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Outcomes of Critical Limb Threatening Ischemia Revascularization in Patients with Chronic Kidney Disease in the BEST - CLI Trial
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Adoptive T-cell therapy against cancer using tumor-infiltrating lymphocytes (TIL) and gene engineered T cells
No full textEffects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes: a meta-analysis of randomised controlled trials.
No full textBackground: GLP-1 receptor agonists reduce the risk of major adverse cardiovascular events (MACE) and can also have kidney benefits. However, whether GLP-1 receptor agonists improve clinically important kidney outcomes remains uncertain. We aimed to comprehensively assess the effects of GLP-1 receptor agonists on kidney and cardiovascular disease outcomes by performing a meta-analysis of randomised controlled trials.
Methods: For this meta-analysis, we searched MEDLINE, Embase, and the Cochrane Central Register of Controlled Trials for randomised controlled trials that included at least 500 participants with type 2 diabetes, compared a GLP-1 receptor agonist with placebo with at least 12 months of follow-up, and reported a primary clinical kidney or cardiovascular outcome, from database inception to March 26, 2024. Post hoc, we included the SELECT trial (NCT03574597), which enrolled participants with cardiovascular disease and a BMI of 27 kg/m2 or more without diabetes. Study-level summary data were extracted independently by two authors for inclusion in this random-effects analysis. The main kidney outcome was a composite outcome, consisting of kidney failure (kidney replacement therapy or a persistent estimated glomerular filtration rate [eGFR] \u3c15 mL/min per 1·73 m2), a sustained reduction in eGFR by at least 50% or the nearest equivalent, or death from kidney failure. The main cardiovascular outcome was MACE, consisting of cardiovascular death, non-fatal myocardial infarction, or non-fatal stroke. This study is registered with PROSPERO, CRD42024528864.
Findings: Of the 5140 records identified through the literature search, 11 trials, involving 85 373 participants (29 386 female, 55 987 male), were included in the meta-analysis. In participants with type 2 diabetes (67 769), GLP-1 receptor agonists reduced the composite kidney outcome by 18% compared with placebo (hazard ratio [HR] 0·82, 95% CI 0·73-0·93; I2 =26·41%), kidney failure by 16% (HR 0·84, 0·72-0·99; I2 =0%), MACE by 13% (HR 0·87, 0·81-0·93; I2 =49·75%), and all-cause death by 12% (HR 0·88, 0·83-0·93; I2 =0%). The effect on the composite kidney outcome (HR 0·81, 95% CI 0·72-0·92; I2 =23·11%), kidney failure (HR 0·84, 0·72-0·98; I2 =0%), MACE (HR 0·86, 0·80-0·92; I2 =48·9%), and all-cause death (HR 0·87, 0·82-0·91; I2 =0%) was similar when the SELECT trial was included, with no evidence of heterogeneity between this trial and those including participants with type 2 diabetes (pheterogeneity \u3e0·05). There was no difference in the risk of serious adverse events, including acute pancreatitis and severe hypoglycaemia, between the GLP-1 receptor agonist and placebo groups (risk ratio [RR] 0·95, 95% CI 0·90-1·01; I2 =88·5%). However, treatment discontinuation due to adverse events occurred more frequently in the GLP-1 receptor agonist groups (RR 1·51, 95% CI 1·18-1·94; I2 =96·3%).
Interpretation: We found evidence that GLP-1 receptor agonists significantly reduce clinically important kidney events, kidney failure, and cardiovascular events.
Funding: None
Time is brain: detection of nonconvulsive seizures and status epilepticus during acute stroke evaluation using point-of-care electroencephalography.
No full textOBJECTIVES: Seizures are both a common mimic and a potential complication of acute stroke. Although EEG can be helpful to evaluate this differential diagnosis, conventional EEG infrastructure is resource-intensive and unable to provide timely monitoring to match the emergent context of a stroke code. We aimed to evaluate the real-world use and utility of a point-of-care EEG device as an adjunct to acute stroke evaluation.
MATERIALS AND METHODS: We performed a retrospective observational cohort study at a tertiary care community teaching hospital by identifying patients who underwent point-of-care EEG monitoring using Rapid Response EEG system (Ceribell Inc., Sunnyvale, CA) during stroke code evaluation of acute neurological deficits during the study period from January 1, 2020 to December 31, 2020. We assessed the frequency of seizures and highly epileptiform patterns among patients with either confirmed strokes or stroke mimics.
RESULTS: Point-of-care EEG monitoring was used in the wake of a stroke code in 70 patients. Of these, neuroimaging and clinical information resulted in a diagnosis of stroke in 38 patients (28 ischemic, 6 hemorrhagic, 4 transient ischemic attack; median NIHSS score of 6.5 [IQR 2.0-12.0]) and absence of any stroke in 32 patients. Point-of-care EEG detected seizures and highly epileptiform patterns in 6 (15.8 %) stroke patients and 11 (34.4 %) stroke-mimic patients, including 2 patients with persistent expressive aphasia due to repeated focal seizures.
CONCLUSIONS: Point-of-care EEG has utility for detecting nonconvulsive seizures in patients undergoing acute stroke evaluations
Prevent Acute Chest Syndrome checklist (PACScheck): A quality improvement initiative to reduce acute chest syndrome.
No full textBACKGROUND: Acute chest syndrome (ACS) is a life-threatening complication of sickle cell disease (SCD). The Prevent Acute Chest Syndrome checklist (PACScheck) was created to drive appropriate ordering of opioids, incentive spirometry (IS), intravenous fluids (IVF), evaluation of oxygen desaturation, and bronchodilator use.
OBJECTIVES: Decrease the development of ACS by 5% in a hospitalized pediatric SCD population.
METHODS: A multidisciplinary team conducted a quality improvement (QI) project between April 2020 and August 2021 on an inpatient pediatric hematology unit. At-risk hospitalizations were patients with SCD who did not have ACS upon hospital admission. PACScheck was implemented and weekly run charts assessed documentation. Process control (p) charts, geometric control (g) charts, and chi-square tests assessed checklist process measures pre- and post-PACScheck. G chart assessed the number of encounters between ACS events.
RESULTS: A total of 483 at-risk hospitalizations were identified in the 12 months prior and 363 during the study period. A g chart demonstrated that fewer encounters developed ACS during PACScheck. A p chart demonstrated that IS documentation increased during PACScheck. A run chart of PACScheck documentation demonstrated a median of 100% documentation at least once per hospitalization during the last six months of the intervention.
CONCLUSION: Development of ACS can be reduced by implementing a best-practices checklist (PACScheck) on an inpatient pediatric hematology unit with a multidisciplinary team
Risk Factors for COVID-19-Related Hospitalization and Death in Patients With Cancer: The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS).
No full textImportance: Retrospective case series have identified having cancer and receiving treatment for cancer as risk factors for inferior COVID-19 outcomes.
Objective: To determine risk factors for hospitalization and death in patients with cancer with COVID-19 infection.
Design, setting, and participants: The National Cancer Institute COVID-19 in Cancer Patients Study (NCCAPS) is a prospective longitudinal natural history cohort study examining the impact of COVID-19 on patients with cancer. Adults were eligible within 14 days of an initial positive SARS-CoV-2 test result if they were receiving active treatment for cancer or had prior stem cell/bone marrow transplant or CAR T-cell treatment. The statistical analysis took place between September 2024 and April 2025.
Main outcomes and measures: The primary objective of the study was to determine patient factors, therapy types, and cancer types associated with COVID-19 severity, defined as hospitalization for or death from COVID-19 within 30 and 90 days after the first positive SARS-CoV-2 test result. Multivariable regressions were performed for COVID-19-specific hospitalization and mortality (proportional hazard and cause-specific hazard models).
Results: Of 1572 eligible adult patients (median [range] age, 60 [18-93] years; 840 female [53.4%]), 1066 (67.8%) had a solid tumor, with 683 (64.0%) having metastatic disease; breast (252 [23.6%]) and lung cancer (148 [13.9%]) were most common. At enrollment, 1013 patients (64.4%) were unvaccinated for SARS-CoV-2. COVID-19-related mortality at 90 days was 3.0% and did not increase at subsequent time points. The cumulative incidence of COVID-19-specific death in the first 90 days was highest in patients with lymphoma, intermediate in patients with acute leukemia and lung cancer, and lowest in patients with other solid tumors and other hematologic cancers. In multivariable analysis, receipt of chemotherapy (hazard ratio [HR], 1.97; 95% CI, 1.52-2.54) and baseline history of stroke, atrial fibrillation, or pulmonary embolism (HR, 1.78; 95% CI, 1.33-2.38) were associated with a higher risk of hospitalization. Vaccination prior to SARS-CoV-2 infection was associated with a lower risk of hospitalization (HR, 0.52; 95% CI, 0.38-0.70). Over 2 years of follow-up, there were 1739 cancer treatment disruptions, of which 881 (50.7%) were attributed to COVID-19, with most disruptions occurring within the first 30 days.
Conclusions and relevance: The results of this prospective cohort study showed that COVID-19 had a significant impact on patients with cancer, including hospitalization, treatment disruptions, and death
Multimodal evaluation of cerebrospinal fluid from breast cancer leptomeningeal metastases using circulating tumor cell detection, single-cell sequencing, and proteomics.
No full textBACKGROUND: Patients with human epidermal growth factor receptor 2 positive (HER2+) or triple-negative breast cancer are at higher risk than those with other breast cancer subtypes for developing brain metastases, including leptomeningeal metastases. Despite advances in the treatment of primary breast tumors, the prognosis of breast cancer patients with brain metastases remains poor. Frequent and sensitive monitoring of response to treatments is crucial to optimize treatments for brain metastases. Multimodal molecular analyses of cells in cerebrospinal fluid (CSF) may provide a less invasive approach than biopsy for monitoring disease in the central nervous system.
METHODS: A 41-year-old female with refractory leptomeningeal metastases from HER2 + breast cancer had serial sampling of cerebrospinal fluid (CSF) from an Ommaya reservoir prior to, and after, the addition of sacituzumab govitecan to her treatment regimen. Cytopathologic clinical analysis, circulating tumor cell enumeration, single-cell RNA sequencing, and cytokine profiling assays were performed on collected samples.
RESULTS: A reduction in CSF tumor cells and absence of HER2-expressing cells was observed following treatment, with MRI confirming decreased tumor size. Single-cell RNA sequencing revealed diverse tumor and immune cell populations in CSF, highlighting gene expression signatures associated with breast cancer and triple negative disease and dynamic changes in cellular composition throughout the course of treatment. Cytokine profiling identified increased pro-inflammatory cytokines post-treatment.
CONCLUSION: These findings highlight the potential utility of molecular profiling of CSF as an early indicator of treatment response and an approach for identifying resistance mechanisms and optimal combination therapies
Understaffed and overworked: The stark reality of acute care surgeon staffing in the United States, an Eastern Association for the Surgery of Trauma multicenter study.
No full textOBJECTIVES: Rightsizing the workforce to clinical demand requires a balance of work intensity, productivity, and a definition of clinical full-time equivalent (cFTE). We hypothesized a shortage of acute care surgeons based on a 204-shift per year (average, 17 per month) definition of a 1.0 cFTE established in our prior mixed-methods study (two service weeks plus five calls per month).
METHODS: This multicenter study used mixed methods, integrating clinical schedules (CY2022), work relative value units, and qualitative insights from semistructured interviews (July 2023 to June 2024). Schedules were converted to shifts (8-14 hours). Hospitals were short-staffed when shift demand exceeded supply based on each surgeon\u27s cFTE. Interviews explored clinical demand and staffing challenges. Descriptive analysis and a deductive-inductive thematic analysis were performed.
RESULTS: Forty Level I/II hospitals representing 412 acute care surgeons (287 cFTEs) from 25 states were included. Seventy-nine percent of hospitals were short-staffed. Compared with well-staffed hospitals, short-staffed hospitals had fewer cFTEs (6.5 [interquartile range (IQR), 3] vs. 8.6 [IQR, 3], p \u3c 0.05), a higher demand for clinical work (1,889 [IQR, 933] vs. 1,388 [IQR, 674] shifts, p = 0.05) and a higher work relative value unit/cFTE (8,779 vs. 7,456, p = 0.12). The aggregate clinical demand exceeded available surgeon capacity by 21% overall. Based on volume, a 1.0 cFTE is needed for every 285 (IQR, 169) trauma admissions. There was a deficit of 75 cFTEs across the centers. Key themes identified were related to the value of acute care surgery and balancing unpredictable demand, intensity, and efficiency.
CONCLUSION: There appears to be a shortage of acute care surgeons in the United States when a definition of 204 shifts per year cFTE is applied. Hospitals face significant financial and administrative barriers to workforce expansion despite the overabundance of clinical volume. Future research is needed to ascertain the effects of expanding the existing workforce on both clinical outcomes and surgeon well-being.
LEVEL OF EVIDENCE: Prognostic and Epidemiologic; Level III
Efficacy and safety of obeldesivir in low-risk, non-hospitalised patients with COVID-19 (OAKTREE): a phase 3, randomised, double-blind, placebo-controlled study.
No full textBackground: Obeldesivir is an oral nucleoside analogue prodrug antiviral that inhibits SARS-CoV-2 replication. We aimed to assess the efficacy, safety, and tolerability of obeldesivir for the treatment of COVID-19 in non-hospitalised individuals at low risk of progression to severe disease.
Methods: OAKTREE was a phase 3, randomised, double-blind, placebo-controlled trial in 107 centres (including research centres, primary care centres, and hospitals) in Japan and the USA. Low-risk, non-hospitalised adults and adolescents with mild-to-moderate COVID-19 were enrolled within 3 days of symptom onset. Eligible participants were randomly assigned 1:1 using permuted block randomisation (block size of four), stratified by historical completion of a primary COVID-19 vaccination series, to receive either oral obeldesivir 350 mg or matched placebo twice daily for 5 days. The primary efficacy endpoint was time to COVID-19 symptom alleviation by day 29, which was assessed in all randomly assigned participants who received one or more doses of study drug, had positive SARS-CoV-2 RT-PCR (per central laboratory testing) at baseline, and had COVID-19 symptom data (full analysis positive set). The primary safety endpoint was the incidence of adverse events and laboratory abnormalities and was assessed in all randomly assigned participants who received one or more doses of study drug. As a secondary endpoint we assessed change from baseline in nasal swab viral RNA copy number at day 5 in all randomly assigned participants who received one or more doses of study drug and had a quantifiable baseline value. This trial is registered with ClinicalTrials.gov, NCT05715528, and is complete.
Findings: Between Feb 13, 2023 and Oct 31, 2023, 1955 participants (1155 female and 800 male; 1698 White, 207 Black, 42 Asian, and eight Other) were randomly assigned and received at least one dose of either obeldesivir (n=979) or placebo (n=976). Overall, 1368 (70·0%) participants had completed a primary COVID-19 vaccination series and 1938 (99·6%) were seropositive for SARS-CoV-2 antibodies. There were 884 participants in each group in the full analysis positive set. Among those in the full analysis positive set who completed the symptom questionnaire (ie, who had COVID-19 symptom data; 879 obeldesivir, 882 placebo), median time to COVID-19 symptom alleviation was 5·9 days (95% CI 5·4-6·1) in the obeldesivir group and 6·0 days (5·8-6·3) in the placebo group (hazard ratio 1·099 [95% CI 0·997-1·211], p=0·068). The least-squares mean change from baseline in viral RNA copy number at day 5 was -2·13 log10 copies per mL (SE 0·04) and -1·95 log10 copies per mL (0·04) for the obeldesivir group (n=637) and placebo group (n=622), respectively, with a least-squares mean difference of -0·18 (95% CI -0·30 to -0·06) log10 copies per mL (p=0·0037). The safety profile was comparable between groups. 53 (5·4%) of 979 participants in the obeldesivir group and 56 (5·7%) of 976 participants in the placebo group had one or more treatment-emergent adverse events. 753 (77·5%) participants in the obeldesivir group and 757 (78·5%) participants in the placebo group had one or more graded laboratory abnormalities, most of which were grade 1 or 2.
Interpretation: Obeldesivir was generally safe and well tolerated, with greater reduction of SARS-CoV-2 viral RNA copy number versus placebo at day 5. However, obeldesivir did not significantly reduce time to symptom alleviation, possibly reflecting the challenges of assessing efficacy in this population in an era of high rates of vaccine-induced and natural immunity.
FUNDING: Gilead Sciences