Jacobs Institute of Women's Health
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Comparison of Timing of Definitive Pelvic Fixation in Pelvic Fracture Treated with Preperitoneal Pelvic Packing or Angioembolization
No full textBACKGROUND: Preperitoneal pelvic packing (PPP) and angioembolization (AE) are current hemostatic techniques in bleeding pelvic fracture patients. Concerns exist that PPP may delay definitive internal fixation of pelvic fractures. This study aims to determine whether PPP results in delayed internal fixation compared to AE. STUDY DESIGN: A retrospective cohort study was conducted using the Trauma Quality Improvement Program database from 2017 to 2021. Adults with isolated pelvic fractures requiring transfusion within 24 hours were included. Patients underwent internal fixation and received either PPP (n=90) or AE only (n=253). Inverse probability of treatment weighting was used to adjust for confounding variables. The primary outcome was time from admission to internal fixation; secondary outcomes included in-hospital mortality and hospital resource utilization. RESULTS: Time to definitive fixation was not significantly different between groups (PPP median 51.4 hours vs. AE median 37.5 hours; p=0.071). In-hospital mortality was higher in the PPP group (4.4% vs. 0.6%; p=0.009). The PPP group had longer ICU and hospital stays, extended mechanical ventilation duration, and higher rates of acute kidney injury and severe sepsis. No significant difference in transfusion volume within 4 hours was observed between the groups. CONCLUSIONS: PPP does not significantly delay definitive internal fixation. However, the implementation of PPP for patients with pelvic fractures may be associated with increased complications and hospital resource utilization compared to AE alone as a hemostatic measure
If We Build It, Why They Do Not Come? An American College of Surgeons National Quality Improvement Collaborative to Understand Barriers to Completion of Cancer Treatment
No full textPURPOSE: Many patients face barriers to cancer care, leading to disparities in cancer-specific outcomes. Specifically, missing multiple radiation treatments can be associated with increased locoregional recurrence. We sought to assess the frequency and reasons for missed radiotherapy among accredited cancer programs participating in a national quality improvement (QI) collaborative addressing barriers to care. METHODS: The Breaking Barriers National QI Collaborative conducted through the American College of Surgeons Cancer Programs enrolled 342 accredited cancer programs, prospectively recording patients scheduled for a 15-45-day course of radiotherapy over five separate, 60-day data collection periods (March-December 2023). Programs identified those who missed ≥three treatments, referred to as at risk of worse outcomes, and queried reasons for missed radiotherapy. Kruskal-Wallis tests assessed differences in rates of missed treatments. RESULTS: In total, 332 programs (97.1%) identified at-risk patients, totaling 5,221 patients who missed ≥three treatments. The median percentage of at-risk patients per program was 9.4% (IQR, 4.5-16.5). Programs located in the Northeast (median, 11.3% [IQR, 5.4-17.3]) had the highest proportion of at-risk patients (P = .014). Patients with rectal (13.0%) and gynecologic (11.4%) cancers were most frequently at risk (P \u3c .001). Overall, 91.0% of hospitals reported missed radiation treatments due to illness unrelated to treatment, 71.7% due to transportation, 54.2% due to conflicting appointments, and 53.0% due to no longer wishing to pursue treatment. CONCLUSION: Barriers to completing radiotherapy are prevalent among accredited cancer programs nationwide. Future work developing interventions in response to identified barriers in this national QI collaborative may be scalable to other areas of cancer care to improve outcomes
Plasma Biomarkers for Cerebral Amyloid Angiopathy and Implications for Amyloid-Related Imaging Abnormalities: A Comprehensive Review
No full textAnti-amyloid therapies (AATs) are increasingly being recognized as promising treatment options for Alzheimer\u27s disease (AD). Amyloid-related imaging abnormalities (ARIAs), small areas of edema and microbleeds in the brain presenting as abnormal signals in MRIs of the brain for patients with AD, are the most common side effects of AATs. While most ARIAs are asymptomatic, they can be associated with symptoms like nausea, headache, confusion, and gait instability and, less commonly, with more serious complications such as seizures and death. Cerebral amyloid angiopathy (CAA) has been found to be a major risk for ARIA development. The identification of sensitive and reliable non-invasive biomarkers for CAA has been an area of AD research over the years, but with the approval of AATs, this area has taken on a new urgency. This comprehensive review highlights several potential biomarkers, such as Aβ40, Aβ40/42, phosphorylated-tau217, neurofilament light chain, glial fibrillary acidic protein, secreted phosphoprotein 1, placental growth factor, triggering receptor expressed on myeloid cells 2, cluster of differentiation 163, proteomics, and microRNA. Identifying and staging CAA even before its consequences can be detected via neuroimaging are critical to allow clinicians to judiciously select appropriate candidates for AATs, stratify monitoring, properly manage therapeutic regimens for those experiencing symptomatic ARIAs, and optimize the treatment to achieve the best outcomes. Future studies can test potential plasma biomarkers in human beings and evaluate predictive values of individual markers for CAA severity
Relationship between incident cardiovascular disease and quality of life after a breast cancer diagnosis
No full textPURPOSE: Breast cancer survivors are at risk for both poor quality of life (QoL) and cardiovascular disease (CVD). This study examines whether incident CVD after breast cancer independently predicts QoL. METHODS: Using data from the Women\u27s Health Initiative, we included women who were diagnosed with invasive breast cancer during follow-up and free of prevalent CVD prior to breast cancer. CVD was defined as adjudicated coronary heart disease, heart failure, or stroke. Physical and mental QoL, measured by the SF-36 Physical and Mental Component Scores (PCS and MCS, respectively), were recorded after breast cancer. Poor PCS and MCS were defined as scores \u3c 40. We used adjusted time-dependent Cox proportional hazards models, accounting for time to CVD. RESULTS: Among 2912 BC survivors (mean age at BC diagnosis = 67), 1094 (37.6%) and 313 (10.7%) women had a post-breast cancer PCS and MCS score \u3c 40, respectively, at a median of 2.5 years. A higher proportion of women had poor PCS scores post-BC (37.5% vs. 19.2%, P \u3c 0.001) but not MCS (10.4% vs. 8.2%, P = 0.10). After adjustment for key covariates, incident CVD was associated with a 1.95-fold (95% CI 1.42, 2.67) greater risk of poor PCS scores (P \u3c 0.001), but was not associated with poor MCS (HR 1.23, 95% CI 0.57, 2.65, P = 0.59)). CONCLUSIONS: Incident CVD after breast cancer was associated with poor physical QoL but not mental QoL. IMPLICATIONS FOR CANCER SURVIVORS: This study highlights the importance of regular assessments of QoL and need for strategies to improve physical QoL in breast cancer survivors with CVD
Comments on: Cardiovascular Prognosis in Limb Ischemia Patients With Heart Failure and Systolic Dysfunction Following Major Amputation
No full textAssociations of late-life blood pressure with CERAD, Braak, and Thal: Findings from the National Alzheimer\u27s coordinating center neuropathology dataset
No full textMid-life high blood pressure (BP) is a risk factor for Alzheimer\u27s disease (AD). CERAD amyloid β (Aβ) plaques, Braak tau neurofibrillary tangles, and Thal Aβ plaque location are major scoring systems for quantifying neuropathological features of AD. We examined the association of late-life systolic BP (SBP) with CERAD, Braak, and Thal in the National Alzheimer\u27s Coordinating Center (NACC) Neuropathology Dataset. Of 1978 participants with data on CERAD, 762 had scores 0-1 (none to sparse) and 1216 had 2-3 (moderate to frequent). Of 1947 with data on Braak, 411 had stages 0-II (normal to mild) and 1536 had III-VI (moderately to very severe). Of 2132 with data on Thal, 438 had phases 0-I, 428 II-III, and 1266 IV-V. Using the mean of the last four SBP before death, SBP was categorized into \u3c120 (references), 120-139, and ≥140 mmHg. Age-sex-adjusted ORs (95% CIs) associated with SBP ≥140 mmHg for CERAD 2-3 and Braak III-VI were 1.37 (1.03, 1.83, P = 0.03) and 1.26 (0.89, 1.78, P = 0.20), respectively. Similar association was observed for Thal II-III and IV-V. These associations essentially remained unchanged after additional adjustment for APOE and Lewy Body pathology. These findings suggest that higher late-life SBP is associated with markers of presence and severity of neuropathological features of AD. Further studies with larger sample sizes are necessary to confirm the findings
Six Injections of Modified Adjuvanted PQ Grass Is Effective and Well-Tolerated in a Pivotal Phase III Trial
No full textBACKGROUND: PQ Grass 27600 SU (PQ Grass) cumulative dose is a pre-seasonal, six-injection, aluminium-free, modified subcutaneous immunotherapy product under development for the treatment of allergic rhinitis (AR). A pivotal Phase III randomised double-blind, placebo-controlled clinical trial was performed to evaluate the efficacy and safety of PQ Grass in subjects with seasonal AR. METHODS: An adaptive group sequential trial PQGrass306 (G306) with one pre-defined interim analysis was designed, using 2 parallel groups applying a 1:1 active versus placebo randomisation of patients aged 18-65. The primary efficacy endpoint was the EAACI (European Academy of Allergy and Clinical Immunology) Combined Symptom and Medication Score (EAACI-CSMS) averaged over the peak grass pollen season (GPS). RESULTS: 858 subjects were screened and 555 subjects were randomised. Based on the results of the pre-defined interim analysis, the trial was stopped for success showing superiority in favour of PQ Grass. The primary endpoint EAACI-CSMS (peak GPS) demonstrated a highly significant and clinically meaningful point difference of PQ Grass over placebo of -0.27 points (95% CI: -0.42 to -0.12), corresponding to a relative difference of -20.3% (p = 0.0005). Highly consistent and beneficial results were obtained for PQ Grass for all key secondary endpoints. Significant induction of blocking IgG4 and IgA antibody subclasses occurred. PQ Grass was well tolerated, and no unexpected safety signals occurred. CONCLUSIONS: This pivotal Phase III trial demonstrated a significant and clinically meaningful effect on the primary endpoint as well as highly consistent secondary endpoint results and a supportive safety profile
The Marriage of Computable Phenotypes With Machine Learning-A Pathway to Evidence-Based Care for Critically Ill Children
No full textAberrantly Expressed Mitochondrial Lipid Kinase, AGK, Activates JAK2-Histone H3 Axis and BCR Signal: A Mechanistic Study with Implication in CLL Therapy
No full textPURPOSE: Although the B-cell receptor (BCR) signal plays a critical role in chronic lymphocytic leukemia (CLL) cell survival and a target of current therapies (ibrutinib targets Bruton\u27s tyrosine kinase; idelalisib targets PI3Kδ), contribution of the cytokine-driven JAK2 pathway to the CLL cell-survival signaling network is largely undefined. EXPERIMENTAL DESIGN: Patients with CLL were enrolled to investigate expression/activation of JAK2 and acylglycerol kinase (AGK), and their functional implication in primary CLL cell survival. A series of biochemical and molecular biology assays were employed to uncover the underlying mechanism. RESULTS: We detected that compared with normal B cells, CLL cells aberrantly express constitutively active JAK2. Mechanistically, HSP90 forms a chaperoning complex with JAK2, resulting in its aberrant accumulation in CLL cells. We also discovered aberrant upregulation of a novel mitochondrial lipid kinase, AGK, which remains complexed with HSP90 in CLL cells activating JAK2. Although AGK is typically mitochondrial, we detected its nuclear localization in association with JAK2 in some CLL cells. Functionally, JAK2 phosphorylates its noncanonical substrate, histone H3(Y41), but not STAT3, activating transcription of diverse sets of genes in a patient-specific manner. Additionally, JAK2 activates the BCR signal in CLL cells via LYN/Bruton\u27s tyrosine kinase axis. Targeted inhibition of JAK2 as monotherapy, or in combination with the BCR inhibitors or venetoclax (a BCL2 inhibitor), induced apoptosis synergistically in CLL cells. CONCLUSIONS: These findings suggest that aberrantly expressed AGK activates JAK2, independent of cytokine, leading to activation of diverse sets of gene transcription in CLL cells. Combined targeting of JAK2 and BCR signals or BCL2 may be effective in some patients with CLL