To determine the effect of blood component ratios in massive transfusion (MT), we hypothesized that increased use of plasma and platelet to red blood cell (RBC) ratios would result in decreased early ...hemorrhagic death and this benefit would be sustained over the ensuing hospitalization.
Civilian guidelines for massive transfusion (MT > or =10 units of RBC in 24 hours) have typically recommend a 1:3 ratio of plasma:RBC, whereas optimal platelet:RBC ratios are unknown. Conversely, military data shows that a plasma:RBC ratio approaching 1:1 improves long term outcomes in MT combat casualties. There is little consensus on optimal platelet transfusions in either civilian or military practice. At present, the optimal combinations of plasma, platelet, and RBCs for MT in civilian patients is unclear.
Records of 467 MT trauma patients transported from the scene to 16 level 1 trauma centers between July 2005 and June 2006 were reviewed. One patient who died within 30 minutes of admission was excluded. Based on high and low plasma and platelet to RBC ratios, 4 groups were analyzed.
Among 466 MT patients, survival varied by center from 41% to 74%. Mean injury severity score varied by center from 22 to 40; the average of the center means was 33. The plasma:RBC ratio ranged from 0 to 2.89 (mean +/- SD: 0.56 +/- 0.35) and the platelets:RBC ratio ranged from 0 to 2.5 (0.55 +/- 0.50). Plasma and platelet to RBC ratios and injury severity score were predictors of death at 6 hours, 24 hours, and 30 days in multivariate logistic models. Thirty-day survival was increased in patients with high plasma:RBC ratio (> or =1:2) relative to those with low plasma:RBC ratio (<1:2) (low: 40.4% vs. high: 59.6%, P < 0.01). Similarly, 30-day survival was increased in patients with high platelet:RBC ratio (> or =1:2) relative to those with low platelet:RBC ratio (<1:2) (low: 40.1% vs. high: 59.9%, P < 0.01). The combination of high plasma and high platelet to RBC ratios were associated with decreased truncal hemorrhage, increased 6-hour, 24-hour, and 30-day survival, and increased intensive care unit, ventilator, and hospital-free days (P < 0.05), with no change in multiple organ failure deaths. Statistical modeling indicated that a clinical guideline with mean plasma:RBC ratio equal to 1:1 would encompass 98% of patients within the optimal 1:2 ratio.
Current transfusion practices and survival rates of MT patients vary widely among trauma centers. Conventional MT guidelines may underestimate the optimal plasma and platelet to RBC ratios. Survival in civilian MT patients is associated with increased plasma and platelet ratios. Massive transfusion practice guidelines should aim for a 1:1:1 ratio of plasma:platelets:RBCs.
Background
The primary purpose of this study was to histologically determine if there is a significant difference in new bone formation, residual graft material, and connective tissue/other when ...ridge preservation is accomplished using a bovine versus a porcine xenograft.
Methods
Forty‐four patients needing a single rooted tooth extraction and ridge preservation in preparation for dental implant placement were recruited in the study. After minimally traumatic tooth extraction, alveolar ridge dimensions were measured using a custom‐fabricated acrylic stent. Patients were then randomized 1:1 to receive ridge preservation using either bovine or porcine xenograft material. A trimmed dense polytetrafluoroethylene (d‐PTFE) membrane was overlaid on the graft material, the mucoperiosteal flaps were replaced, and the surgical site was sutured. After 18 to 20 weeks of wound healing, sites were surgically re‐entered, ridge dimensions were again measured using the previously fabricated acrylic stents and a bone core sample of the grafted site was harvested for histomorphometric analysis.
Results
Thirty eight of the 44 enrolled patients completed the study, 17 from the bovine group and 21 from the porcine group. Histologically, there were no statistically significant differences between the groups for mean percentage of vital bone formation (bovine = 36.21%, porcine = 31.27%, P = 0.49), residual graft material (bovine = 20.47%, porcine = 19.52%, P = 0.82) and connective tissue/other (bovine = 43.32%, porcine = 49.21%, P = 0.19). For secondary outcomes, there were no significant differences between the groups for mean change in buccal ridge height, lingual ridge height, and ridge width. However, a higher number of patients in the porcine group had additional grafting at the time of implant placement, either because of thin buccal plate or failure of implant stability.
Conclusion
The findings suggest that ridge preservation with porcine xenograft results in comparable histomorphometric outcomes and dimensional stability with bovine xenograft.
Background Probe-based confocal laser endomicroscopy (pCLE) allows real-time detection of neoplastic Barrett's esophagus (BE) tissue. However, the accuracy of pCLE in real time has not yet been ...extensively evaluated. Objective To compare the sensitivity and specificity of pCLE in addition to high-definition white-light endoscopy (HD-WLE) with HD-WLE alone for the detection of high-grade dysplasia (HGD) and early carcinoma (EC) in BE. Design International, prospective, multicenter, randomized, controlled trial. Setting Five tertiary referral centers. Patients A total of 101 consecutive BE patients presenting for surveillance or endoscopic treatment of HGD/EC. Interventions All patients were examined by HD-WLE, narrow-band imaging (NBI), and pCLE, and the findings were recorded before biopsy samples were obtained. The order of HD-WLE and NBI was randomized and performed by 2 independent, blinded endoscopists. All suspicious lesions on HD-WLE or NBI and 4-quadrant random locations were documented. These locations were examined by pCLE, and a presumptive diagnosis of benign or neoplastic (HGD/EC) tissue was made in real time. Finally, biopsies were taken from all locations and were reviewed by a central pathologist, blinded to endoscopic and pCLE data. Main Outcome Measurements Diagnostic characteristics of pCLE. Results The sensitivity and specificity for HD-WLE were 34.2% and 92.7%, respectively, compared with 68.3% and 87.8%, respectively, for HD-WLE or pCLE ( P = .002 and P < .001, respectively). The sensitivity and specificity for HD-WLE or NBI were 45.0% and 88.2%, respectively, compared with 75.8% and 84.2%, respectively, for HD-WLE, NBI, or pCLE ( P = .01 and P = .02, respectively). Use of pCLE in conjunction with HD-WLE and NBI enabled the identification of 2 and 1 additional HGD/EC patients compared with HD-WLE and HD-WLE or NBI, respectively, resulting in detection of all HGD/EC patients, although not statistically significant. Limitations Academic centers with enriched population. Conclusions pCLE combined with HD-WLE significantly improved the ability to detect neoplasia in BE patients compared with HD-WLE. This may allow better informed decisions to be made for the management and subsequent treatment of BE patients. (Clinical trial registration number: NCT00795184 .)
Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma affecting children and is often diagnosed with concurrent metastases. Unfortunately, few effective therapies have been discovered that ...improve the long-term survival rate for children with metastatic disease. Here we determined effectiveness of targeting the receptor tyrosine kinase, EphB4, in both alveolar and embryonal RMS either directly through the inhibitory antibody, VasG3, or indirectly by blocking both forward and reverse signaling of EphB4 binding to EphrinB2, cognate ligand of EphB4. Clinically, EphB4 expression in eRMS was correlated with longer survival. Experimentally, inhibition of EphB4 with VasG3 in both aRMS and eRMS orthotopic xenograft and allograft models failed to alter tumor progression. Inhibition of EphB4 forward signaling using soluble EphB4 protein fused with murine serum albumin failed to affect eRMS model tumor progression, but did moderately slow progression in murine aRMS. We conclude that inhibition of EphB4 signaling with these agents is not a viable monotherapy for rhabdomyosarcoma.
We reviewed published manuscripts from toxicology and epidemiology reporting harmful health effects and doses of persistent organic pollutants (POPs), published between 2000 and 2021. We found 42
, ...32
, and 74 epidemiological studies and abstracted the dose associated with harm in a common Molar unit. We hypothesized that the dose associated with harm would vary between animal and human studies. To test this hypothesis, for each of several POPs, we assessed the significance of variation in the dose associated with a harmful effect categorized as non-thyroid endocrine (NTE), developmental neurotoxicity (DNT), and Thyroid with study type (
, and Epidemiology) using a linear model after adjustment for basis (lipid weight, wet weight). We created a Calculated Safety Factor (CSF) defined as the toxicology dose divided by epidemiology dose needed to exhibit significant harm.
Significant differences were found between study types ranging from <1 to 5.0 orders of magnitude in the dose associated with harm. Our CSFs in lipid weight varied from 12.4 (95% confidence interval (CI) 3.3, 47) for NTE effects in Epidemiology relative to
studies to 6,244 (95% CI 2510, 15530) for DNT effects in Epidemiology relative to
in wet weight representing 12.4 to 6.2 thousand-fold more sensitivity in people relative to animals, and mechanistic models, respectively. In lipid weight, all CSF 95% CI lower bounds across effect categories were less than 6.5. CIs for CSFs ranged from less than one to four orders of magnitude for
, and two to five orders of magnitude for
vs. Epidemiology. A global CSF for all Epidemiology vs. all Toxicology was 104.6 (95% CI 72 to 152), significant at p<0.001.
Ewing sarcoma (EWS) is a malignant tumor arising in bone or soft tissue that occurs in adolescent and young adult patients as well as adults later in life. Although non-metastatic EWS is typically ...responsive to treatment when newly diagnosed, relapsed cases have an unmet need for which no standard treatment approach exists. Recent phase III clinical trials for EWS comparing 7 vs 5 chemotherapy drugs have failed to improve survival. To extend the durability of remission for EWS, we investigated 3 non-chemotherapy adjuvant therapy drug candidates to be combined with chemotherapy. The efficacy of these adjuvant drugs was investigated via anchorage-dependent growth assays, anchorage-independent soft-agar colony formation assays and EWS xenograft mouse models. Enoxacin and entinostat were the most effective adjuvant drug in both long-term in vitro and in vivo adjuvant studies. In the context that enoxacin is an FDA-approved antibiotic, and that entinostat is an investigational agent not yet FDA-approved, we propose enoxacin as an adjuvant drug for further preclinical and clinical investigation in EWS patients.
Rhabdomyosarcoma is the most commonly occurring soft-tissue sarcoma in childhood. Most rhabdomyosarcoma falls into one of two biologically distinct subgroups represented by alveolar or embryonal ...histology. The alveolar subtype harbors a translocation-mediated PAX3:FOXO1A fusion gene and has an extremely poor prognosis. However, tumor cells have heterogeneous expression for the fusion gene. Using a conditional genetic mouse model as well as human tumor cell lines, we show that that Pax3:Foxo1a expression is enriched in G2 and triggers a transcriptional program conducive to checkpoint adaptation under stress conditions such as irradiation in vitro and in vivo. Pax3:Foxo1a also tolerizes tumor cells to clinically-established chemotherapy agents and emerging molecularly-targeted agents. Thus, the surprisingly dynamic regulation of the Pax3:Foxo1a locus is a paradigm that has important implications for the way in which oncogenes are modeled in cancer cells.
Aging is a comorbidity of breast cancer suggesting that aging-associated transcriptome changes may promote breast cancer progression. However, the mechanism underlying the age effect on breast cancer ...remains poorly understood.
We analyzed transcriptomics of the matched normal breast tissues from the 82 breast cancer patients in The Cancer Genome Atlas (TCGA) dataset with linear regression for genes with age-associated expression that are not associated with menopause. We also analyzed differentially expressed genes between the paired tumor and non-tumor breast tissues in TCGA for the identification of age and breast cancer (ABC)-associated genes. A few of these genes were selected for further investigation of their malignancy-regulating activities with in vitro and in vivo assays.
We identified 148 upregulated and 189 downregulated genes during aging. Overlapping of tumor-associated genes between normal and tumor tissues with age-dependent genes resulted in 14 upregulated and 24 downregulated genes that were both age and breast cancer associated. These genes are predictive in relapse-free survival, indicative of their potential tumor promoting or suppressive functions, respectively. Knockdown of two upregulated genes (DYNLT3 and P4HA3) or overexpression of the downregulated ALX4 significantly reduced breast cancer cell proliferation, migration, and clonogenicity. Moreover, knockdown of P4HA3 reduced growth and metastasis whereas overexpression of ALX4 inhibited the growth of xenografted breast cancer cells in mice.
Our study suggests that transcriptome alterations during aging may contribute to breast tumorigenesis. DYNLT3, P4HA3, and ALX4 play significant roles in breast cancer progression.
Breast reconstruction plays a significant role in breast cancer treatment recovery. Introduction of the BREAST-Q questionnaire has facilitated quantifying patient-reported quality-of-life measures, ...promoting improved evidence-based clinical practice. Information regarding the effects of body mass index on patient-reported outcomes and health-related quality of life is significantly lacking.
Consecutive deep inferior epigastric perforator (DIEP) flap breast reconstruction patients prospectively completed BREAST-Q questionnaires preoperatively and at two points postoperatively. The first (postoperative time point A) and second (postoperative time point B) postoperative questionnaires were completed 1 month postoperatively and following breast revision, respectively. Postoperative flap and donor-site complications were recorded prospectively. BREAST-Q scores were compared at all time points and stratified by body mass index group (≤25, >25 to 29.9, 30 to 34.9, and ≥35 kg/m).
Between July of 2012 and August of 2016, 73 patients underwent 130 DIEP flap breast reconstructions. Breast satisfaction and psychosocial and sexual well-being scores increased significantly postoperatively. Chest and abdominal physical well-being scores returned to baseline levels by postoperative point B. Preoperatively, stratified by body mass index, breast satisfaction and psychosocial well-being scores were significantly lower among patients with body mass index of 35 or higher and of more than 30, respectively. After reconstruction, not only were breast satisfaction, psychosocial, and sexual well-being scores significantly improved in all body mass index groups versus baseline, but also between-body mass index group differences were no longer present. Outcome satisfaction, flap, and donor-site morbidity were similar irrespective of body mass index.
Patient-reported outcomes demonstrate significant improvements in breast satisfaction and psychosocial and sexual well-being among patients following DIEP flap reconstruction. Preoperative differences in quality-of-life scores were improved in patients with obesity (body mass index ≥30 kg/m).
Risk, II.
Background: The Air Force Health Study was launched in 1980 as part of a Federal effort to resolve the Agent Orange issue. Objectives: To study diabetes and cancer with additional adjustment for days ...of spraying, calendar period of service, and time spent in Southeast Asia (SEA). Methods: This was a longitudinal study of veterans of Operation Ranch Hand, the unit responsible for spraying Agent Orange and other 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-contaminated herbicides in Vietnam from 1962 to 1971. Results: Associations between TCDD and diabetes and between TCDD and cancer in Ranch Hand veterans are strengthened after adjustment for calendar period of service, days of spraying, and, for cancer, time spent in SEA. Conclusions: Calendar period of service, days of spraying, and time spent in SEA are important confounders in the Air Force Health Study.
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