Machine learning functional impairment classification with electronic health record data.

BACKGROUND: Poor functional status is a key marker of morbidity, yet is not routinely captured in clinical encounters. We developed and evaluated the accuracy of a machine learning algorithm that leveraged electronic health record (EHR) data to provide a scalable process for identification of functional impairment. METHODS: We identified a cohort of patients with an electronically captured screening measure of functional status (Older Americans Resources and Services ADL/IADL) between 2018 and 2020 (N = 6484). Patients were classified using unsupervised learning K means and t-distributed Stochastic Neighbor Embedding into normal function (NF), mild to moderate functional impairment (MFI), and severe functional impairment (SFI) states. Using 11 EHR clinical variable domains (832 variable input features), we trained an Extreme Gradient Boosting supervised machine learning algorithm to distinguish functional status states, and measured prediction accuracies. Data were randomly split into training (80%) and test (20%) sets. The SHapley Additive Explanations (SHAP) feature importance analysis was used to list the EHR features in rank order of their contribution to the outcome. RESULTS: Median age was 75.3 years, 62% female, 60% White. Patients were classified as 53% NF (n = 3453), 30% MFI (n = 1947), and 17% SFI (n = 1084). Summary of model performance for identifying functional status state (NF, MFI, SFI) was AUROC (area under the receiving operating characteristic curve) 0.92, 0.89, and 0.87, respectively. Age, falls, hospitalization, home health use, labs (e.g., albumin), comorbidities (e.g., dementia, heart failure, chronic kidney disease, chronic pain), and social determinants of health (e.g., alcohol use) were highly ranked features in predicting functional status states. CONCLUSION: A machine learning algorithm run on EHR clinical data has potential utility for differentiating functional status in the clinical setting. Through further validation and refinement, such algorithms can complement traditional screening methods and result in a population-based strategy for identifying patients with poor functional status who need additional health resources.

A fine balance of hydrophobic-electrostatic communication pathways in a pH-switching protein.

Allostery is the phenomenon of coupling between distal binding sites in a protein. Such coupling is at the crux of protein function and regulation in a myriad of scenarios, yet determining the molecular mechanisms of coupling networks in proteins remains a major challenge. Here, we report mechanisms governing pH-dependent myristoyl switching in monomeric hisactophilin, whereby the myristoyl moves between a sequestered state, i.e., buried within the core of the protein, to an accessible state, in which the myristoyl has increased accessibility for membrane binding. Measurements of the pH and temperature dependence of amide chemical shifts reveal protein local structural stability and conformational heterogeneity that accompany switching. An analysis of these measurements using a thermodynamic cycle framework shows that myristoyl-proton coupling at the single-residue level exists in a fine balance and extends throughout the protein. Strikingly, small changes in the stereochemistry or size of core and surface hydrophobic residues by point mutations readily break, restore, or tune myristoyl switch energetics. Synthesizing the experimental results with those of molecular dynamics simulations illuminates atomistic details of coupling throughout the protein, featuring a large network of hydrophobic interactions that work in concert with key electrostatic interactions. The simulations were critical for discerning which of the many ionizable residues in hisactophilin are important for switching and identifying the contributions of nonnative interactions in switching. The strategy of using temperature-dependent NMR presented here offers a powerful, widely applicable way to elucidate the molecular mechanisms of allostery in proteins at high resolution.

Comparing outcomes of tunnelled dialysis catheter insertions and exchanges with or without fluoroscopy.

BACKGROUND/OBJECTIVE: To study the safety and outcome profiles of tunnelled dialysis catheter (TDC) insertions and exchanges with fluoroscopy versus without fluoroscopy. METHODS: This was a retrospective cohort study of all TDC insertions or exchanges performed at our centre, between January 2017 and December 2017. Patient demographics, laboratory results and catheter placement information were obtained from electronic records. Immediate technical success, early and late catheter associated complications were collected. Outcomes for TDC inserted with or without fluoroscopy were statistically analysed. RESULTS: A total of 351 TDC insertions and 253 TDC exchanges were performed. Out of 351 TDC insertions, 261 were done with fluoroscopy while 90 were done without. Out of 253 TDC exchanges, 219 were done with fluoroscopy while 34 were done without. For both TDC insertions and exchanges, there were no significant differences in complication rates when done with or without fluoroscopy. Mean duration of catheter patency was longer for TDC inserted without fluoroscopy, after adjusting for site of insertion and presence of previous TDC. CONCLUSIONS: The technique of inserting TDC in the right internal jugular vein (IJV) without fluoroscopy is a safe and effective method in selected patients. This supports the practice of performing the procedure without fluoroscopy, especially in institutions where fluoroscopy facilities are not readily available. This potentially translates into reduced healthcare resources and hospitalisation days, which is particularly valuable in times of limited resources such as the current Coronavirus Disease 2019 (COVID-19) pandemic.

Checkpoint inhibition through small molecule-induced internalization of programmed death-ligand 1.

Programmed death-ligand 1 is a glycoprotein expressed on antigen presenting cells, hepatocytes, and tumors which upon interaction with programmed death-1, results in inhibition of antigen-specific T cell responses. Here, we report a mechanism of inhibiting programmed death-ligand 1 through small molecule-induced dimerization and internalization. This represents a mechanism of checkpoint inhibition, which differentiates from anti-programmed death-ligand 1 antibodies which function through molecular disruption of the programmed death 1 interaction. Testing of programmed death ligand 1 small molecule inhibition in a humanized mouse model of colorectal cancer results in a significant reduction in tumor size and promotes T cell proliferation. In addition, antigen-specific T and B cell responses from patients with chronic hepatitis B infection are significantly elevated upon programmed death ligand 1 small molecule inhibitor treatment. Taken together, these data identify a mechanism of small molecule-induced programmed death ligand 1 internalization with potential therapeutic implications in oncology and chronic viral infections.

Hypertension and chronic kidney disease in Asian populations.

The countries of Asia are home to multiple ethnicities. There are ethnic differences in diet, culture, and attitudes towards health screening, access to care, and treatment of chronic diseases. Chronic kidney disease (CKD) and end-stage kidney disease (ESKD) have rising incidence and prevalence due to increased affliction with non-communicable diseases of diabetes and hypertension. To prevent the expensive complications of ESKD, one of the most important risk factors to control is hypertension in patients with CKD. We performed a narrative review on the prevalence of CKD in patients with hypertension, the prevalence and control of hypertension in patients with CKD, and the dietary sodium intake in CKD populations.

Comparison between lung ultrasonography and current methods for volume assessment in Asian chronic hemodialysis patients.

INTRODUCTION: Volume assessment in end-stage kidney disease patients on hemodialysis (HD) remains inadequate by existing methods: clinical examination, bioimpedance spectroscopy, measurement of inferior vena cava diameter by ultrasound (IVCD), and plasma B-type natriuretic peptide (NT-pro BNP). This study aims to compare the performance of lung ultrasound against existing methods for volume assessment in a HD cohort. METHODS: Two nephrologists independently performed 28-point lung ultrasound immediately before and after midweek HD in 50 patients. Lung congestion was classified into mild, moderate, and severe categories based on lung ultrasound findings. Clinical examination for crepitations and oedema, change in hydration status (∆HS) measured by bioimpedance spectroscopy, NT-pro BNP, IVCD during inspiration (IVCDimin), expiration (IVCDimax), and inferior vena cava collapsibility index were also assessed before and after midweek HD. FINDINGS: In all, 61% of patients with normohydration status by bioimpedance spectroscopy had moderate or severe lung congestion on lung ultrasound. There were significant correlations between predialysis lung ultrasound, and NT-pro BNP (r = 0.432, P = 0.004), ∆HS (r = 0.447, P < 0.001), and IVCD parameters (P < 0.05). Some correlations weakened postdialysis (∆HS [r = 0.322, P = 0.01] and IVCDimax [r = 0.307, P = 0.03]), whereas NT-pro BNP and ∆HS paradoxically increased in 28% and 30% of the cohort, respectively. On receiver operator curve analysis, most methods of volume assessment had limited discriminatory power to detect mild lung congestion. DISCUSSION: Lung ultrasound demonstrates some comparability with existing volume assessment methods in Asian dialysis patients. However, it appears more effective at detecting subclinical pulmonary congestion, and tracking fluid changes real-time compared to bioimpedance spectroscopy and NT-pro BNP.

Going to war on COVID-19: Mobilizing an academic nephrology group practice.

AIM: The COVID-19 pandemic poses unprecedented operational challenges to nephrology divisions in every country as they cope with COVID-19-related kidney disease in addition to regular patient care. Although general approaches have been proposed, there is a lack of practical guidance for nephrology division response in a hospital facing a surge of cases. Here, we describe the specific measures that our division has taken in the hope that our experience in Singapore may be helpful to others. METHODS: Descriptive narrative. RESULTS: A compilation of operational responses to the COVID-19 pandemic taken by a nephrology division at a Singapore university hospital. CONCLUSION: Nephrology operational readiness for COVID-19 requires a clinical mindset shift from usual standard of care to a crisis exigency model that targets best outcomes for available resources. Rapid multi-disciplinary efforts that evolve flexibly with the local dynamics of the outbreak are required.

The inefficacy of LinkedIn? A latent change model and experimental test of using LinkedIn for job search.

Job applicants are increasingly turning to LinkedIn for their job search, so much so that it is supplanting traditional job search tools in many ways. Despite this widespread usage, scholarly research that explores its efficacy and the mechanisms for job search success (or failure) in this context is lacking. Accordingly, we rely upon social-cognitive theory and self-regulation theory to explore beneficial and adverse outcomes of searching for a job on LinkedIn as well as these outcomes' influence on job search success. Using a multivariate latent change analysis model, our longitudinal data across 2 samples support a self-regulatory frame but not a social-cognitive view, suggesting that a change in LinkedIn use for job search is positively related to a subsequent change in ego depletion, which leads to an ensuing adverse change in job search success. Additionally, as opposed to what is predicted by social-cognitive theory and typically found in the literature, an increase in job search behavior on LinkedIn was found to lead to poorer job search self-efficacy. In Study 3, we conduct a between-person experiment that explores this finding with results showing that upward social comparisons on LinkedIn lead to lower levels of self-efficacy. In all, the more that individuals use LinkedIn for job search, the worse their job search self-efficacy becomes, the more they become depleted, and the poorer their ensuing job search success. Results suggest some caution should be taken when conducting a job search on LinkedIn. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Results of the endovascular treatment system for occluded native arteriovenous fistula.

BACKGROUND: Arteriovenous fistula is the definitive vascular access for patients on long-term haemodialysis. The aim of this study is to present the techniques and results of the Endovascular Treatment System that we have developed for managing the occluded native arteriovenous fistula. METHODS: The current study is a retrospective chart review on all patients who presented with an occluded native arteriovenous fistula and underwent attempted recanalization between 1 January 2005 and 31 December 2014. RESULTS: A total of 130 patients were included in the study. Post-intervention primary access patency was 83.8% at 6 months, 78.7% at 12 months, 64.6% at 2 years and 59.6% at 3 years. Post-intervention assisted access patency in fistulas-in-use was 86.5% at 6 months, 81% at 12 months, 66.8% at 2 years and 61.2% at 3 years. Post-intervention secondary patency for all cases was 84.7% at 6 months, 80.2% at 12 months, 66.1% at 2 years and 62% at 3 years. Post-intervention secondary patency in fistula-in-use was 91.1% at 6 months, 90% at 12 months, 85% at 2 years and 74.6% at 3 years. Access survival nor patency differed significantly when incisional thrombectomy was compared to angioplasty with or without stenting with access survival of 91.2% and 92.5% at 12 months and access patency of 82.9% and 89.7% at 12 months (P = 0.834 and P = 0.898, respectively). CONCLUSIONS: In autologous arteriovenous thrombosed fistulae, the use of endovascular techniques to revive the access is a viable and safe technique to employ in most cases.

Noncirrhotic hyperammonemia: A factor behind dementia to alter mental status.

Healthcare givers were recommended to check serum ammonia level for elderly patients with acute-on-chronic alteration of mental status. Early initiation of antihyperammonemia therapy may benefit improvement of alteration of mental status. Baseline mental status becomes necessary for diagnose the acute alteration of mental status and monitor the therapeutic process.

IgG4-Related Kidney Disease: A Curious Case of Interstitial Nephritis with Hypocomplementemia.

IgG4-related kidney disease has been relatively newly recognized over the last two decades as a combination of an autoimmune and allergic disorder, with elevated serum IgG4 level and hypocomplementemia among its characteristic features. Here we report the case of a man with interstitial nephritis presenting with acute kidney injury and hypocomplementemia but normal serum IgG4 level and provide a literature review of IgG4-related kidney disease. This case highlights the importance of IgG4-related kidney disease as an important differential diagnosis in any patient presenting with a clinical syndrome mimicking acute interstitial nephritis with hypocomplementemia. A high index of suspicion with a low threshold for performing a native kidney biopsy would be paramount as patients do respond well to corticosteroid therapy.

Multicentre, randomised, blinded, control trial of drug-eluting balloon vs Sham in recurrent native dialysis fistula stenoses.

BACKGROUND: Endovascular treatment of autogenous arteriovenous haemodialysis fistula stenosis has high reintervention rates. We investigate the effect of drug-eluting balloons in the treatment of recurrent haemodialysis fistula stenosis. METHODS: This is a randomised, controlled, investigator-initiated and run, prospective, blinded, multicentre trial. Patients with recurrent autogenous arteriovenous haemodialysis fistula stenosis received standard endovascular treatment plus drug-eluting balloon or standard endovascular treatment plus uncoated balloon (Sham). Primary endpoint was late lumen loss in trial area on ultrasound at 6 weeks, 3, 6 and 12 months. Secondary endpoints were freedom from reintervention to the Index Trial Area and decline in fistula flow (Qa). Interim analysis was performed at 6 months (unblinded due to timeliness). RESULTS: Patients with 132 recurrent stenoses (48% in bare Nitinol stents) were randomised with 70 receiving drug-eluting balloon and 62 Sham. At 6 months, decline in late lumen loss was 0.23 ± 0.03 mm/month for Sham and 0.045 ± 0.03 mm/month for drug-eluting balloon arm, a significant difference (0.18 mm, p = 0.0002). At 12 months, this difference persisted at 0.12 mm (p = 0.0003). At 6 months, significant difference in late lumen loss for instent restenoses (p = 0.0004) was observed, with non-significant difference for unstented restenoses (p = 0.065). Mean time for freedom from reintervention was 10.14 months for Sham versus 42.39 months for drug-eluting balloon (p = 0.001). The same was shown for instent (p = 0.014) and unstented (p = 0.029) restenoses. Qa decline rate at 6 months was 36.89 mL/min/month (Sham) and 0.41 mL/min (drug-eluting balloon). The difference was significant (36.48 mL/min; p = 0.02) and persisted to 12 months (p = 0.44). CONCLUSION: Paclitaxel drug-eluting balloon significantly delays restenosis after angioplasty for recurrent autogenous arteriovenous haemodialysis fistula stenosis, persisting to 12 months. Drug-eluting balloon significantly increases freedom from reintervention at 12 months with these effects true in stented and unstented fistulas.

TRA-8 anti-DR5 monoclonal antibody and gemcitabine induce apoptosis and inhibit radiologically validated orthotopic pancreatic tumor growth.

PURPOSE: To evaluate agonistic TRA-8 monoclonal antibody to human death receptor 5 (DR5) and gemcitabine in vitro and in an orthotopic pancreatic cancer model. EXPERIMENTAL DESIGN: Pancreatic cancer cell lines were screened for DR5 expression, cytotoxicity, and apoptosis induced by TRA-8, gemcitabine, or gemcitabine and TRA-8. An orthotopic model of pancreatic cancer was established in severe combined immunodeficient mice. Mice were treated with TRA-8, gemcitabine, or a combination for one or two cycles of therapy. Tumor growth (ultrasound) and survival were analyzed. RESULTS: All five pancreatic cancer cell lines showed DR5 protein expression and varying sensitivity to TRA-8-mediated cytotoxicity. MIA PaCa-2 cells were very sensitive to TRA-8, moderately resistant to gemcitabine, with additive cytotoxicity to the combination. S2-VP10 cells were resistant to TRA-8 and sensitive to gemcitabine with synergistic sensitivity to the combination. Combination treatment in vitro produced enhanced caspase-3 and caspase-8 activation. A single cycle of therapy produced comparable efficacy for single-agent TRA-8 and the combination of TRA-8 and gemcitabine, with significant reduction in tumor size and prolonged survival compared with gemcitabine alone or control animals. With two cycles of therapy, TRA-8 and combination therapy produced enhanced inhibition of tumor growth compared with single-agent gemcitabine or untreated animals. However, the combination regimen showed enhanced survival as compared with single-agent TRA-8. CONCLUSIONS: Pancreatic cancer cell lines express varying levels of DR5 and differ in their sensitivity to TRA-8 and gemcitabine-induced cytotoxicity. TRA-8 with two cycles of gemcitabine therapy produced the best overall survival.

Combination treatment with TRA-8 anti death receptor 5 antibody and CPT-11 induces tumor regression in an orthotopic model of pancreatic cancer.

PURPOSE: Evaluate the response of human pancreatic cancer cell lines and orthotopic tumors to TRA-8, an agonistic antibody to death receptor 5, in combination with irinotecan (CPT-11). EXPERIMENTAL DESIGN: MIA PaCa-2 and S2VP10 cells were treated with TRA-8 and/or CPT 11. Cell viability was determined by ATP assay. JC-1 mitochondrial depolarization and Annexin V assays confirmed cell death by apoptosis. Immunoblotting was used to evaluate protein changes. MIA PaCa-2 cells were injected into the pancreas of severe combined immunodeficient mice. Mice underwent abdominal ultrasound to quantitate tumor size before and after treatment with twice weekly injections of 200 microg TRA-8 and/or 25 mg/kg CPT-11 for one or two treatment cycles, each lasting 2 weeks. RESULTS: MIA PaCa-2 cells were more sensitive to TRA-8 and showed additive cytotoxicity, whereas S2VP10 cells showed synergistic cytotoxicity when treated with TRA-8 and CPT-11. Cell death occurred via apoptosis with increased cleavage of caspase-3, caspase-8, and caspase-9 and proapoptotic proteins Bid and poly(ADP)ribose polymerase after combination treatment compared with either agent alone. XIAP and Bcl-XL inhibitors of apoptosis were down-regulated. After a single cycle of in vivo combination therapy, tumor sizes had diminished significantly (P<0.001) at 8 days posttreatment compared with no treatment, CPT-11, and TRA-8; and there was a 50-day increase in survival with combination treatment over untreated controls (P=0.0002), 30 days over TRA-8, and a 36-day increase over CPT-11 monotherapy (P=0.0003). With two cycles of TRA-8/CPT-11 treatment, mean survival time increased significantly (P<0.001) to 169 days versus untreated controls, TRA-8 or CPT-11 (76, 121, or 108 days, respectively). CONCLUSIONS: Combination TRA-8 and CPT-11 therapy produced enhanced cytotoxicity and survival in the MIA PaCa-2 orthotopic model of pancreatic cancer.

Regulation of NF-kappaB-dependent gene expression by the POU domain transcription factor Oct-1.

Maintenance of the cells of the vessel wall in a quiescent state is an important aspect of normal vascular physiology. Transcriptional repressors are widely believed to regulate this process, yet the exact factors involved and the mechanism of repression are not known. Here, we report that the POU domain transcription factor Oct-1 represses the expression of E-selectin and vascular cell adhesion molecule (VCAM-1), two cytokine-inducible, NF-kappaB-dependent endothelial-leukocyte adhesion molecules that participate in the leukocyte recruitment phase of the inflammatory response. Co-transfection and microinjection studies demonstrate that Oct-1 blocks tumor necrosis factor alpha-stimulated E-selectin and VCAM-1 expression. Gene expression arrays indicate that control of tumor necrosis factor alpha-induced, NF-kappaB-dependent gene expression by Oct-1 is promoter-specific. A DNA-binding mutant of Oct-1 represses NF-kappaB-dependent reporter gene expression. Biochemically, Oct-1 interacts with p65, suggesting that Oct-1 is involved in the regulation of NF-kappaB transactivation function. NF-kappaB-dependent gene expression is more pronounced in Oct-1-deficient than in wild-type murine embryonic fibroblasts, and reintroduction of human Oct-1 abolishes these differences. Finally, the cytokine interleukin-6 induces Oct-1 gene expression, providing a biologically relevant means by which NF-kappaB-dependent gene expression can be selectively reverted by Oct-1 to quiescent levels.

Treatment with gemcitabine and TRA-8 anti-death receptor-5 mAb reduces pancreatic adenocarcinoma cell viability in vitro and growth in vivo.

Gemcitabine is a first line agent for pancreatic cancer, but yields minimal survival benefit. This study evaluated in vitro and in vivo effects of a monoclonal antibody (TRA-8) to human death receptor 5, combined with gemcitabine, using two human pancreatic cancer cell lines, S2VP10 and MIA PaCa-2. A subcutaneous model of pancreatic cancer was employed to test in vivo efficacy. S2VP10 and MIA PaCa-2 cells were treated with varying doses of gemcitabine and TRA-8. Cell viability and apoptosis were determined with an adenosine triphosphate assay and annexin V staining, respectively. Mitochondrial membrane destabilization was evaluated with fluorescence-activated cell sorting analysis of JC-1 stained cells. Caspase activation was evaluated by Western blot analysis. MIA PaCa-2 subcutaneous xenografts in athymic nude mice were evaluated for response to treatment with 200 mug of TRA-8 (intraperitoneal on days 9, 13, 16, 20, 23, and 27 postimplant) and 120 mg/kg gemcitabine (I.P. on days 10, 17, and 24). Tumor growth was measured with calipers. MIA PaCa-2 and S2VP10 cells receiving combination treatment with TRA-8 and gemcitabine demonstrated enhanced cytotoxicity, annexin V staining, and mitochondrial destabilization compared to either agent alone. Combination treatment produced enhanced caspase-3 and -8 activation in both cell lines compared with either agent alone. In vivo studies demonstrated mean subcutaneous tumor surface area (produce of two largest diameters) doubling times of 38 days untreated, 32 days gemcitabine, 49 days TRA-8, and 64 days combination treatment. TRA-8 is an apoptosis-inducing agonistic monoclonal antibody that produced synergistic cytotoxicity in combination with gemcitabine in vitro through enhanced caspase activation. These findings, with substantial inhibition of tumor growth in a mouse pancreatic cancer xenograft model receiving combination therapy, are encouraging for anti-death receptor therapy in the treatment of pancreatic cancer.

DNA amplification method tolerant to sample degradation.

Despite recent advances in linear whole genome amplification of intact DNA/RNA, amplification of degraded nucleic acids in an unbiased fashion remains a serious challenge for genetic diagnosis. We describe a new whole genome amplification procedure, RCA-RCA (Restriction and Circularization-Aided Rolling Circle Amplification), which retains the allelic differences among degraded amplified genomes while achieving almost complete genome coverage. RCA-RCA utilizes restriction digestion and whole genome circularization to generate genomic sequences amenable to rolling circle amplification. When intact genomic DNA is used, RCA-RCA retains gene-amplification differences (twofold or higher) between complex genomes on a genome-wide scale providing highly improved concordance with unamplified material as compared with other amplification methodologies including multiple displacement amplification. Using RCA-RCA, formalin-fixed samples of modest or substantial DNA degradation were successfully amplified and screened via array-CGH or Taqman PCR that displayed retention of the principal gene amplification features of the original material. Microsatellite analysis revealed that RCA-RCA amplified genomic DNA is representative of the original material at the nucleotide level. Amplification of cDNA is successfully performed via RCA-RCA and results to unbiased gene expression analysis (R(2) = 0.99). The simplicity and universal applicability of RCA-RCA make it a powerful new tool for genome analysis with unique advantages over previous amplification technologies.