Randomized Placebo-Controlled Trial of 60-Day Percutaneous Peripheral Nerve Stimulation Treatment Indicates Relief of Persistent Postoperative Pain, and Improved Function After Knee Replacement.

OBJECTIVES: Total knee arthroplasty (TKA) is an effective surgery for end-stage knee osteoarthritis, but chronic postoperative pain and reduced function affect up to 20% of patients who undergo such surgery. There are limited treatment options, but percutaneous peripheral nerve stimulation (PNS) is a promising nonopioid treatment option for chronic, persistent postoperative pain. The objective of the present study was to evaluate the effect of a 60-day percutaneous PNS treatment in a multicenter, randomized, double-blind, placebo-controlled trial for treating persistent postoperative pain after TKA. MATERIALS AND METHODS: Patients with postoperative pain after knee replacement were screened for this postmarket, institutional review board-approved, prospectively registered (NCT04341948) trial. Subjects were randomized to receive either active PNS or placebo (sham) stimulation. Subjects and a designated evaluator were blinded to group assignments. Subjects in both groups underwent ultrasound-guided placement of percutaneous fine-wire coiled leads targeting the femoral and sciatic nerves on the leg with postoperative pain. Leads were indwelling for eight weeks, and the primary efficacy outcome compared the proportion of subjects in each group reporting ≥50% reduction in average pain relative to baseline during weeks five to eight. Functional outcomes (6-minute walk test; 6MWT and Western Ontario and McMaster Universities Osteoarthritis Index) and quality of life (Patient Global Impression of Change) also were evaluated at end of treatment (EOT). RESULTS: A greater proportion of subjects in the PNS groups (60%; 12/20) than in the placebo (sham) group (24%; 5/21) responded with ≥50% pain relief relative to baseline (p = 0.028) during the primary endpoint (weeks 5-8). Subjects in the PNS group also walked a significantly greater distance at EOT than did those in the placebo (sham) group (6MWT; +47% vs -9% change from baseline; p = 0.048, n = 18 vs n = 20 completed the test, respectively). Prospective follow-up to 12 months is ongoing. CONCLUSIONS: This study provides evidence that percutaneous PNS decreases persistent pain, which leads to improved functional outcomes after TKA at EOT.

Reduce intraoperative albumin utilisation in cardiac surgical patients: a quality improvement initiative.

BACKGROUND: Albumin continues to be used routinely by cardiac anaesthesiologists perioperatively despite lack of evidence for improved outcomes. The Multicenter Perioperative Outcomes Group (MPOG) data ranked our institution as one of the highest intraoperative albumin users during cardiac surgery. Therefore, we designed a quality improvement project (QIP) to introduce a bundle of interventions to reduce intraoperative albumin use in cardiac surgical patients. METHODS: Our institutional MPOG data were used to analyse the FLUID-01-C measure that provides the number of adult cardiac surgery cases where albumin was administered intraoperatively by anaesthesiologists from 1 July 2019 to 30 June 2022. The QIP involved introduction of the following interventions: (1) education about appropriate albumin use and indications (January 2021), (2) email communications reinforced with OR teaching (March 2021), (3) removal of albumin from the standard pharmacy intraoperative medication trays (April 2021), (4) grand rounds presentation discussing the QIP and highlighting the interventions (May 2021) and (5) quarterly provider feedback (starting July 2021). Multivariable segmented regression models were used to assess the changes from preintervention to postintervention time period in albumin utilisation, and its total monthly cost. RESULTS: Among the 5767 cardiac surgery cases that met inclusion criteria over the 3-year study period, 16% of patients received albumin intraoperatively. The total number of cases that passed the metric (albumin administration was avoided), gradually increased as our interventions went into effect. Intraoperative albumin utilisation (beta=-101.1, 95% CI -145 to -56.7) and total monthly cost of albumin (beta=-7678, 95% CI -10712 to -4640) demonstrated significant decrease after starting the interventions. CONCLUSIONS: At a single academic cardiac surgery programme, implementation of a bundle of simple and low-cost interventions as part of a coordinated QIP were effective in significantly decreasing intraoperative use of albumin, which translated into considerable costs savings.

The Pandemic Response Commons.

Objectives: A data commons is a software platform for managing, curating, analyzing, and sharing data with a community. The Pandemic Response Commons (PRC) is a data commons designed to provide a data platform for researchers studying an epidemic or pandemic. Methods: The PRC was developed using the open source Gen3 data platform and is based upon consortium, data, and platform agreements developed by the not-for-profit Open Commons Consortium. A formal consortium of Chicagoland area organizations was formed to develop and operate the PRC. Results: The consortium developed a general PRC and an instance of it for the Chicagoland region called the Chicagoland COVID-19 Commons. A Gen3 data platform was set up and operated with policies, procedures, and controls for a NIST SP 800-53 revision 4 Moderate system. A consensus data model for the commons was developed, and a variety of datasets were curated, harmonized and ingested, including statistical summary data about COVID cases, patient level clinical data, and SARS-CoV-2 viral variant data. Discussion and conclusions: Given the various legal and data agreements required to operate a data commons, a PRC is designed to be in place and operating at a low level prior to the occurrence of an epidemic, with the activities increasing as required during an epidemic. A regional instance of a PRC can also be part of a broader data ecosystem or data mesh consisting of multiple regional commons supporting pandemic response through sharing regional data.

Multicenter Development and Prospective Validation of eCARTv5: A Gradient Boosted Machine Learning Early Warning Score.

Rationale: Early detection of clinical deterioration using early warning scores may improve outcomes. However, most implemented scores were developed using logistic regression, only underwent retrospective internal validation, and were not tested in important patient subgroups. Objectives: To develop a gradient boosted machine model (eCARTv5) for identifying clinical deterioration and then validate externally, test prospectively, and evaluate across patient subgroups. Methods: All adult patients hospitalized on the wards in seven hospitals from 2008- 2022 were used to develop eCARTv5, with demographics, vital signs, clinician documentation, and laboratory values utilized to predict intensive care unit transfer or death in the next 24 hours. The model was externally validated retrospectively in 21 hospitals from 2009-2023 and prospectively in 10 hospitals from February to May 2023. eCARTv5 was compared to the Modified Early Warning Score (MEWS) and the National Early Warning Score (NEWS) using the area under the receiver operating characteristic curve (AUROC). Measurements and Main Results: The development cohort included 901,491 admissions, the retrospective validation cohort included 1,769,461 admissions, and the prospective validation cohort included 46,330 admissions. In retrospective validation, eCART had the highest AUROC (0.835; 95%CI 0.834, 0.835), followed by NEWS (0.766 (95%CI 0.766, 0.767)), and MEWS (0.704 (95%CI 0.703, 0.704)). eCART's performance remained high (AUROC ≥0.80) across a range of patient demographics, clinical conditions, and during prospective validation. Conclusions: We developed eCARTv5, which accurately identifies early clinical deterioration in hospitalized ward patients. Our model performed better than the NEWS and MEWS retrospectively, prospectively, and across a range of subgroups.

Sprint-inspired One-on-One Post-Go-Live Training Session (Mini-Sprint) Improves Provider Electronic Health Record Efficiency and Satisfaction.

BACKGROUND: Inefficient electronic health record (EHR) usage increases the documentation burden on physicians and other providers, which increases cognitive load and contributes to provider burnout. Studies show that EHR efficiency sessions, optimization sprints, reduce burnout using a resource-intense five-person team. We implemented sprint-inspired one-on-one post-go-live efficiency training sessions (mini-sprints) as a more economical training option directed at providers. OBJECTIVES: We evaluated a post-go-live mini-sprint intervention to assess provider satisfaction and efficiency. METHODS: NorthShore University HealthSystem implemented one-on-one provider-to-provider mini-sprint sessions to optimize provider workflow within the EHR platform. The physician informaticist completed a 9-point checklist of efficiency tips with physician trainees covering schedule organization, chart review, speed buttons, billing, note personalization/optimization, preference lists, quick actions, and quick tips. We collected postsession survey data assessing for net promoter score (NPS) and open-ended feedback. We conducted financial analysis of pre- and post-mini-sprint efficiency levels and financial data. RESULTS: Seventy-six sessions were conducted with 32 primary care physicians, 28 specialty physicians, and 16 nonphysician providers within primary care and other areas. Thirty-seven physicians completed the postsession survey. The average NPS for the completed mini-sprint sessions was 97. The proficiency score had a median of 6.12 (Interquartile range (IQR): 4.71-7.64) before training, and a median of 7.10 (IQR: 6.25-8.49) after training. Financial data analysis indicates that higher level billing codes were used at a greater frequency post-mini-sprint. The revenue increase 12 months post-mini-sprint was $213,234, leading to a return of $75,559.50 for 40 providers, or $1,888.98 per provider in a 12-month period. CONCLUSION: Our data show that mini-sprint sessions were effective in optimizing efficiency within the EHR platform. Financial analysis demonstrates that this type of training program is sustainable and pays for itself. There was high satisfaction with the mini-sprint training modality, and feedback indicated an interest in further mini-sprint training sessions for physicians and nonphysician staff.

Hydroxyapatite ceramic-coated femoral components in younger patients followed up for 27 to 32 years.

Aims: This study reports the results of 38 total hip arthroplasties (THAs) in 33 patients aged less than 50 years, using the JRI Furlong hydroxyapatite ceramic (HAC)-coated femoral component. Methods: We describe the survival, radiological, and functional outcomes of 33 patients (38 THAs) at a mean follow-up of 27 years (25 to 32) between 1988 and 2018. Results: Of the surviving 30 patients (34 THAs), there were four periprosthetic fractures: one underwent femoral revision after 21 years, two had surgical fixation as the stem was deemed stable, and one was treated nonoperatively due to the patient's comorbidities. The periprosthetic fracture patients showed radiological evidence of change in bone stock around the femoral stem, which may have contributed to the fractures; this was reflected in change of the canal flare index at the proximal femur. Two patients (two hips) were lost to follow-up. Using aseptic loosening as the endpoint, 16 patients (18 hips; 48%) needed acetabular revision. None of the femoral components were revised for aseptic loosening, demonstrating 100% survival. The estimate of the cumulative proportion surviving for revisions due to any cause was 0.97 (standard error 0.03). Conclusion: In young patients with high demands, the Furlong HAC-coated femoral component gives excellent long-term results.

The role of noncovalent BTK inhibitors in the era of covalent BTK inhibitors.

Despite significantly improving outcomes in patients with B-cell malignancies, covalent Bruton tyrosine kinase (BTK) inhibitors are limited by toxicities and the development of resistance. Some toxicities can be life-threatening, such as cardiotoxicity. These toxicities result from off-target effects of covalent BTK inhibitors and frequently lead to dose reductions and discontinuations of the drug. Noncovalent BTK inhibitors bind BTK in a unique fashion and, to date, have demonstrated an excellent safety profile as well as efficacy against a variety of B-cell malignancies. In addition, noncovalent BTK inhibitors have, for the first time, demonstrated efficacy in patients who progressed on other BTK inhibitors. Long-term data and comparative studies are needed to further investigate their efficacy and role in the landscape covalent BTK Inhibitors.

Impact of Race and Social Determinants of Health on Outcomes in Patients with Aggressive B-cell nHL Treated with CAR-T.

Healthcare disparities driven by multiple social, economic, and/or environmental factors lead to inequalities in health outcomes. CAR-T cell immunotherapy is an effective therapy for relapsed/refractory B-cell non-Hodgkin lymphoma (r/r B-NHL). However, data are limited on the impact of the convergence of race and social determinants of health on outcomes for patients treated with CAR-T therapy. We examined the impact of interactions between race and insurance type on health care utilization and outcomes in patients treated with CAR-T for aggressive B-NHL. Adult patients with r/r B-NHL treated with CD19 CAR-T were identified between 2015 and 2021 across 13 US academic centers. Insurance type, demographic and clinical data were collected and analyzed via Chi-squared and Kaplan-Meier analysis. Cox multivariable regression (MVA) was used to determine the impact of race/ethnicity and other variables on survival. 466 adult patients were included in our analysis. Median follow-up after CAR-T was 12.7 months. Median progression free survival (mPFS) was longer for Caucasians (11.5 months) than for African Americans (3.5 months, HR 1.56 [1.03-2.4], p=0.04) or Asians (2.7 months, HR 1.7 [1.02-2.67], p=0.04). Differences in median overall survival (mOS) were not significant. For Medicare (n=206) vs Medicaid (n=33) vs private insurance (n=219) vs self-pay (n=7): mPFS was 15.9 vs 4.2 vs 6.0 vs 0.9 months (p<0.001) and mOS was 31.2 vs 12.8 vs 21.5 vs 3.2 months (p<0.001), respectively. Collectively, our multi-center retrospective analysis showed that race and insurance status can impact outcomes for patients treated with CAR-T cell therapy.

Adherence to stewardship recommendations for antibiotic discontinuation reduces antibiotic-associated adverse drug events.

Inappropriate antibiotic use may lead to increased adverse drug events (ADEs). This study assessed whether an antimicrobial stewardship recommendation to discontinue antibiotics in patients with low likelihood for bacterial infection reduced antibiotic duration and antibiotic-associated ADEs. At a 4-hospital system, hospitalized adult patients receiving empiric antibiotics for suspected infection were identified between May 2, 2016 and June 30, 2018. For those patients who were deemed unlikely to have a bacterial infection, a note was left by an infectious diseases physician recommending antibiotic discontinuation. Patient cases were considered "adherent" to recommendations if antibiotics were discontinued within 48 hours of the note and "non-adherent" to recommendations if antibiotics were continued beyond this. Duration of antibiotics and potential antibiotic-associated ADEs were collected retrospectively. Attribution of the adverse event to the antibiotic was decided upon by the investigators. The incidence of ADEs and duration of antibiotics between the adherent and non-adherent groups were compared. Of 253 patients deemed unlikely to have a bacterial infection, 114 (45%) treatment teams stopped antibiotics within 48 hours of the recommendation, and 139 (55%) continued antibiotics. The total number of ADEs was significantly higher in the non-adherent group compared to the adherent group (34 ADEs vs 9 ADEs, P = .001). The median number of total prescribed antibiotic days was higher in the non-adherent group than in the adherent group (5 days vs 1 day, P < .001). This study demonstrates that stewardship programs may prevent ADEs by recommending antibiotic discontinuation in patients with low suspicion for bacterial infection.

Association between maternal employment status and presence of children with major congenital anomalies in Denmark.

IMPORTANCE: The burden of caring for children with complex medical problems such as major congenital anomalies falls principally on mothers, who in turn suffer a variety of potentially severe economic consequences. As well, health consequences of caregiving often further impact the social and economic prospects of mothers of children with major congenital anomalies (MCMCAs). Evaluating the long-term economic consequences of extensive in-home caregiving among MCMCAs can inform strategies to mitigate these effects. OBJECTIVE: To assess whether MCMCAs face reduced employment and increased need for disability benefits over a 20-year period. DESIGN: A population-based matched cohort study. SETTING: Denmark. PARTICIPANTS: All women who gave birth to a singleton child with a major congenital anomaly in Denmark between January 1, 1997 and December 31, 2017 (n = 23,637) and a comparison cohort of mothers matched by maternal age, parity, and infant's year of birth (n = 234,586). EXPOSURES: Liveborn infant with a major congenital anomaly. MAIN OUTCOMES AND MEASURES: The primary outcome was mothers' employment status, stratified by their child's age. Employment status was categorized as employed, outside the workforce (on temporary leave, holding a flexible job, or pursuing education), or unemployed; the number of weeks in each category was measured over time. The secondary outcome was time to receipt of a disability pension, which in Denmark implies permanent exit from the labor market. We used a negative binomial regression model to estimate the number of weeks in each employment category, stratified by the child's age (i.e., 0-1 year, > 1-6 years, 7-13 years, 14-18 years). A Cox proportional hazards regression model was used to compute hazard ratios as a measure of the relative risk of receiving a disability pension. Rate ratios and hazard ratios were adjusted for maternal demographics, pregnancy history, health, and infant's year of birth. RESULTS: During 1-6 years after delivery, MCMCAs were outside the workforce for a median of 50 weeks (IQR, 6-107 weeks), while members of the comparison cohort were outside the workforce for a median of 48 weeks (IQR, 4-98 weeks), corresponding to an adjusted rate ratio [ARR] of 1.05 (95% confidence interval [CI], 1.04-1.07). During the first year after delivery, MCMCAs were more likely to be employed than mothers in the comparison cohort (ARR, 1.08; 95% CI, 1.06-1.10). At all timepoints thereafter, MCMCAs had a lower rate of workforce participation. The rate of being outside the workforce was 5% higher than mothers in the comparison cohort during 1-6 years after delivery (ARR, 1.05; 95% CI, 1.04-1.07), 9% higher during 7-13 years after delivery (ARR, 1.09; 95% CI, 1.06-1.12), and 12% higher during 14-18 years after delivery (ARR, 1.12; 95% CI, 1.07-1.18). Overall, MCMCAs had a 20% increased risk of receiving a disability pension during follow-up than mothers in the matched comparison cohort [incidence rates 3.10 per 1000 person-years (95% CI, 2.89-3.32) vs. 2.34 per 1000 person-years (95% CI, 2.29-2.40), adjusted hazard ratio, 1.20; 95% CI, 1.11-1.29]. CONCLUSION AND RELEVANCE: MCMCAs were less likely to participate in the Danish workforce, less likely to be employed, and more likely to receive disability pensions than mothers of unaffected children. The rate of leaving the workforce intensified as their affected children grew older. The high demands of caregiving among MCMCAs may have long-term employment consequences even in nations with comprehensive and heavily tax-supported childcare systems, such as Denmark.

AcumenTM hypotension prediction index guidance for prevention and treatment of hypotension in noncardiac surgery: a prospective, single-arm, multicenter trial.

BACKGROUND: Intraoperative hypotension is common during noncardiac surgery and is associated with postoperative myocardial infarction, acute kidney injury, stroke, and severe infection. The Hypotension Prediction Index software is an algorithm based on arterial waveform analysis that alerts clinicians of the patient's likelihood of experiencing a future hypotensive event, defined as mean arterial pressure < 65 mmHg for at least 1 min. METHODS: Two analyses included (1) a prospective, single-arm trial, with continuous blood pressure measurements from study monitors, compared to a historical comparison cohort. (2) A post hoc analysis of a subset of trial participants versus a propensity score-weighted contemporaneous comparison group, using external data from the Multicenter Perioperative Outcomes Group (MPOG). The trial included 485 subjects in 11 sites; 406 were in the final effectiveness analysis. The post hoc analysis included 457 trial participants and 15,796 comparison patients. Patients were eligible if aged 18 years or older, American Society of Anesthesiologists (ASA) physical status 3 or 4, and scheduled for moderate- to high-risk noncardiac surgery expected to last at least 3 h. MEASUREMENTS: minutes of mean arterial pressure (MAP) below 65 mmHg and area under MAP < 65 mmHg. RESULTS: Analysis 1: Trial subjects (n = 406) experienced a mean of 9 ± 13 min of MAP below 65 mmHg, compared with the MPOG historical control mean of 25 ± 41 min, a 65% reduction (p < 0.001). Subjects with at least one episode of hypotension (n = 293) had a mean of 12 ± 14 min of MAP below 65 mmHg compared with the MPOG historical control mean of 28 ± 43 min, a 58% reduction (p< 0.001). Analysis 2: In the post hoc inverse probability treatment weighting model, patients in the trial demonstrated a 35% reduction in minutes of hypotension compared to a contemporaneous comparison group [exponentiated coefficient: - 0.35 (95%CI - 0.43, - 0.27); p < 0.001]. CONCLUSIONS: The use of prediction software for blood pressure management was associated with a clinically meaningful reduction in the duration of intraoperative hypotension. Further studies must investigate whether predictive algorithms to prevent hypotension can reduce adverse outcomes. TRIAL REGISTRATION: Clinical trial number: NCT03805217. Registry URL: https://clinicaltrials.gov/ct2/show/NCT03805217 . Principal investigator: Xiaodong Bao, MD, PhD. Date of registration: January 15, 2019.

Decentralizing Health Care: History and Opportunities of Web3.

This paper explores the relationship between the development of the internet and health care, highlighting their parallel growth and mutual influence. It delves into the transition from the early, static days of Web 1.0, akin to siloed physician expertise in health care, to the more interactive and patient-centric era of Web 2.0, which was accompanied by advancements in medical technologies and patient engagement. This paper then focuses on the emerging era of Web3-the decentralized web-which promises a transformative shift in health care, particularly in how patient data are managed, accessed, and used. This shift toward Web3 involves using blockchain technology for decentralized data storage to enhance patient data access, control, privacy, and value. This paper also examines current applications and pilot projects demonstrating Web3's practical use in health care and discusses key questions and considerations for its successful implementation.

Autologous stem cell boost improves persistent immune effector cell associated hematotoxicity following BCMA directed chimeric antigen receptor T (CAR T) cell therapy in multiple myeloma.

Persistent Immune Effector Cell Associated Hematotoxicity (ICAHT) is a significant side effect of BCMA CAR T-Cell therapy in patients with relapsed multiple myeloma (MM). The use of stem cell boosts in ICAHT has been described, however studies have been limited by small patient numbers and short follow up. Herein, we report on our multi-institutional experience of ICAHT, defined by an absolute neutrophil count (ANC) of ≤ 1000, thrombocytopenia with a platelet count ≤ 50,000 or/and anemia as hemoglobin (hgb) ≤9 g/dL, in patients who received BCMA CAR T therapy, and the effects of subsequent stem cell boost on hematopoietic reconstitution and clinical outcome. In this study, ICAHT was observed in 60% (n = 61/101) of patients at D + 21, and risk factors for its development included history of a prior ASCT, higher number of prior lines of therapy, a decreased platelet count prior to lymphodepletion and history of ICANS. 28% of patients with ICAHT received a stem cell boost at a median of 116 days due to profound and prolonged cytopenias often requiring ongoing transfusion support. Stem cell boost significantly improved cytopenias at 3 and 6 months follow up without any adverse effects on PFS and OS, underscoring the safety of this procedure.

Interaction between cold ischemia time and Kidney Donor Profile Index on postrenal transplant outcomes.

We analyzed whether there is an interaction between the Kidney Donor Profile Index (KDPI) and cold ischemia time (CIT) in recipients of deceased donor kidney transplant (KTs). Adults who underwent KTs in the United States between 2014 and 2020 were included and divided into 3 KDPI groups (≤20%, 21%-85%, >85%) and 4 CIT strata (<12, 12-17.9, 18-23.9, ≥24 hours). Multivariate analyses were used to test the interaction between KDPI and CIT for the following outcomes: primary graft nonfunction (PGNF), delayed graft function (DGF), estimated glomerular filtration rate (eGFR) at 6 and 12 months, patient survival, graft survival, and death-censored graft survival (DCGS). A total of 69,490 recipients were analyzed: 18,241 (26.3%) received a graft with KDPI ≤20%, 46,953 (67.6%) with KDPI 21%-85%, and 4,296 (6.2%) with KDPI >85%. Increasing KDPI and CIT were associated with worse post-KT outcomes. Contrary to our hypothesis, howerver, the interaction between KDPI and CIT was statistically significant only for PGNF and DGF and eGFR at 6 months. Paradoxically, the negative coefficient of the interaction suggested that increasing duration of CIT was more detrimental for low and intermediate-KDPI organs relative to high-KDPI grafts. Conversely, for mortality, graft survival, and DCGS, we found that the interaction between CIT and KDPI was not statistically significant. We conclude that, high KDPI and prolonged CIT are independent risk factors for inferior outcomes after KT. Their interaction, however, is statistically significant only for the short-term outcomes and more pronounced on low and intermediate-KDPI grafts than high-KDPI kidneys.

Causes, Diagnostic Testing, and Treatments Related to Clinical Deterioration Events among High-Risk Ward Patients.

OBJECTIVE: Timely intervention for clinically deteriorating ward patients requires that care teams accurately diagnose and treat their underlying medical conditions. However, the most common diagnoses leading to deterioration and the relevant therapies provided are poorly characterized. Therefore, we aimed to determine the diagnoses responsible for clinical deterioration, the relevant diagnostic tests ordered, and the treatments administered among high-risk ward patients using manual chart review. DESIGN: Multicenter retrospective observational study. SETTING: Inpatient medical-surgical wards at four health systems from 2006-2020 PATIENTS: Randomly selected patients (1,000 from each health system) with clinical deterioration, defined by reaching the 95th percentile of a validated early warning score, electronic Cardiac Arrest Risk Triage (eCART), were included. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Clinical deterioration was confirmed by a trained reviewer or marked as a false alarm if no deterioration occurred for each patient. For true deterioration events, the condition causing deterioration, relevant diagnostic tests ordered, and treatments provided were collected. Of the 4,000 included patients, 2,484 (62%) had clinical deterioration confirmed by chart review. Sepsis was the most common cause of deterioration (41%; n=1,021), followed by arrhythmia (19%; n=473), while liver failure had the highest in-hospital mortality (41%). The most common diagnostic tests ordered were complete blood counts (47% of events), followed by chest x-rays (42%), and cultures (40%), while the most common medication orders were antimicrobials (46%), followed by fluid boluses (34%), and antiarrhythmics (19%). CONCLUSIONS: We found that sepsis was the most common cause of deterioration, while liver failure had the highest mortality. Complete blood counts and chest x-rays were the most common diagnostic tests ordered, and antimicrobials and fluid boluses were the most common medication interventions. These results provide important insights for clinical decision-making at the bedside, training of rapid response teams, and the development of institutional treatment pathways for clinical deterioration. KEY POINTS: Question: What are the most common diagnoses, diagnostic test orders, and treatments for ward patients experiencing clinical deterioration? Findings: In manual chart review of 2,484 encounters with deterioration across four health systems, we found that sepsis was the most common cause of clinical deterioration, followed by arrythmias, while liver failure had the highest mortality. Complete blood counts and chest x-rays were the most common diagnostic test orders, while antimicrobials and fluid boluses were the most common treatments. Meaning: Our results provide new insights into clinical deterioration events, which can inform institutional treatment pathways, rapid response team training, and patient care.

Population pharmacokinetics and humanized dosage regimens matching the peak, area, trough, and range of amikacin plasma concentrations in immune-competent murine bloodstream and lung infection models.

Amikacin is an FDA-approved aminoglycoside antibiotic that is commonly used. However, validated dosage regimens that achieve clinically relevant exposure profiles in mice are lacking. We aimed to design and validate humanized dosage regimens for amikacin in immune-competent murine bloodstream and lung infection models of Acinetobacter baumannii. Plasma and lung epithelial lining fluid (ELF) concentrations after single subcutaneous doses of 1.37, 13.7, and 137 mg/kg of body weight were simultaneously modeled via population pharmacokinetics. Then, humanized amikacin dosage regimens in mice were designed and prospectively validated to match the peak, area, trough, and range of plasma concentration profiles in critically ill patients (clinical dose: 25-30 mg/kg of body weight). The pharmacokinetics of amikacin were linear, with a clearance of 9.93 mL/h in both infection models after a single dose. However, the volume of distribution differed between models, resulting in an elimination half-life of 48 min for the bloodstream and 36 min for the lung model. The drug exposure in ELF was 72.7% compared to that in plasma. After multiple q6h dosing, clearance decreased by ~80% from the first (7.35 mL/h) to the last two dosing intervals (~1.50 mL/h) in the bloodstream model. Likewise, clearance decreased by 41% from 7.44 to 4.39 mL/h in the lung model. The humanized dosage regimens were 117 mg/kg of body weight/day in mice [administered in four fractions 6 h apart (q6h): 61.9%, 18.6%, 11.3%, and 8.21% of total dose] for the bloodstream and 96.7 mg/kg of body weight/day (given q6h as 65.1%, 16.9%, 10.5%, and 7.41%) for the lung model. These validated humanized dosage regimens and population pharmacokinetic models support translational studies with clinically relevant amikacin exposure profiles.

Consensus recommendations on the management of toxicity associated with CD3×CD20 bispecific antibody therapy.

ABSTRACT: Bispecific antibodies (BsAb) that target CD3 and CD20 represent a new milestone in the treatment of patients with B-cell non-Hodgkin lymphoma. These drugs have demonstrated remarkable single-agent activity in patients with heavily pretreated disease, and 3 drugs have so far received regulatory approvals in various countries. However, BsAbs can potentially lead to severe toxicity associated with T-cell activation, particularly cytokine release syndrome (CRS). The anticipated widespread use of these off-the-shelf products poses challenges for implementation and highlights the need for guidance in anticipating, mitigating, and managing adverse events. In clinical trials, guidance for the evaluation and treatment of CRS and neurotoxicity associated with BsAb therapy has been modeled after algorithms originally created for chimeric antigen receptor (CAR) T-cell therapies and other immune effector therapies, yet notable differences in timing, quality, and severity exist between the toxicities of BsAbs and CAR T-cell therapies. We therefore convened an international panel of academic and community practice physicians, advanced practitioners, registered nurses, and pharmacists with experience using CD3×CD20 BsAbs in clinical trial and off-trial settings to provide comprehensive, consensus-based recommendations specific to the assessment and management of CD3×CD20 BsAb-related toxicities.

A phase 1-2 trial of DA-EPOCH-R plus ixazomib for MYC-aberrant lymphoid malignancies: the DACIPHOR regimen.

ABSTRACT: MYC-aberrant non-Hodgkin lymphoma (NHL) is associated with poor outcomes with conventional chemotherapy. Ixazomib is an orally bioavailable proteasome inhibitor that targets drivers of MYC expression and has demonstrated preclinical activity in aggressive MYC-aberrant NHL. We conducted a phase 1/2 study evaluating the safety and efficacy of DA-EPOCH-R with adjunctive ixazomib in aggressive MYC-aberrant NHL. For induction, patients received 6 cycles of DA-EPOCH-R with ixazomib administered twice per 21-day cycle; responders continued weekly ixazomib maintenance for up to 1 year. Primary objectives were to determine the maximum tolerated dose in phase 1 and efficacy of DA-EPOCH-R with ixazomib as measured by 12-month progression-free survival (PFS) rate in phase 2. Thirty-six patients were evaluable for response. Median age was 63 years (range, 31-77) and 44% had double-hit lymphoma (DHL)/triple-hit lymphoma (THL). In phase 1, 3 mg of ixazomib was established as recommended phase 2 dose. Twenty-nine (76.3%) patients completed 6 cycles of DA-EPOCH-R and 25 (65.8%) underwent dose escalations. The ORR after induction was 97% (95% confidence interval, 81-100) with a CR rate of 69%. At median follow-up of 18.8 months, the 12-month PFS and overall survival (OS) rates were 78% and 86%, respectively. For DHL/THL vs dual expressor lymphomas (DEL), 12-month PFS rates were 53% vs 95% and 12-month OS rates were 65% vs 100%, respectively. Grade ≥3 toxicities were predominantly hematologic. Twenty-seven (75%) of patients experienced neuropathy, nearly all low-grade. DA-EPOCH-R induction with adjunctive ixazomib is feasible and appears effective in patients with DEL. This trial was registered at www.clinicaltrials.gov as #NCT02481310.