Prevalence and Causes of Diagnostic Errors in Hospitalized Patients Under Investigation for COVID-19.

BACKGROUND: The COVID-19 pandemic required clinicians to care for a disease with evolving characteristics while also adhering to care changes (e.g., physical distancing practices) that might lead to diagnostic errors (DEs). OBJECTIVE: To determine the frequency of DEs and their causes among patients hospitalized under investigation (PUI) for COVID-19. DESIGN: Retrospective cohort. SETTING: Eight medical centers affiliated with the Hospital Medicine ReEngineering Network (HOMERuN). TARGET POPULATION: Adults hospitalized under investigation (PUI) for COVID-19 infection between February and July 2020. MEASUREMENTS: We randomly selected up to 8 cases per site per month for review, with each case reviewed by two clinicians to determine whether a DE (defined as a missed or delayed diagnosis) occurred, and whether any diagnostic process faults took place. We used bivariable statistics to compare patients with and without DE and multivariable models to determine which process faults or patient factors were associated with DEs. RESULTS: Two hundred and fifty-seven patient charts underwent review, of which 36 (14%) had a diagnostic error. Patients with and without DE were statistically similar in terms of socioeconomic factors, comorbidities, risk factors for COVID-19, and COVID-19 test turnaround time and eventual positivity. Most common diagnostic process faults contributing to DE were problems with clinical assessment, testing choices, history taking, and physical examination (all p < 0.01). Diagnostic process faults associated with policies and procedures related to COVID-19 were not associated with DE risk. Fourteen patients (35.9% of patients with errors and 5.4% overall) suffered harm or death due to diagnostic error. LIMITATIONS: Results are limited by available documentation and do not capture communication between providers and patients. CONCLUSION: Among PUI patients, DEs were common and not associated with pandemic-related care changes, suggesting the importance of more general diagnostic process gaps in error propagation.

Establishing an Orthopedic Excess Hospital Days in Acute Care Program.

BACKGROUND: Excess days in acute care (EDAC) after total joint arthroplasty (TJA) represent a large economic burden. We developed an Orthopedic EDAC program that triages TJA patients to the appropriate service line (orthopedic vs medicine) and level of care (observation vs inpatient) on re-presentation. We developed and used evidence-based protocols for the treatment of TJA patients who are rehospitalized. METHODS: We defined Orthopedic EDAC as the length of stay (LOS) during readmission and observation stays. Our target population included TJA and revision TJA patients. Patients between April 2017 and September 2017 and between October 2017 and September 2018 were defined as pre-implementation and post-implementation of the Orthopedic EDAC program, respectively. RESULTS: A total of 2,662 patients underwent TJA and revision TJA during the pre-implementation and post-implementation periods. Twenty-three patients were managed on observation status during the study period. Readmissions decreased from 49 (6.1%) during pre-implementation to 37 (2.0%) during post-implementation (P = .004). By design, more rehospitalized patients were on the orthopedic surgery service after implementation of the Orthopedic EDAC program (n = 49; 70%) versus before (n = 22; 35%; P = .028). EDAC LOS decreased from 7.75 days to 4.73 days (P = .005). CONCLUSION: In this single-center, before-after pilot of a novel Orthopedic EDAC program, we demonstrated a reduction in readmissions and Orthopedic EDAC LOS, as well as improved continuity of care for TJA patients on representation.

Right ventricular outflow tract velocity time integral-to-pulmonary artery systolic pressure ratio: a non-invasive metric of pulmonary arterial compliance differs across the spectrum of pulmonary hypertension.

Pulmonary arterial compliance (PAC), invasively assessed by the ratio of stroke volume to pulmonary arterial (PA) pulse pressure, is a sensitive marker of right ventricular (RV)-PA coupling that differs across the spectrum of pulmonary hypertension (PH) and is predictive of outcomes. We assessed whether the echocardiographically derived ratio of RV outflow tract velocity time integral to PA systolic pressure (RVOT-VTI/PASP) (a) correlates with invasive PAC, (b) discriminates heart failure with preserved ejection-associated PH (HFpEF-PH) from pulmonary arterial hypertension (PAH), and (c) is associated with functional capacity. We performed a retrospective cohort study of patients with PAH (n = 70) and HFpEF-PH (n = 86), which was further dichotomized by diastolic pressure gradient (DPG) into isolated post-capillary PH (DPG < 7 mmHg; Ipc-PH, n = 54), and combined post- and pre-capillary PH (DPG ≥ 7 mm Hg; Cpc-PH, n = 32). Of the 156 patients, 146 had measurable RVOT-VTI or PASP and were included in further analysis. RVOT-VTI/PASP correlated with invasive PAC overall (ρ = 0.61, P < 0.001) and for the PAH (ρ = 0.38, P = 0.002) and HFpEF-PH (ρ = 0.63, P < 0.001) groups individually. RVOT-VTI/PASP differed significantly across the PH spectrum (PAH: 0.13 [0.010-0.25] vs. Cpc-PH: 0.20 [0.12-0.25] vs. Ipc-PH: 0.35 [0.22-0.44]; P < 0.001), distinguished HFpEF-PH from PAH (AUC = 0.72, 95% CI = 0.63-0.81) and Cpc-PH from Ipc-PH (AUC = 0.78, 95% CI = 0.68-0.88), and remained independently predictive of 6-min walk distance after multivariate analysis (standardized ß-coefficient = 27.7, 95% CI = 9.2-46.3; P = 0.004). Echocardiographic RVOT-VTI/PASP is a novel non-invasive metric of PAC that differs across the spectrum of PH. It distinguishes the degree of pre-capillary disease within HFpEF-PH and is predictive of functional capacity.

MEK inhibition abrogates sunitinib resistance in a renal cell carcinoma patient-derived xenograft model.

BACKGROUND: Renal cell carcinoma (RCC) patients treated with tyrosine kinase inhibitors (TKI) typically respond initially, but usually develop resistance to therapy. We utilised transcriptome analysis to identify gene expression changes during development of sunitinib resistance in a RCC patient-derived xenograft (PDX) model. METHODS: RCC tumours were harvested during pre-treatment, response and escape phases. Direct anti-proliferative effects of sunitinib plus MEK inhibitor were assessed. Activation status (phosphorylation) of MEK1/2 and ERK1/2 was determined, myeloid-derived suppressor cells (MDSC) sub-fractions were quantitated and G-CSF was measured by ELISA. RESULTS: During the response phase, tumours exhibited 91% reduction in volume, characterised by decreased expression of cell survival genes. After 4-week treatment, tumours developed resistance to sunitinib, associated with increased expression of pro-angiogenic and cell survival genes. During tumour escape, cellular movement, inflammatory response and immune cell trafficking genes were induced, along with intra-tumoural accumulation of MDSC. In this PDX model, either continuous treatment with sunitinib plus MEK inhibitor PD-0325901, or switching from sunitinib to PD-0325901 was effective. The combination of PD-0325901 with TKI suppressed intra-tumoural phospho-MEK1/2, phospho-ERK1/2 and MDSC. CONCLUSIONS: Continuous treatment with sunitinib alone did not maintain anti-tumour response; addition of MEK inhibitor abrogated resistance, leading to improved anti-tumour efficacy.

The ineligible patient: how to treat patients not included in clinical studies.

PURPOSE: Targeted therapies are currently the standard of care for metastatic renal cell carcinoma (mRCC). Five VEGF pathway inhibitors (sorafenib, sunitinib, bevacizumab in combination with interferon-alpha, pazopanib, and axitinib) and two mTOR inhibitors (everolimus and temsirolimus) are now FDA approved for mRCC based on results from phase III randomized clinical trials (RCTs). However, several subgroups of patients are excluded from enrollment due to strict eligibility criteria. The toxicity and efficacy of targeted therapies in these populations are unknown. METHODS: PubMed was searched for citations of the pivotal phase III RCTs leading to FDA approval. These publications were cross-referenced with their associated entries on www.ClinicalTrials.gov, and both were abstracted for eligibility criteria for patient enrollment. Based on this data, PubMed was searched for both prospective and retrospective studies evaluating toxicity and efficacy of targeted therapies for mRCC in these ineligible patient subgroups. RESULTS: We reviewed published toxicity and efficacy data in several ineligible patient subgroups, including patients with non-clear cell renal cell carcinoma, poor performance status, poor renal function, CNS metastases, significant cardiac comorbidities, and prior systemic therapy. CONCLUSIONS: Targeted therapies appear to be safe in most ineligible patient populations, including patients with poor renal function. However, patients with preexisting cardiac comorbidities are at greater risk of developing cardiac toxicity on sunitinib. Targeted therapies appear to have some efficacy in maintaining stable disease in these subgroups, but are limited to rare partial responses. Prospective cohort studies are needed to accurately assess the safety and efficacy of targeted therapies in ineligible patient subgroups.

Distinct functions of human RECQ helicases WRN and BLM in replication fork recovery and progression after hydroxyurea-induced stalling.

Human WRN and BLM genes are members of the conserved RECQ helicase family. Mutations in these genes are associated with Werner and Bloom syndromes. WRN and BLM proteins are implicated in DNA replication, recombination, repair, telomere maintenance, and transcription. Using microfluidics-assisted display of DNA for replication track analysis (ma-RTA), we show that WRN and BLM contribute additively to normal replication fork progression, and non-additively, in a RAD51-dependent pathway, to resumption of replication after arrest by hydroxyurea (HU), a replication-stalling drug. WRN but not BLM is required to support fork progression after HU. Resumption of replication by forks may be necessary but is not sufficient for timely completion of the cell cycle after HU arrest, as depletion of WRN or BLM compromises fork recovery to a similar degree, but only BLM depletion leads to extensive delay of cell division after HU, as well as more pronounced chromatin bridging. Finally, we show that recovery from HU includes apparent removal of some of the DNA that was synthesized immediately after release from HU, a novel phenomenon that we refer to as nascent strand processing, NSP.

The human WRN and BLM RecQ helicases differentially regulate cell proliferation and survival after chemotherapeutic DNA damage.

Loss-of-function mutations in the human RecQ helicase genes WRN and BLM respectively cause the genetic instability/cancer predisposition syndromes Werner syndrome and Bloom syndrome. To identify common and unique functions of WRN and BLM, we systematically analyzed cell proliferation, cell survival, and genomic damage in isogenic cell lines depleted of WRN, BLM, or both proteins. Cell proliferation and survival were assessed before and after treatment with camptothecin, cis-diamminedichloroplatinum(II), hydroxyurea, or 5-fluorouracil. Genomic damage was assessed, before and after replication arrest, by gamma-H2AX staining, which was quantified at the single-cell level by flow cytometry. Cell proliferation was affected strongly by the extent of WRN and/or BLM depletion, and more strongly by BLM than by WRN depletion (P = 0.005). The proliferation of WRN/BLM-codepleted cells, in contrast, did not differ from BLM-depleted cells (P = 0.34). BLM-depleted and WRN/BLM-codepleted cells had comparably impaired survival after DNA damage, whereas WRN-depleted cells displayed a distinct pattern of sensitivity to DNA damage. BLM-depleted and WRN/BLM-codepleted cells had similar, significantly higher gamma-H2AX induction levels than did WRN-depleted cells. Our results provide new information on the role of WRN and BLM in determining cell proliferation, cell survival, and genomic damage after chemotherapeutic DNA damage or replication arrest. We also provide new information on functional redundancy between WRN and BLM. These results provide a strong rationale for further developing WRN and BLM as biomarkers of tumor chemotherapeutic responsiveness.

Frequency of abnormal findings detected by comprehensive clinical evaluation at 1 year after allogeneic hematopoietic cell transplantation.

Consensus guidelines recommend various screening examinations for survivors after allogeneic hematopoietic cell transplantation (HCT), but how often these examinations detect abnormal findings is unknown. We reviewed the medical records of 118 patients who received comprehensive, standardized evaluations at 1 year after allogeneic HCT at Fred Hutchinson Cancer Research Center/Seattle Cancer Care Alliance. Abnormal findings were common, including moderate to severe pulmonary dysfunction (16%), fasting hyperlipidemia (56%), osteopenia (52%), osteoporosis (6%), and active chronic graft-versus-host disease (cGVHD) (64%). Recurrent malignancy (4%) and cGVHD (29%) were detected in previously unsuspected cases. Only 3% of patients had no abnormal findings. We conclude that comprehensive evaluation at 1 year after allogeneic HCT detects a high prevalence of medical problems. Longer follow-up is needed to determine whether early detection and intervention affect later morbidity and mortality.