Logistics of managing a trauma whole blood inventory in a civilian level 1 trauma center.

BACKGROUND: Institutional data on initiating and maintaining a low-titer O positive whole blood (LTOWB) inventory for the civilian trauma sector may help other institutions start a LTOWB program. This study from a level 1 trauma center with a hospital-based donor center highlights challenges faced during the collection, maintenance, and utilization of LTOWB. STUDY DESIGN AND METHODS: Male O positive donors with low (≤1:100) anti-A and anti-B antibody titers were recruited for LTOWB collection. The daily inventory goal of 4 LTOWB units was kept in the emergency department refrigerator and transfused to adult male trauma patients. Unused units older than 10 days were reprocessed into packed red blood cells. RESULTS: Of 900 donors screened, 61% qualified and 52% of eligible donors provided a collective total of 505 LTOWB units over 2.5 years. The number of collected units directly correlated with the availability of inventory; 42% of the units were transfused, 54% were reprocessed, and 4% were discarded. The inventory goal was maintained for 56% of the year 2018 and 83% of the year 2019. Over these 2 years, 52% of patients had their transfusion needs fully met, 41% had their needs partially met, and 6.5% did not have their needs met. DISCUSSION: Initial challenges to LTOWB implementation were inventory shortages, low utilization rates, and failure to meet clinical demand. Proposed solutions include allowing for a higher yet safe titer, extending shelf life, expanding the donor pool, identifying barriers to utilization, and permitting use in female trauma patients beyond childbearing age.

Different factors limit early- and late-season windows of opportunity for monarch development.

Seasonal windows of opportunity are intervals within a year that provide improved prospects for growth, survival, or reproduction. However, few studies have sufficient temporal resolution to examine how multiple factors combine to constrain the seasonal timing and extent of developmental opportunities. Here, we document seasonal changes in milkweed (Asclepias fascicularis)-monarch (Danaus plexippus) interactions with high resolution throughout the last three breeding seasons prior to a precipitous single-year decline in the western monarch population. Our results show early- and late-season windows of opportunity for monarch recruitment that were constrained by different combinations of factors. Early-season windows of opportunity were characterized by high egg densities and low survival on a select subset of host plants, consistent with the hypothesis that early-spring migrant female monarchs select earlier-emerging plants to balance a seasonal trade-off between increasing host plant quantity and decreasing host plant quality. Late-season windows of opportunity were coincident with the initiation of host plant senescence, and caterpillar success was negatively correlated with heatwave exposure, consistent with the hypothesis that late-season windows were constrained by plant defense traits and thermal stress. Throughout this study, climatic and microclimatic variations played a foundational role in the timing and success of monarch developmental windows by affecting bottom-up, top-down, and abiotic limitations. More exposed microclimates were associated with higher developmental success during cooler conditions, and more shaded microclimates were associated with higher developmental success during warmer conditions, suggesting that habitat heterogeneity could buffer the effects of climatic variation. Together, these findings show an important dimension of seasonal change in milkweed-monarch interactions and illustrate how different biotic and abiotic factors can limit the developmental success of monarchs across the breeding season. These results also suggest the potential for seasonal sequences of favorable or unfavorable conditions across the breeding range to strongly affect monarch population dynamics.

A pilot study of stored low titer group O whole blood + component therapy versus component therapy only for civilian trauma patients.

BACKGROUND: This pilot assessed transfusion requirements during resuscitation with whole blood followed by standard component therapy (CT) versus CT alone, during a change in practice at a large urban Level I trauma center. METHODS: This was a single-center prospective cohort pilot study. Male trauma patients received up to 4 units of cold-stored low anti-A, anti-B group O whole blood (LTOWB) as initial resuscitation followed by CT as needed (LTOWB + CT). A control group consisting of women and men who presented when LTOWB was unavailable, received CT only (CT group). Exclusion criteria included antiplatelet or anticoagulant medication and death within 24 hours. The primary outcome was total transfusion volume at 24 hours. Secondary outcomes were mortality, morbidity, and intensive care unit- and hospital-free days. RESULTS: Thirty-eight patients received LTOWB, with a median of 2.0 (interquartile range [IQR] 1.0-3.0) units of LTOWB transfused. Thirty-two patients received CT only. At 24 hours after presentation, the LTOWB +CT group had received a median of 2,138 mL (IQR, 1,275-3,325 mL) of all blood products. The median for the CT group was 4,225 mL (IQR, 1,900-5,425 mL; p = 0.06) in unadjusted analysis. When adjusted for Injury Severity Score, sex, and positive Focused Assessment with Sonography for Trauma, LTOWB +CT group patients received 3307 mL of blood products, and CT group patients received 3,260 mL in the first 24 hours (p = 0.95). The adjusted median ratio of plasma to red cells transfused was higher in the LTOWB + CT group (0.85 vs. 0.63 at 24 hours after admission; p = 0.043. Adjusted mortality was 4.4% in the LTOWB + CT group, and 11.7% in the CT group (p = 0.19), with similar complications, intensive care unit-, and hospital-free days in both groups. CONCLUSION: Beginning resuscitation with LTOWB results in equivalent outcomes compared with resuscitation with CT only. LEVEL OF EVIDENCE: Therapeutic (Prospective study with 1 negative criterion, limited control of confounding factors), level III.

Discovery of AZD8154, a Dual PI3Kγδ Inhibitor for the Treatment of Asthma.

Starting from our previously described PI3Kγ inhibitors, we describe the exploration of structure-activity relationships that led to the discovery of highly potent dual PI3Kγδ inhibitors. We explored changes in two positions of the molecules, including macrocyclization, but ultimately identified a simpler series with the desired potency profile that had suitable physicochemical properties for inhalation. We were able to demonstrate efficacy in a rat ovalbumin challenge model of allergic asthma and in cells derived from asthmatic patients. The optimized compound, AZD8154, has a long duration of action in the lung and low systemic exposure coupled with high selectivity against off-targets.

Measuring trade-offs that matter: assessing the impact of a new electronic cross-match policy on the turnaround time and the cross-match workload efficiency.

BACKGROUND: Our traditional cross-match (XM) policy generated a significant number of XM units that were never issued. To minimize the unnecessary XM workload, we proposed a new policy where orders eligible for the electronic XM (EXM) are pended until orders to issue red blood cells (RBCs) are received. To address concerns that this new policy might unduly delay blood availability, we conducted a study to assess whether the new policy was noninferior to the traditional policy with regard to the turnaround time (TAT). STUDY DESIGN AND METHODS: We monitored the TAT and XM workload efficiency (XM-to-issue [C : I] ratio) for a total of 8 weeks split between the two policies' periods. The primary outcome was the proportion of RBC issue requests that was turned around in less than 12 minutes. RESULTS: Fifty percent (1133 of 2265) of issue requests were turned around in 12 minutes or less under the traditional policy compared to 43.9% (975 of 2223) under the new policy (absolute difference of 6.1%; 95% confidence interval [CI], 3.2%-9.1%; p < 0.001). The adjusted overall median TAT was slower by 1 minute (13 min vs. 14 min, p < 0.001) but the adjusted C : I ratio was better (1.00 vs. 1.15; p < 0.001) under the new policy. CONCLUSION: Our study showed that the impact of the new policy on the TAT was not inferior to the traditional policy. Since the median TAT of 14 minutes under the new policy met the published benchmarks, the trade-off between delays in the TAT and efficiency gains in the XM workload remained acceptable for patient care.

Immunoglobulin M red blood cell alloantibodies are frequently adsorbed by rabbit erythrocyte stroma.

BACKGROUND: Rabbit erythrocyte stroma (RESt, Immucor) adsorption is often used to remove cold autoantibodies from patient samples to facilitate detection of underlying alloantibodies. However, reports in the literature show that adsorption of clinically significant alloantibodies can occur. A 2006 study by Storry and colleagues suggested that immunoglobulin (Ig)M antibodies are adsorbed by RESt regardless of antigen specificity. In our study, we further investigated the adsorption of IgM red blood cell alloantibodies by RESt. STUDY DESIGN AND METHODS: A total of 12 sera containing monoclonal IgM antibodies of various specificities (anti- D, -C, -c, -E, -e, -K, -Jk(b), and -S) and titers, which were all shown to exhibit only IgM reactivity after dithiothreitol treatment, and two sera with polyclonal IgG (anti-Fy(a) and -K) were all adsorbed by RESt. Titers of unadsorbed, once-adsorbed, and twice-adsorbed IgM and IgG antibodies were determined in parallel. RESULTS: Ten of the 12 monoclonal IgM samples showed significant (more than fourfold) reduction in titer after RESt adsorptions. Both of the polyclonal IgG samples tested showed insignificant (fourfold or less) reduction in titer. CONCLUSIONS: RESt is known to effectively remove IgM cold autoantibodies. Our results show that monoclonal IgM alloantibodies are also frequently adsorbed by RESt with significant reduction in titer. Adsorption is variable and some IgM alloantibodies are not adsorbed. Further studies may elucidate the effect of RESt adsorption on IgG alloantibodies. Caution is needed when RESt is employed to remove interferences by cold autoantibodies in pretransfusion testing, and the risk of missed IgM alloantibodies must be considered.

Polymorphisms in the VEGFA and VEGFR-2 genes and neovascular age-related macular degeneration.

PURPOSE: Genetic factors influence an individual's risk for developing neovascular age-related macular degeneration (AMD), a leading cause of irreversible blindness. Previous studies on the potential genetic link between AMD and vascular endothelial growth factor (VEGF), a key regulator of angiogenesis and vascular permeability, have yielded conflicting results. In the present case-control association study, we aimed to determine whether VEGF or its main receptor tyrosine kinase VEGFR-2 is genetically associated with neovascular AMD. METHODS: A total of 515 Caucasian patients with neovascular AMD and 253 ethically-matched controls were genotyped for polymorphisms in the VEGFA and VEGFR-2 genes. A tagging single nucleotide polymorphism (tSNP) approach was employed to cover each gene plus two kilobases on each side, spanning the promoter and 3' untranslated regions. SNPs with a minimum allele frequency of 10% were covered by seven tSNPs in VEGFA and 20 tSNPs in VEGFR-2. Two VEGFA SNPs previously linked with AMD, rs1413711 and rs3025039, were also analyzed. RESULTS: The 29 VEGFA and VEGFR-2 SNPs analyzed in our cohort demonstrated no significant association with neovascular AMD. A single rare haplotype in the VEGFR-2 gene was associated with the presence of neovascular AMD (p=0.034). CONCLUSIONS: This study is the first to investigate the association of VEGFR-2 polymorphisms with AMD and evaluates VEGFA genetic variants in the largest neovascular AMD cohort to date. Despite the angiogenic and permeability-enhancing effects of VEGF/VEGFR-2 signaling, we found minimal evidence of a significant link between polymorphisms in the VEGFA and VEGFR-2 genes and neovascular AMD.

Visual outcomes with 23-gauge transconjunctival sutureless vitrectomy.

PURPOSE: To evaluate the outcomes of patients treated with 23-gauge transconjunctival sutureless vitrectomy for various posterior segment conditions. METHODS: A retrospective chart review of 81 consecutive 23-gauge vitrectomy cases done by a single vitreoretinal surgeon for various posterior segment conditions was done. All surgery was performed using the two-step 23-gauge system developed by Dutch Ophthalmic Research Center. All patients had at least 3-month follow-up. Main outcome measures included visual acuity, intraocular pressure, and operative complications. RESULTS: Mean follow-up was 6.5 months (range 3-9 months). Mean overall preoperative visual acuity was 20/150 and final acuity was 20/70 (P < 0.0001). Mean intraocular pressure on postoperative day 1 was 14 mmHg (range 6-28 mmHg). There was a single case of intraoperative retinal tear that required treatment with cryotherapy. Twenty eyes of 48 phakic eyes (42%) had worsening of cataracts in the postoperative period. There were no postoperative complications of endophthalmitis or retinal detachment. CONCLUSIONS: Twenty-three-gauge transconjunctival sutureless vitrectomy is an effective surgical technique in the management of vitreoretinal diseases. Complications were rare and compared favorably with published literature on 20-gauge and 25-gauge surgery.

Association of complement factor H and LOC387715 genotypes with response of exudative age-related macular degeneration to intravitreal bevacizumab.

PURPOSE: To investigate whether there is an association between complement factor H (CFH) or LOC387715 genotypes with response to treatment with intravitreal bevacizumab for exudative age-related macular degeneration (AMD). DESIGN: Retrospective cohort study. PARTICIPANTS: The study cohort consisted of 86 patients being treated for neovascular AMD with bevacizumab alone. METHODS: Genotype determination for the CFH Y402H and LOC387715 A69S polymorphisms was performed by allele-specific digestion of polymerase chain reaction products. All patients were treated with 1.25 mg intravitreal bevacizumab at 6-week intervals until choroidal neovascularization was no longer active. MAIN OUTCOME MEASURES: CFH Y402H and LOC387715 A69S polymorphisms. Choroidal neovascular lesion characteristics were ascertained by fluorescein angiography. Snellen visual acuity (VA) was measured before and after treatment. RESULTS: For the CFH Y402H polymorphism, patients with the CFH TT genotype had the largest choroidal neovascular lesions (P = 0.02). With treatment, VA improved from 20/248 to 20/166 for the CFH TT genotype and from 20/206 to 20/170 for the TC genotype, but fell from 20/206 to 20/341 for the CFH CC genotype (P = 0.016). Only 10.5% of patients with the CFH CC genotype demonstrated improved VA with treatment, compared with 53.7% of CFH TT and TC genotypes (P = 0.004). For the LOC387715 A69S variant, patients with the TT genotype had the largest choroidal neovascular lesions (P = 0.012). There was no significant difference in response to bevacizumab treatment according to LOC387715 genotype. CONCLUSIONS: The AMD-associated CFH Y402H and LOC387715 A69S variants were associated with differences in choroidal neovascular lesion size in this study. Patients with the CFH CC genotype fared significantly worse with intravitreal bevacizumab than did those with the CFH TC and TT genotypes, suggesting a potential pharmacogenetic relationship. Prospective studies to confirm or refute this observation should be considered.