h and is able to dynamically update its solution in microseconds.

The COVID-19 pandemic has heightened social isolation and loneliness. There is a lack of consensus on rating scales to measure these constructs. Our objectives were to identify commonly used loneliness and social isolation scales over the last two decades and test their user characteristics. 7928 articles were searched in PubMed/MEDLINE, CINAHL, Web of Science, and APA PsychINFO databases. 41 articles were included based on study criteria. Among fourteen scales reported, UCLA 3-item loneliness scale was found to be most commonly used. The scale is specifically developed for telephone use and is the fastest taking less than a minute for self-administration.

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic malignancy. HCC is one of the leading causes of cancer deaths worldwide. The oral multi-tyrosine kinase inhibitor Sorafenib is the standard first-line therapy in patients with advanced unresectable HCC. Despite the significant survival benefit in HCC patients post treatment with Sorafenib, many patients had progressive disease as a result of acquiring drug resistance. Circumventing resistance to Sorafenib by exploring and targeting possible molecular mechanisms and pathways is an area of active investigation worldwide. Epithelial-to-mesenchymal transition (EMT) is a cellular process allowing epithelial cells to assume mesenchymal traits. HCC tumour cells undergo EMT to become immune evasive and develop resistance to Sorafenib treatment. Immune checkpoint molecules control immune escape in many tumours, including HCC. The aim of this study is to investigate whether combined inhibition of EMT and immune checkpoints can re-sensitise HCC to Sorafenib treatment. Post treatment with Sorafenib, HCC cells PLC/PRF/5 and Hep3B were monitored for induction of EMT and immune checkpoint molecules using quantitative reverse transcriptase (qRT)- PCR, western blot, immunofluorescence, and motility assays. The effect of combination treatment with SB431542, a specific inhibitor of the transforming growth factor (TGF)-β receptor kinase, and siRNA mediated knockdown of programmed cell death protein ligand-1 (PD-L1) on Sorafenib resistance was examined using a cell viability assay. We found that three days of Sorafenib treatment activated EMT with overexpression of TGF-β1 in both HCC cell lines. Following Sorafenib exposure, increase in the expression of PD-L1 and other immune checkpoints was observed. SB431542 blocked the TGF-β1-mediated EMT in HCC cells and also repressed PD-L1 expression. Likewise, knockdown of PD-L1 inhibited EMT. Moreover, the sensitivity of HCC cells to Sorafenib was enhanced by combining a blockade of EMT with SB431542 and knockdown of PD-L1 expression. Sorafenib-induced motility was attenuated with the combined treatment of SB431542 and PD-L1 knockdown. Our findings indicate that treatment with Sorafenib induces EMT and expression of immune checkpoint molecules, which contributes to Sorafenib resistance in HCC cells. Thus, the combination treatment strategy of inhibiting EMT and immune checkpoint molecules can re-sensitise HCC cells to Sorafenib.

The past decade has seen many advancements in the development of three-dimensional (3D) in vitro models in pharmaceutical sciences and industry. Specifically, organoids present a self-organising, self-renewing and more physiologically relevant model than conventional two-dimensional (2D) cell cultures. Liver organoids have been developed from a variety of cell sources, including stem cells, cell lines and primary cells. They have potential for modelling patient-specific disease and establishing personalised therapeutic approaches. Additionally, liver organoids have been used to test drug efficacy and toxicity. Herein we summarise cell sources for generating liver organoids, the advantages and limitations of each cell type, as well as the application of the organoids in modelling liver diseases. We focus on the use of liver organoids as tools for drug validation and toxicity assessment.