19043 research outputs found
Sort by
A Prospective, Observational Study of Non-Invasive Venous Waveform Analysis (NIVA) for the Detection of Acute Low Volume Blood Loss in Humans
No full textBackground: Accurate non-invasive monitoring for the diagnosis of hemorrhage is an unmet need in acute care settings. Non-Invasive Venous waveform Analysis (NIVA) has demonstrated significant sensitivity in detecting acute hemorrhage with 8–10 % blood volume loss. To determine whether NIVA can accurately and non-invasively detect lower volumes of blood loss, we performed a prospective observational study using a digital blood volume monitor at an American Red Cross (ARC) donation center to assess NIVA\u27s performance at lower blood volume loss. Methods: Venous waveforms were successfully captured in 33 ARC-approved patients. Waveforms were recorded for the duration of whole blood donation and then transformed from the time domain to the frequency domain. The ratiometric power contribution of the cardiac frequencies was used to calculate a representative volume status value, the IntraVAscular Number (IVAN). Results: A significant decrease in the IVAN output was observed after just 200 mL (3–4 % blood volume) of whole blood donation (p \u3c 0.05). The ROC curve demonstrated an Area Under the Curve (AUC) of 0.65 for the ability of delta IVAN to detect 200 mL of blood loss. The Receiver Operating Characteristic (ROC) curve demonstrated an AUC of 0.91 for the ability of delta IVAN to detect 500 mL of blood loss. Conclusion: There remains a large unmet need for accurate and timely detection of acute hemorrhage. This study supports the potential application of NIVA in the detection of acute low-volume human blood loss. NIVA is a novel technology that uses previously undetectable low-amplitude venous signals of the cardiac pulse, which may prove useful for more accurate and early detection of acute hemorrhage
Natural Variation of the Streptococcal Group a Carbohydrate Biosynthesis Genes Impacts Host–Pathogen Interaction
No full textStreptococcus pyogenes is a leading cause of infection-related mortality in humans globally. The characteristic cell wallanchored group A carbohydrate (GAC) is expressed by all S. pyogenes strains and consists of a polyrhamnose backbone with alternating N-acetylglucosamine (GlcNAc) side chains, of which 25% are decorated with glycerol phosphate (GroP). The genes in the gacA-L cluster are critical for GAC biosynthesis, with gacH-L being responsible for the characteristic GlcNAc–GroP decoration, which confers the agglutination in rapid test diagnostic assays and contributes to S. pyogenes pathogenicity. Historical research papers described S. pyogenes isolates, so-called A-variant strains, that lost the characteristic GlcNAc side chain following serial animal passage. Genomic analysis of a single viable historic parent/A-variant strain pair revealed a premature inactivating stop codon in gacI, explaining the described loss of the GlcNAc side chain. Subsequently, we analysed the genetic variation of the 12 gacA-L genes in a collection of 2021 S. pyogenes genome sequences. Although all gac genes (gacA-L) displayed genetic variation, we only identified 26 isolates (1.3%) with a premature stop codon in one of the gac genes. Twelve out of 26 (46%) isolates contained a premature stop codon in gacH, which encodes the enzyme responsible for the GroP modification. To study the functional consequences of the different premature stop codons for GacH function, we plasmid-expressed three gacH variants in a S. pyogenes gacH-deficient strain. Cell wall analysis confirmed GacH loss of function for the studied gacH variants through the significant reduction of GAC GroP, complete resistance to killing by the human bactericidal enzyme group IIA-secreted phospholipase and susceptibility to zinc toxicity. Overall, our data provide a comprehensive overview of the genetic variation of the gacA-L cluster in a global population of S. pyogenes strains and the functional consequences of rare inactivating mutations in gacH for host interaction
Chimeric Antigen Receptor T-Cell Therapy for High-Grade B-Cell Lymphoma NOS
No full textCD19 chimeric antigen receptor T-cell (CAR-T) therapy is a pivotal part of the treatment algorithm for large B-cell lymphoma (LBCL) in the second- and third-line settings based on numerous clinical trials. However, these studies included very few patients with a diagnosis of high-grade B-cell lymphoma, not otherwise specified (HGBCL-NOS) and it is unclear if outcomes are similar to those observed with more common LBCL histologies. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, we identified 111 HGBCL-NOS patients who received CAR-T therapy. The cytokine release syndrome (CRS) rate was 74% (7.7% grade 3+), median onset was 4 days (1–17) and immune effector cell-associated neurotoxicity syndrome rate was 45.2% (22.6% grade 3+), median onset was 7 days (1–17). At 2 years post-CAR-T infusion, the probability of overall survival and progression-free survival were 41.6% and 28.7% respectively. The 2-year non-relapse mortality and relapse/progression were 3.1% (95% confidence interval [CI]: 0.6–7.6) and 68.1% (95% CI: 57.9–77.6) respectively. Our analysis illustrates that patients with HGBCL-NOS represent a particularly difficult group to treat, even with CAR-T therapy. We observed that one third of patients achieved a durable response; however, the overall results were less favourable, with lower overall response rate, overall survival and progression-free survival as compared to published reports on LBCL
CD19 CAR T-Cell Therapy for Primary Mediastinal Large B-Cell Lymphoma: A CIBMTR Analysis
No full textT cells engineered with CD19-directed chimeric antigen receptors (CD19 CAR) T cells have become standard treatment for patients with high risk, relapsed or refractory (R/R) large B-cell lymphomas (LBCL). However, outcomes in patients with rare subsets of LBCL, such as primary mediastinal large B-cell lymphoma (PBMCL), have not been well characterized. The impact of prior immune checkpoint inhibitor (ICI) treatment, commonly used to treat R/R PMBCL, is also unknown. To address these gaps, we retrospectively analyzed CIBMTR registry data including PMBCL patients undergoing CD19 CAR T-cell therapy per standard-of-care. A total of 135 PMBCL adults from 66 centers were included. Median age at the time of CAR T-cell therapy was 32. Thirty-nine patients (28.9%) had received an ICI prior to CAR T-cell therapy. The best overall and complete response (CR) rates after CD19 CAR T-cell therapy were 79% and 67.7%, respectively. The 2-year progression-free (PFS) and overall survival (OS) were 58.6% (95% CI, 49.7–67.3) and 80.8% (95% CI, 72.6–87.8), respectively. The 2-year cumulative incidence (CI) of relapse and non-relapse mortality (NRM) were 36% (95% CI, 27.8–44.7) and 5.4% (95% CI, 1.9–10.5), respectively. We observed grade ≥ 3 CRS and ICANS in 6.1% and 14.7%, respectively. Prior ICI exposure was associated with lower 2-year CI of relapse (ICI-exposed, 21.7%; ICI-naïve, 41.6%; p = 0.03) and higher 2-year NRM (ICI-exposed, 11.7%; ICI-naïve, 2.8%; p = 0.03). We could not confirm statistically different PFS (p = 0.19) or OS (p = 0.26) between ICI-exposed and ICI-naïve patients. CD19 CAR T-cell therapy led to high rates of durable responses in PMBCL patients with low rates of severe toxicities
Maternal Undernourishment Impairs Murine Placental Development During Pregnancy
No full textBackground: Maternal undernourishment (MUN) is a public health issue in developed and underdeveloped countries. There is a wide range of causes, from poor access to nutrition to hyperemesis gravidarum. This condition can adversely affect the development of the placenta, the critical interface between mother and fetus, producing adverse outcomes such as anemia, hemorrhage, developmental delays, and low birth weight (LBW) neonates. Methods: We use a murine undernourishment model to examine the consequences of MUN on the placenta at the whole organ and trophoblast (extraembryonic cells that form the placenta) levels. Pregnant dams of this model consumed a combined reduced protein and caloric diet during gestation, resulting in the generation of LBW offspring. We examined placental vascularization (immunostaining), vascular reactivity (myography), and blood perfusion (laser-Doppler flowmetry). We further examined drivers of placental pathology during MUN in both whole placenta and primary trophoblast cells, such as oxidative stress (including mitochondrial), on trophoblast quantity, apoptosis, proliferation, and differentiation. Therapeutic drugs were also investigated to elucidate the pathways involved and as possible interventions. Results: Analysis revealed that MUN reduced placental weight, altered the labyrinth/junctional zone ratio, and compromised overall trophoblast integrity and pool size. Increased oxidative stress production and dysregulated endogenous antioxidant mechanisms contribute to the associated impairments in the MUN placenta. Uterine blood flow, umbilical vein vasoreactivity, placental vascularization, and placental efficiency are also hindered, effects modulated by oxidative stress, including that produced by mitochondrial and toll-like receptor 4-sensitive pathways. Conclusions: MUN upregulates oxidative stress in the placenta, an effect that consequently reduces trophoblast pools while impairing placental development and vascular function. Our study also implicates mitochondrial superoxide production and TLR4 in the detrimental impact of MUN on placental vascular function and development while identifying therapeutic agents as possible add-on interventions
Improved Embryo Yield in Repeat IVF Cycles Following Suboptimal Euploid Embryo Yield: A Potential Effect of Regression to the Mean
No full textBeyond Capacity: An EAST Multicenter Mixed-Methods Study Exploring Surgeon Perceptions on Patient Ratios in Acute Care Surgery
No full textBackground Optimal provider-to-patient (PtP) ratios in acute care surgery (ACS) remain undefined despite their importance for care quality and provider sustainability. This study aimed to understand surgeon perspectives on maximum ideal ratios across trauma, emergency general surgery (EGS) and surgical intensive care unit (SICU) services. Methods This multicenter mixed-methods study combined quantitative surveys and semistructured interviews with ACS surgeons at level I/II trauma centers across the USA (1 August 2023–19 April 2024). Service line census data were also collected. Interviews were recorded, transcribed and qualitative analysis performed; surveys were analyzed with descriptive statistics. Results Fifty-two interviews were completed. Survey response rate was 50.3% (212/421 eligible division leadership and faculty) from 40 centers across 24 states. The perceived maximum safe patient load for trauma and EGS was \u3c20 patients when working independently, and up to 40 patients with full team support. SICU ratios were lower with most reporting ≤10 patients for independent coverage and ≤20 with team support. Regarding appropriate patient loads for junior residents and advanced practice providers, most respondents recommended ≤10 patients for trauma/EGS and ≤7 for SICU. For senior residents, most recommended ≤13 patients for trauma/EGS and ≤7 for SICU. Notably, 72% of centers exceeded their own leadership-recommended maximums for at least one service line. Qualitative analysis revealed patient acuity, team experience and competing demands as key workload modulators, with concerns about care quality degradation and burnout at higher ratios. Conclusions This study establishes potential upper threshold benchmarks for ACS PtP ratios with strong agreement across institutions. Division leadership should consider developing staffing models that account for patient acuity and service complexity while implementing escalation protocols for sustained high workloads. Current practices frequently exceed maximum ideal ratios, highlighting the need for evidence-based staffing guidelines that balance financial constraints with mounting evidence linking workload intensity and density to adverse outcomes. Level of evidence IV
