Citations

Lower body negative pressure (LBNP) is often used to simulate blood loss in humans. However, it is unknown if the effects of actual blood loss (BL) on cerebral blood flow regulation is analogous to simulated blood loss during LBNP. Nine healthy men (32±6 y) were studied at baseline, during 3 levels of LBNP (5 min each at ‐15, ‐30, ‐45 mmHg), and during 3 levels of blood loss (5 min each at 333, 667, 1000 mL). LBNP and BL conditions were randomized. Intra‐arterial mean arterial pressure (MAP) was similar during LBNP compared with BL (p>0.20). Central venous pressure (CVP; 2.8±0.7 vs. 4.0±0.8, 1.2±0.6 vs. 3.5±0.8, 0.2±0.9 vs. 2.1±0.9 mmHg for level 1, 2, and 3; p<0.01) and stroke volume (71±4 vs. 80±3, 60±3 vs. 74±3, 51±2 vs. 68±4 mL for level 1, 2, and 3; p<0.01) were lower during LBNP compared with BL. Despite differences in CVP, middle cerebral artery velocity (MCAv) and cerebrovascular conductance index (CVCi) were similar between LBNP and BL at each level (MCAv at level 3: 62±6 vs. 66±5 cm/s; p=0.37; CVCi at level 3: 0.72±0.05 vs. 0.73±0.05 cm/s/mmHg; p=0.29). Furthermore, the slope of the relationship between MAP and MCAv was not different between LBNP and BL (1.06 vs. 1.07 cm/s/mmHg). Our results suggest that the cerebral hemodynamic responses to LBNP are similar to actual blood loss. Grant Funding Source : Supported by U.S. Army MRMC Combat Casualty Care Research Program Grant # W81XWH‐11‐1‐0823

The relationship between mean arterial pressure (MAP), muscle sympathetic nerve activity (MSNA), and total peripheral resistance (TPR) is altered in young women versus men and postmenopausal women due to endogenous sex hormone differences. Exogenous sex hormones in the form of oral contraceptive pills (OCPs) may further affect this relationship. We performed a retrospective review of 136 premenopausal women in whom MSNA and arterial pressure were measured, including 78 women with natural menstrual cycles in the early follicular phase (26±1 yr) and 58 women in the placebo phase of OCPs (24±1 yr). TPR and cardiac output (CO) were measured in a subset of women in whom continuous intra‐arterial blood pressure was recorded. Compared to those with natural menstrual cycles, women on OCPs had greater MAP (89±1 vs. 84±1 mmHg, p<0.01) and tended to have lower MSNA (15±1 vs. 18±1 bursts/100 heart beats, p=0.06). MAP and MSNA were positively correlated (r=0.22, p<0.05), TPR and MSNA were positively associated (r=0.41, p<0.05) and CO and MSNA (r=‐0.44, p<0.05) were inversely associated in naturally cycling women (n=26) but not in women on OCPs (r=0.15, r=0.11, r=‐0.01, respectively; p>0.05; n=38). In contrast to naturally cycling women, there appears to be no relationship between MSNA and hemodynamics in women on OCPs, suggesting that these women may regulate their blood pressure differently than women. Grant Funding Source : Supported by NIH

Abstract Background Smoking is associated with colorectal cancer (CRC) risk. Previous studies suggested this association may be restricted to certain molecular subtypes of CRC, but large-scale comprehensive analysis is lacking. Methods A total of 9789 CRC cases and 11 231 controls of European ancestry from 11 observational studies were included. We harmonized smoking variables across studies and derived sex study–specific quartiles of pack-years of smoking for analysis. Four somatic colorectal tumor markers were assessed individually and in combination, including BRAF mutation, KRAS mutation, CpG island methylator phenotype (CIMP), and microsatellite instability (MSI) status. A multinomial logistic regression analysis was used to assess the association between smoking and risk of CRC subtypes by molecular characteristics, adjusting for age, sex, and study. All statistical tests were 2-sided and adjusted for Bonferroni correction. Results Heavier smoking was associated with higher risk of CRC overall and stratified by individual markers (Ptrend &lt; .001). The associations differed statistically significantly between all molecular subtypes, which was the most statistically significant for CIMP and BRAF. Compared with never-smokers, smokers in the fourth quartile of pack-years had a 90% higher risk of CIMP-positive CRC (odds ratio = 1.90, 95% confidence interval = 1.60 to 2.26) but only 35% higher risk for CIMP-negative CRC (odds ratio = 1.35, 95% confidence interval = 1.22 to 1.49; Pdifference = 2.1 x 10-6). The association was also stronger in tumors that were CIMP positive, MSI high, or KRAS wild type when combined (Pdifference &lt; .001). Conclusion Smoking was associated with differential risk of CRC subtypes defined by molecular characteristics. Heavier smokers had particularly higher risk of CRC subtypes that were CIMP positive and MSI high in combination, suggesting that smoking may be involved in the development of colorectal tumors via the serrated pathway.

Getting around the blood–brain barrier The meninges comprise three membranes that surround and protect the central nervous system (CNS). Recent studies have noted the existence of myeloid cells resident there, but little is known about their ontogeny and function, and whether other meningeal immune cell populations have important roles remains unclear (see the Perspective by Nguyen and Kubes). Cugurra et al. found in mice that a large proportion of continuously replenished myeloid cells in the dura mater are not blood derived, but rather transit from cranial bone marrow through specialized channels. In models of CNS injury and neuroinflammation, the authors demonstrated that these myeloid cells have an immunoregulatory phenotype compared with their more inflammatory blood-derived counterparts. Similarly, Brioschi et al. show that the meninges host B cells that are also derived from skull bone marrow, mature locally, and likely acquire a tolerogenic phenotype. They further found that the brains of aging mice are infiltrated by a second population of age-associated B cells, which come from the periphery and may differentiate into autoantibody-secreting plasma cells after encountering CNS antigens. Together, these two studies may inform future treatment of neurological diseases. Science , abf7844, abf9277, this issue p. eabf7844 , p. eabf9277 ; see also abj8183, p. 396

Introduction: Thrombo-inflammatory syndrome (TIS) characterized by a pathophysiological state of hypercoagulability, heightened platelet function, and inflammation has been observed in patients with acute myocardial infarction, and HIV. Hypothesis: The incidence of TIS is observed at a high rate in COVID-19 patients and worsens with symptom severity Methods: Blood samples from COVID-19 positive hospitalized patients (n=24) was collected for coagulation and platelet function analysis using point-of-care thromboelastography, TEG6s (Haemonetics, Corp) and routine labs were collected to measure markers of inflammation, coagulation, and organ damage (Table). Disease severity was grouped according to oxygen supplementation requirements and comparisons were made using unpaired t-test and chi-squared tests. Thrombo-inflammation was defined as the presence of both hypercoagulability by TEG [Clot initiation (R) < 4.6, fibrin clot strength (FCS) >32mm, and platelet fibrin clot strength (PFCS) >69] and D-dimer >ULN. Results: Ninety- five percent of COVID positive patients had at least one co-morbidity with the incidence of hypertension (71%), diabetes (50%), and obesity (42%) being the most frequent. A total of 63% (16/24) of patients had TIS, the incidence was significantly increased with escalating disease severity (p=0.03). A significant stepwise (p<0.05) increase in FCS, D-Dimer, WBC count, lactate dehydrogenase, and procalcitonin was observed with worsening respiratory function (table). MA-ADP a measure of platelet function was in the high normal range for 81 % of patients. Conclusions: Thrombo-inflammatory is observed with most COVID patients, importantly heightened platelet function is a component of the syndrome and raises the question if antiplatelet therapy is needed in select COVID patients. Selective assessments with TEG6s may facilitate antithrombotic personalization.

Abstract Purpose: Chemoradiotherapy for locally advanced cervical cancer fails in over a third of patients. Biomarkers with therapeutic implications are therefore needed. We investigated the relationship between an established prognostic marker, maximum standardized uptake value (SUVmax) on 18F-fluorodeoxyglucose positron emission tomography, and the inflammatory and immune state of cervical cancers. Experimental Design: An SUVmax most prognostic for freedom from progression (FFP) was identified and compared with known prognostic clinical variables in a cohort of 318 patients treated with definitive radiation with prospectively collected clinical data. Gene set enrichment analysis (GSEA) and CIBERSORT of whole-transcriptome data from 68 patients were used to identify biological pathways and immune cell subpopulations associated with high SUVmax. IHC using a tissue microarray (TMA, N = 82) was used to validate the CIBERSORT findings. The impact of macrophages on cervical cancer glucose metabolism was investigated in coculture experiments. Results: SUVmax &lt;11.4 was most prognostic for FFP (P = 0.001). The GSEA showed that high SUVmax is associated with increased gene expression of inflammatory pathways, including JAK/STAT3 signaling. CIBERSORT and CD68 staining of the TMA showed high SUVmax tumors are characterized by a monocyte-predominant immune infiltrate. Coculture of cervical cancer cells with macrophages or macrophage-conditioned media altered glucose uptake, and IL6 and JAK/STAT3 signaling contribute to this effect. Conclusions: SUVmax is a prognostic marker in cervical cancer that is associated with activation of inflammatory pathways and tumor infiltration of myeloid-derived immune cells, particularly macrophages. Macrophages contribute to changes in cervical cancer glucose metabolism. See related commentary by Williamson et al., p. 4136

AbstractBackgroundThe management of achalasia has improved due to diagnostic and therapeutic innovations. However, variability in care delivery remains and no established measures defining quality of care for this population exist. We aimed to use formal methodology to establish quality indicators for achalasia patients.MethodsQuality indicator concepts were identified from the literature, consensus guidelines and clinical experts. Using RAND/University of California, Los Angeles (UCLA) Appropriateness Method, experts in achalasia independently ranked proposed concepts in a two‐round modified Delphi process based on 1) importance, 2) scientific acceptability, 3) usability, and 4) feasibility. Highly valid measures required strict agreement (≧ 80% of panelists) in the range of 7–9 for across all four categories.Key ResultsThere were 17 experts who rated 26 proposed quality indicator topics. In round one, 2 (8%) quality measures were rated valid. In round two, 19 measures were modified based on panel suggestions, and experts rated 10 (53%) of these measures as valid, resulting in a total of 12 quality indicators. Two measures pertained to patient education and five to diagnosis, including discussing treatment options with risk and benefits and using the most recent version of the Chicago Classification to define achalasia phenotypes, respectively. Other indicators pertained to treatment options, such as the use of botulinum toxin for those not considered surgical candidates and management of reflux following achalasia treatment.Conclusions & InferencesUsing a robust methodology, achalasia quality indicators were identified, which can form the basis for establishing quality gaps and generating fully specified quality measures.