Timing of antibiotic treatment identifies distinct clinical presentations among patients presenting with suspected septic shock.

Objective: Recent clinical guidelines for sepsis management emphasize immediate antibiotic initiation for suspected septic shock. Though hypotension is a high-risk marker of sepsis severity, prior studies have not considered the precise timing of hypotension in relation to antibiotic initiation and how clinical characteristics and outcomes may differ. Our objective was to evaluate antibiotic initiation in relation to hypotension to characterize differences in sepsis presentation and outcomes in patients with suspected septic shock. Methods: Adults presenting to the emergency department (ED) June 2012-December 2018 diagnosed with sepsis (Sepsis-III electronic health record [EHR] criteria) and hypotension (non-resolving for ≥30 min, systolic blood pressure <90 mmHg) within 24 h. We categorized patients who received antibiotics before hypotension ("early"), 0-60 min after ("immediate"), and >60 min after ("late") treatment. Results: Among 2219 patients, 55% received early treatment, 13% immediate, and 32% late. The late subgroup often presented to the ED with hypotension (median 0 min) but received antibiotics a median of 191 min post-ED presentation. Clinical characteristics notable for this subgroup included higher prevalence of heart failure and liver disease (p < 0.05) and later onset of systemic inflammatory response syndrome (SIRS) criteria compared to early/immediate treatment subgroups (median 87 vs. 35 vs. 20 min, p < 0.0001). After adjustment, there was no difference in clinical outcomes among treatment subgroups. Conclusions: There was significant heterogeneity in presentation and timing of antibiotic initiation for suspected septic shock. Patients with later treatment commonly had hypotension on presentation, had more hypotension-associated comorbidities, and developed overt markers of infection (eg, SIRS) later. While these factors likely contribute to delays in clinician recognition of suspected septic shock, it may not impact sepsis outcomes.

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.

Discharge Practices for COVID-19 Patients: Rapid Review of Published Guidance and Synthesis of Documents and Practices at 22 US Academic Medical Centers.

BACKGROUND: There are currently no evidence-based guidelines that provide standardized criteria for the discharge of COVID-19 patients from the hospital. OBJECTIVE: To address this gap in practice guidance, we reviewed published guidance and collected discharge protocols and procedures to identify and synthesize common practices. DESIGN: Rapid review of existing guidance from US and non-US public health organizations and professional societies and qualitative review using content analysis of discharge documents collected from a national sample of US academic medical centers with follow-up survey of hospital leaders SETTING AND PARTICIPANTS: We reviewed 65 websites for major professional societies and public health organizations and collected documents from 22 Academic Medical Centers (AMCs) in the US participating in the HOspital MEdicine Reengineering Network (HOMERuN). RESULTS: We synthesized data regarding common practices around 5 major domains: (1) isolation and transmission mitigation; (2) criteria for discharge to non-home settings including skilled nursing, assisted living, or homeless; (3) clinical criteria for discharge including oxygenation levels, fever, and symptom improvement; (4) social support and ability to perform activities of daily living; (5) post-discharge instructions, monitoring, and follow-up. LIMITATIONS: We used streamlined methods for rapid review of published guidance and collected discharge documents only in a focused sample of US academic medical centers. CONCLUSION: AMCs studied showed strong consensus on discharge practices for COVID-19 patients related to post-discharge isolation and transmission mitigation for home and non-home settings. There was high concordance among AMCs that discharge practices should address COVID-19-specific factors in clinical, functional, and post-discharge monitoring domains although definitions and details varied.

Prevalence and characterisation of diagnostic error among 7-day all-cause hospital medicine readmissions: a retrospective cohort study.

BACKGROUND: The prevalence and aetiology of diagnostic error among hospitalised adults is unknown, though likely contributes to patient morbidity and mortality. We aim to identify and characterise the prevalence and types of diagnostic error among patients readmitted within 7 days of hospital discharge. METHODS: Retrospective cohort study at a single urban academic hospital examining adult patients discharged from the medical service and readmitted to the same hospital within 7 days between January and December 2018. The primary outcome was diagnostic error presence, identified through two-physician adjudication using validated tools. Secondary outcomes included severity of error impact and characterisation of diagnostic process failures contributing to error. RESULTS: There were 391 cases of unplanned 7-day readmission (5.2% of 7507 discharges), of which 376 (96.2%) were reviewed. Twenty-one (5.6%) admissions were found to contain at least one diagnostic error during the index admission. The most common problem areas in the diagnostic process included failure to order needed test(s) (n=11, 52.4%), erroneous clinician interpretation of test(s) (n=10, 47.6%) and failure to consider the correct diagnosis (n=8, 38.1%). Nineteen (90.5%) of the diagnostic errors resulted in moderate clinical impact, primarily due to short-term morbidity or contribution to the readmission. CONCLUSION: The prevalence of diagnostic error among 7-day medical readmissions was 5.6%. The most common drivers of diagnostic error were related to clinician diagnostic reasoning. Efforts to reduce diagnostic error should include strategies to augment diagnostic reasoning and improve clinician decision-making around diagnostic studies.

Regulation of the ATM-activator protein Aven by CRM1-dependent nuclear export.

Aven is a regulator of apoptosis whose overexpression is associated with poor prognosis in several cancers, including childhood acute lymphoblastic leukemia and acute myeloid leukemia. We have recently shown that Aven serves as an activator and substrate of ATM, thereby modulating the DNA-damage response and G(2)/M cell cycle progression. Under physiological conditions, the cellular localization of Aven is mainly cytosolic, but a small fraction of the protein is present in the nucleus. Here, we show that treatment of cells with leptomycin B, an inhibitor of Exportin-1/CRM (chromosomal region maintenance) 1, resulted in nuclear accumulation of Aven. Furthermore, we identified a functional LR-NES between amino acid residues 282-292 of the human Aven protein, a sequence that is evolutionary conserved among a range of vertebrate species. Disruption of this LR-NES by site-directed mutagenesis resulted in enhanced nuclear localization of Aven, but did not alter the ability of the protein to induce G(2)/M cell cycle arrest in interphase Xenopus laevis extracts. However, elimination of the LR-NES sequence led to a reduction in the capacity of Aven to arrest Xenopus oocytes containing intact nuclei. Our results suggest that the regulation of nucleocytoplasmatic traffic of Aven could modulate its ability to influence cell cycle progression.