Description of a Multi-faceted COVID-19 Pandemic Physician Workforce Plan at a Multi-site Academic Health System.

BACKGROUND: The evolving COVID-19 pandemic has and continues to present a threat to health system capacity. Rapidly expanding an existing acute care physician workforce is critical to pandemic response planning in large urban academic health systems. INTERVENTION: The Medical Emergency-Pandemic Operations Command (MEOC)-a multi-specialty team of physicians, operational leaders, and support staff within an academic Department of Medicine in Calgary, Canada-partnered with its provincial health system to rapidly develop a comprehensive, scalable pandemic physician workforce plan for non-ventilated inpatients with COVID-19 across multiple hospitals. The MEOC Pandemic Plan comprised seven components, each with unique structure and processes. METHODS: In this manuscript, we describe MEOC's Pandemic Plan that was designed and implemented from March to May 2020 and re-escalated in October 2020. We report on the plan's structure and process, early implementation outcomes, and unforeseen challenges. Data sources included MEOC documents, health system, public health, and physician engagement implementation data. KEY RESULTS: From March 5 to October 26, 2020, 427 patients were admitted to COVID-19 units in Calgary hospitals. In the initial implementation period (March-May 2020), MEOC communications reached over 2500 physicians, leading to 1446 physicians volunteering to provide care on COVID-19 units. Of these, 234 physicians signed up for hospital shifts, and 227 physicians received in-person personal protective equipment simulation training. Ninety-three physicians were deployed on COVID-19 units at four large acute care hospitals. The resurgence of cases in September 2020 has prompted re-escalation including re-activation of COVID-19 units. CONCLUSIONS: MEOC leveraged an academic health system partnership to rapidly design, implement, and refine a comprehensive, scalable COVID-19 acute care physician workforce plan whose components are readily applicable across jurisdictions or healthcare crises. This description may guide other institutions responding to COVID-19 and future health emergencies.

Association of NT-proBNP and BNP With Future Clinical Outcomes in Patients With ESKD: A Systematic Review and Meta-analysis.

RATIONALE & OBJECTIVE: Use of brain natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP) for cardiovascular (CV) risk assessment in patients with end-stage kidney disease (ESKD) remains unclear. We examined the associations between different threshold elevations of these peptide levels and clinical outcomes in patients with ESKD. STUDY DESIGN: Systematic review and meta-analysis. SETTING & STUDY POPULATIONS: We searched MEDLINE and EMBASE (through September 2019) for observational studies of adults with ESKD (estimated glomerular filtration rate≤15mL/min/1.73m2 or receiving maintenance dialysis). SELECTION CRITERIA FOR STUDIES: Studies that reported NT-proBNP or BNP levels and future CV events, CV mortality, or all-cause mortality. DATA EXTRACTION: Cohort characteristics and measures of risk associated with study-specified peptide thresholds. ANALYTICAL APPROACH: Hazard ratios (HRs) for clinical outcomes associated with different NT-proBNP and BNP ranges were categorized into common thresholds and pooled using random-effects meta-analysis. RESULTS: We identified 61 studies for inclusion in our review (19,688 people). 49 provided sufficient detail for inclusion in meta-analysis. Pooled unadjusted HRs for CV mortality were progressively greater for greater thresholds of NT-proBNP, from 1.45 (95% CI, 0.91-2.32) for levels>2,000pg/mL to 5.95 (95% CI, 4.23-8.37) for levels>15,000pg/mL. Risk for all-cause mortality was significantly higher at all NT-proBNP thresholds ranging from> 1,000 to> 20,000pg/mL (HR range, 1.53-4.00). BNP levels>550pg/mL were associated with increased risk for CV mortality (HR, 2.54; 95% CI, 1.49-4.33), while the risks for all-cause mortality were 2.04 (95% CI, 0.82-5.12) at BNP levels>100pg/mL and 2.97 (95% CI, 2.21-3.98) at BNP levels>550pg/mL. Adjusted analyses demonstrated similarly greater risks for CV and all-cause mortality with greater NT-proBNP concentrations. LIMITATIONS: Incomplete outcome reporting and risk for outcome reporting bias. Estimation of risk for CV events for specific thresholds of both peptides were limited by poor precision. CONCLUSIONS: ESKD-specific NT-proBNP and BNP level thresholds of elevation are associated with increased risk for CV and all-cause mortality. This information may help guide interpretation of NT-proBNP and BNP levels in patients with ESKD.

Arsenic Triglutathione [As(GS)3] Transport by Multidrug Resistance Protein 1 (MRP1/ABCC1) Is Selectively Modified by Phosphorylation of Tyr920/Ser921 and Glycosylation of Asn19/Asn23.

The ATP-binding cassette (ABC) transporter multidrug resistance protein 1 (MRP1/ABCC1) is responsible for the cellular export of a chemically diverse array of xenobiotics and endogenous compounds. Arsenic, a human carcinogen, is a high-affinity MRP1 substrate as arsenic triglutathione [As(GS)3]. In this study, marked differences in As(GS)3 transport kinetics were observed between MRP1-enriched membrane vesicles prepared from human embryonic kidney 293 (HEK) (Km 3.8 µM and Vmax 307 pmol/mg per minute) and HeLa (Km 0.32 µM and Vmax 42 pmol/mg per minute) cells. Mutant MRP1 lacking N-linked glycosylation [Asn19/23/1006Gln; sugar-free (SF)-MRP1] expressed in either HEK293 or HeLa cells had low Km and Vmax values for As(GS)3, similar to HeLa wild-type (WT) MRP1. When prepared in the presence of phosphatase inhibitors, both WT- and SF-MRP1-enriched membrane vesicles had a high Km value for As(GS)3 (3-6 µM), regardless of the cell line. Kinetic parameters of As(GS)3 for HEK-Asn19/23Gln-MRP1 were similar to those of HeLa/HEK-SF-MRP1 and HeLa-WT-MRP1, whereas those of single glycosylation mutants were like those of HEK-WT-MRP1. Mutation of 19 potential MRP1 phosphorylation sites revealed that HEK-Tyr920Phe/Ser921Ala-MRP1 transported As(GS)3 like HeLa-WT-MRP1, whereas individual HEK-Tyr920Phe- and -Ser921Ala-MRP1 mutants were similar to HEK-WT-MRP1. Together, these results suggest that Asn19/Asn23 glycosylation and Tyr920/Ser921 phosphorylation are responsible for altering the kinetics of MRP1-mediated As(GS)3 transport. The kinetics of As(GS)3 transport by HEK-Asn19/23Gln/Tyr920Glu/Ser921Glu were similar to HEK-WT-MRP1, indicating that the phosphorylation-mimicking substitutions abrogated the influence of Asn19/23Gln glycosylation. Overall, these data suggest that cross-talk between MRP1 glycosylation and phosphorylation occurs and that phosphorylation of Tyr920 and Ser921 can switch MRP1 to a lower-affinity, higher-capacity As(GS)3 transporter, allowing arsenic detoxification over a broad concentration range.

Monomethylarsenic diglutathione transport by the human multidrug resistance protein 1 (MRP1/ABCC1).

The ATP-binding cassette (ABC) transporter protein multidrug resistance protein 1 (MRP1; ABCC1) plays an important role in the cellular efflux of the high-priority environmental carcinogen arsenic as a triglutathione conjugate [As(GS)(3)]. Most mammalian cells can methylate arsenic to monomethylarsonous acid (MMA(III)), monomethylarsonic acid (MMA(V)), dimethylarsinous acid (DMA(III)), and dimethylarsinic acid (DMA(V)). The trivalent forms MMA(III) and DMA(III) are more reactive and toxic than their inorganic precursors, arsenite (As(III)) and arsenate (As(V)). The ability of MRP1 to transport methylated arsenicals is unknown and was the focus of the current study. HeLa cells expressing MRP1 (HeLa-MRP1) were found to confer a 2.6-fold higher level of resistance to MMA(III) than empty vector control (HeLa-vector) cells, and this resistance was dependent on GSH. In contrast, MRP1 did not confer resistance to DMA(III), MMA(V), or DMA(V). HeLa-MRP1 cells accumulated 4.5-fold less MMA(III) than HeLa-vector cells. Experiments using MRP1-enriched membrane vesicles showed that transport of MMA(III) was GSH-dependent but not supported by the nonreducing GSH analog, ophthalmic acid, suggesting that MMA(III)(GS)(2) was the transported form. MMA(III)(GS)(2) was a high-affinity, high-capacity substrate for MRP1 with apparent K(m) and V(max) values of 11 µM and 11 nmol mg(-1)min(-1), respectively. MMA(III)(GS)(2) transport was osmotically sensitive and inhibited by several MRP1 substrates, including 17ß-estradiol 17-(ß-D-glucuronide) (E(2)17ßG). MMA(III)(GS)(2) competitively inhibited the transport of E(2)17ßG with a K(i) value of 16 µM, indicating that these two substrates have overlapping binding sites. These results suggest that MRP1 is an important cellular protective pathway for the highly toxic MMA(III) and have implications for environmental and clinical exposure to arsenic.