Burden and Cost of Caring for US Veterans With CKD: Initial Findings From the VA Renal Information System (VA-REINS).

Kidney disease is a common, complex, costly, and life-limiting condition. Most kidney disease registries or information systems have been limited to single institutions or regions. A national US Department of Veterans Affairs (VA) Renal Information System (VA-REINS) was recently developed. We describe its creation and present key initial findings related to chronic kidney disease (CKD) without kidney replacement therapy (KRT). Data from the VA's Corporate Data Warehouse were processed and linked with national Medicare data for patients with CKD receiving KRT. Operational definitions for VA user, CKD, acute kidney injury, and kidney failure were developed. Among 7 million VA users in fiscal year 2014, CKD was identified using either a strict or liberal operational definition in 1.1 million (16.4%) and 2.5 million (36.3%) veterans, respectively. Most were identified using an estimated glomerular filtration rate laboratory phenotype, some through proteinuria assessment, and very few through International Classification of Diseases, Ninth Revision coding. The VA spent ∼$18 billion for the care of patients with CKD without KRT, most of which was for CKD stage 3, with higher per-patient costs by CKD stage. VA-REINS can be leveraged for disease surveillance, population health management, and improving the quality and value of care, thereby enhancing VA's capacity as a patient-centered learning health system for US veterans.

A vimentin binding small molecule leads to mitotic disruption in mesenchymal cancers.

Expression of the transcription factor FOXC2 is induced and necessary for successful epithelial-mesenchymal transition, a developmental program that when activated in cancer endows cells with metastatic potential and the properties of stem cells. As such, identifying agents that inhibit the growth of FOXC2-transformed cells represents an attractive approach to inhibit chemotherapy resistance and metastatic dissemination. From a high throughput synthetic lethal screen, we identified a small molecule, FiVe1, which selectively and irreversibly inhibits the growth of mesenchymally transformed breast cancer cells and soft tissue sarcomas of diverse histological subtypes. FiVe1 targets the intermediate filament and mesenchymal marker vimentin (VIM) in a mode which promotes VIM disorganization and phosphorylation during metaphase, ultimately leading to mitotic catastrophe, multinucleation, and the loss of stemness. These findings illustrate a previously undescribed mechanism for interrupting faithful mitotic progression and may ultimately inform the design of therapies for a broad range of mesenchymal cancers.

Targeted Delivery of an Anti-inflammatory PDE4 Inhibitor to Immune Cells via an Antibody-drug Conjugate.

Phosphodiesterase 4 (PDE4) inhibitors are approved for the treatment of some moderate to severe inflammatory conditions. However, dose-limiting side effects in the central nervous system and gastrointestinal tract, including nausea, emesis, headache, and diarrhea, have impeded the broader therapeutic application of PDE4 inhibitors. We sought to exploit the wealth of validation surrounding PDE4 inhibition by improving the therapeutic index through generation of an antibody-drug conjugate (ADC) that selectively targets immune cells through the CD11a antigen. The resulting ADC consisted of a human αCD11a antibody (based on efalizumab clone hu1124) conjugated to an analog of the highly potent PDE4 inhibitor GSK256066. Both the human αCD11a ADC and a mouse surrogate αCD11a ADC (based on the M17 clone) rapidly internalized into immune cells and suppressed lipololysaccharide (LPS)-induced TNFα secretion in primary human monocytes and mouse peritoneal cells, respectively. In a carrageenan-induced air pouch inflammation mouse model, treatment with the ADC significantly reduced inflammatory cytokine production in the air pouch exudate. Overall, these results provide compelling evidence for the feasibility of delivering drugs with anti-inflammatory activity selectively to the immune compartment via CD11a and the development of tissue-targeted PDE4 inhibitors as a promising therapeutic modality for treating inflammatory diseases.

Synthetic studies towards Zetekitoxin AB: preparation of 4,5-epi-11-hydroxy-saxitoxinol.

A concise synthesis of 4,5-epi-11-hydroxy-saxitoxinol utilizing D-ribose to direct an asymmetric Mannich reaction. This approach allows many modes of reactivity, which can be used to access various analogs of saxitoxin.

Nursing Home Status Adjustment for Standardized Mortality and Hospitalization in Dialysis Facility Reports.

Rationale & Objective: Compared to the original nursing home status (any nursing home stay in the previous calendar year), new nursing home status variables were developed to improve the risk adjustment of Standardized Mortality/Hospitalization Ratio (SMR/SHR) models used in public reporting of dialysis quality of care, such as the Annual Dialysis Facility Report. Study Design: Retrospective observational study. Setting & Participants: 625,040 US maintenance dialysis patients with >90 kidney failure days in 2019. Predictors: Nursing home status variables; patient characteristics; comorbid conditions. Outcomes: Mortality/hospitalization. Analytical Approach: We assigned patients and patient times (SMR/SHR model) to one of 3 mutually exclusive categories: long-term care (≥90 days), short-term care (1-89 days), or non-nursing home, based on nursing home stay during the previous 365 days from the first day of the time period at risk. Nursing home status was derived from the Nursing Home Minimum Data Set. Comparisons of hazard ratios from adjusted models, facility SMR/SHR performance, and model C-statistics between the original/new models were performed. Results: SMR's hazard ratio of original nursing home status (2.09) was lower than both ratios of short-term care (2.38) and long-term care (2.43), whereas SHR's hazard ratio of original nursing home status (1.10) was between the ratios of long-term care (1.01) and short-term care (1.20). There was a difference in hazard ratios between short-term care and long-term care for both measures. Small percentages of facilities changed performance categories: 0.7% for SMR and 0.4% for SHR. The SMR C-statistic improved whereas the SHR C-statistic was relatively unchanged. Limitations: Limited capture of subacute rehabilitation stays in the nursing home by using a 90-day cutoff for short-term care and long-term care; unable to draw causal inference about nursing home care. Conclusions: Use of a nursing home metric that effectively separates short-term from long-term nursing home utilization results in more meaningful risk adjustment that generally comports with Medicare payment policy, potentially resulting in more interpretable results for dialysis stakeholders.

Synthesis and biological evaluation of novel FiVe1 derivatives as potent and selective agents for the treatment of mesenchymal cancers.

Epithelial-mesenchymal transition (EMT) endows stem cell-like properties to cancer cells. Targeting this process represents a potential therapeutic approach to overcome cancer metastasis and chemotherapy resistance. FiVe1 was identified from an EMT-based synthetic lethality screen and was found to inhibit the stem cell-like properties and proliferation of not only cancer cells undergoing EMT, but also more broadly in mesenchymal cancers that include therapeutically intractable soft tissue sarcomas. FiVe1 functions by directly binding to the type III intermediate filament protein vimentin (VIM) in a mode that induces hyperphosphorylation of Ser56, which results in selective disruption of mitosis and induced multinucleation in transformed VIM-expressing mesenchymal cancer cell types. Cell-based potency (IC50 = 1.6 µM, HT-1080 fibrosarcoma), poor solubility (<1 µM) and low oral bioavailability limits the direct application of FiVe1 as an in vivo probe or therapeutic agent. To overcome these drawbacks, we performed structure-activity relationship (SAR) studies and synthesized a set of 35 new compounds, consisting of diverse modifications of the FiVe1 scaffold. Among these compounds, 4e showed a marked improvement in potency (IC50 = 44 nM, 35-fold improvement, HT-1080) and cell type selectivity (19-fold improvement), when compared to FiVe1. Improvements in the potency of 4e, in terms of overall cytotoxicity, directly correlate with VIM Ser56 phosphorylation status and the oral bioavailability and pharmacokinetic profiles of 4e in mouse are superior to FiVe1. Successful optimization also resulted in potent and selective derivatives 11a, 11j and 11k, which exhibited superior pharmacological profiles, in terms of metabolic stability and aqueous solubility. Collectively, these optimization efforts have resulted in the development of promising FiVe1 analogs with potential applications in the treatment of mesenchymal cancers, as well as in the study of VIM-related biology.

Acute Kidney Injury Requiring Dialysis and Incident Dialysis Patient Outcomes in US Outpatient Dialysis Facilities.

BACKGROUND AND OBJECTIVES: About 30% of patients with AKI may require ongoing dialysis in the outpatient setting after hospital discharge. A 2017 Centers for Medicare & Medicaid Services policy change allows Medicare beneficiaries with AKI requiring dialysis to receive outpatient treatment in dialysis facilities. Outcomes for these patients have not been reported. We compare patient characteristics and mortality among patients with AKI requiring dialysis and patients without AKI requiring incident dialysis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We used a retrospective cohort design with 2017 Medicare claims to follow outpatients with AKI requiring dialysis and patients without AKI requiring incident dialysis up to 365 days. Outcomes are unadjusted and adjusted mortality using Kaplan-Meier estimation for unadjusted survival probability, Poisson regression for monthly mortality, and Cox proportional hazards modeling for adjusted mortality. RESULTS: In total, 10,821 of 401,973 (3%) Medicare patients requiring dialysis had at least one AKI claim, and 52,626 patients were Medicare patients without AKI requiring incident dialysis. Patients with AKI requiring dialysis were more likely to be White (76% versus 70%), non-Hispanic (92% versus 87%), and age 60 or older (82% versus 72%) compared with patients without AKI requiring incident dialysis. Unadjusted mortality was markedly higher for patients with AKI requiring dialysis compared with patients without AKI requiring incident dialysis. Adjusted mortality differences between both cohorts persisted through month 4 of the follow-up period (all P=0.01), then, they declined and were no longer statistically significant. Adjusted monthly mortality stratified by Black and other race between patients with AKI requiring dialysis and patients without AKI requiring incident dialysis was lower throughout month 4 (1.5 versus 0.60, 1.20 versus 0.84, 1.00 versus 0.80, and 0.95 versus 0.74; all P<0.001), which persisted through month 7. Overall adjusted mortality risk was 22% higher for patients with AKI requiring dialysis (1.22; 95% confidence interval, 1.17 to 1.27). CONCLUSIONS: In fully adjusted analyses, patients with AKI requiring dialysis had higher early mortality compared with patients without AKI requiring incident dialysis, but these differences declined after several months. Differences were also observed by age, race, and ethnicity within both patient cohorts.

Starting out - Do not write off a placement before you've given it a chance.

Never dismiss a placement or take it for granted. We all hear stories about the ones we would not want to do at any cost. I've been there.

Transition states. Trapping a transition state in a computationally designed protein bottle.

The fleeting lifetimes of the transition states (TSs) of chemical reactions make determination of their three-dimensional structures by diffraction methods a challenge. Here, we used packing interactions within the core of a protein to stabilize the planar TS conformation for rotation around the central carbon-carbon bond of biphenyl so that it could be directly observed by x-ray crystallography. The computational protein design software Rosetta was used to design a pocket within threonyl-transfer RNA synthetase from the thermophile Pyrococcus abyssi that forms complementary van der Waals interactions with a planar biphenyl. This latter moiety was introduced biosynthetically as the side chain of the noncanonical amino acid p-biphenylalanine. Through iterative rounds of computational design and structural analysis, we identified a protein in which the side chain of p-biphenylalanine is trapped in the energetically disfavored, coplanar conformation of the TS of the bond rotation reaction.