The presence of minimal residual disease (MRD) by multiparametric flow cytometry (MFC) has been associated with adverse outcomes in AML patients treated with chemotherapy alone, but its impact in the ...setting of allogeneic hematopoietic SCT (HSCT) is less clear. We studied 88 patients who underwent myeloablative (MA) or reduced-intensity conditioned allogeneic HSCT for AML in first or subsequent remission at our center. MRD status was determined using three-color MFC on pre-HSCT BM aspirates, and patients were stratified by MRD status into MRD-negative, low-level MRD-positive (<1%) or high-level MRD-positive groups (1-4.9%). Two-year survival estimates in these groups were 66.8%, 51% and 30%, respectively (P=0.012), and 2-year estimates of relapse were 7.6, 37 and 70% (P<0.001). Pre-HSCT MRD was related to disease characteristics including secondary AML (P=0.002) and primary induction failure (P=0.005), but, despite these strong correlations, MRD remained independently associated with poorer survival in multivariate analysis (hazard ratio, 1.92; P=0.014). Pre-HSCT MRD is associated with adverse clinical outcomes in AML patients undergoing reduced-intensity or MA HSCT in first or subsequent remission and should be integrated into transplant strategies for patients with AML.
AbstractBackgroundSchistosomiasis caused by Schistosoma mansoni ( Sm) is a chronic, debilitating and potentially deadly neglected tropical disease. The licensure of a vaccine to prevent ...schistosomiasis would represent a major breakthrough in public health. MethodsThe safety and immunogenicity of a candidate Sm vaccine were assessed in this phase I, double-blind, dose-escalation trial. Seventy-two healthy Sm-naïve 18–50 year olds were randomized to receive 3 doses ∼ 8 weeks apart of saline placebo, or 10 µg, 30 µg, or 100 µg of recombinant Sm-Tetraspanin-2 vaccine formulated on aluminum hydroxide adjuvant ( Sm-TSP-2/Al) with or without 5 µg of glucopyranosyl lipid A aqueous formulation (GLA-AF). Clinical and serologic responses were assessed for 1 year after dose 3. ResultsVaccines were safe and well-tolerated. The most common reactions were injection site tenderness and pain, and headache and fatigue. Tenderness and pain were more frequent in groups receiving vaccine with GLA-AF than placebo (p = 0.0036 and p = 0.0014, respectively). Injection site reactions among those given Sm-TSP-2/Al with GLA-AF lasted 1.22 and 1.33 days longer than those receiving Sm-TSP-2/Al without GLA-AF or placebo (p < 0.001 for both). Dose- and adjuvant-related increases in serum IgG against Sm-TSP-2 were observed. Peak IgG levels occurred 14 days after dose 3. Seroresponse frequencies were low among recipients of Sm-TSP-2/Al without GLA-AF, but higher among subjects receiving 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF. More seroresponses were observed among those given 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF compared to placebo (p = 0.023 and p < 0.001, respectively). Seroresponse frequencies were 0%, 30%, 50%, and 89%, respectively, among those given placebo, or 10 µg, 30 µg or 100 µg of Sm-TSP-2/Al with GLA-AF, suggesting a dose–response relationship for Sm-TSP-2/Al with GLA-AF (p = 0.0001). ConclusionsSm-TSP-2/Al with or without GLA-AF was safe and well tolerated in a Sm-naïve population. A vaccine like the one under development may represent our best hope to eliminating this neglected tropical disease.
BACKGROUND
Delirium, a common syndrome with heterogeneous etiologies and clinical presentations, is associated with poor long‐term outcomes. Recording and analyzing all delirium equally could be ...hindering the field's understanding of pathophysiology and identification of targeted treatments. Current delirium subtyping methods reflect clinically evident features but likely do not account for underlying biology.
METHODS
The Delirium Subtyping Initiative (DSI) held three sessions with an international panel of 25 experts.
RESULTS
Meeting participants suggest further characterization of delirium features to complement the existing Diagnostic and Statistical Manual of Mental Disorders Fifth Edition Text Revision diagnostic criteria. These should span the range of delirium‐spectrum syndromes and be measured consistently across studies. Clinical features should be recorded in conjunction with biospecimen collection, where feasible, in a standardized way, to determine temporal associations of biology coincident with clinical fluctuations.
DISCUSSION
The DSI made recommendations spanning the breadth of delirium research including clinical features, study planning, data collection, and data analysis for characterization of candidate delirium subtypes.
Highlights
Delirium features must be clearly defined, standardized, and operationalized.
Large datasets incorporating both clinical and biomarker variables should be analyzed together.
Delirium screening should incorporate communication and reasoning.
Purpose
Blood flow to skeletal muscles and removal of metabolic by-products during a sport climb are essential to optimise performance and recovery. New Zealand blackcurrant (NZBC) extract ...has enhanced blood flow and performance in other exercise modalities. We examined the effect of NZBC extract on sport climbing performance and recovery.
Methods
The study employed a double-blind, randomised, crossover design. Male sport climbers (
n
= 18, age 24 ± 6 years, height 179 ± 6 cm, mass 71.4 ± 7.8 kg, French grade 6a-8b) undertook 7 days supplementation of NZBC extract (600 mg day
−1
CurraNZ™ containing 210 mg anthocyanins) or a placebo (PL). Climbing ability was assessed through hang time (HT), pull-ups and total climbing time (TCT) in 3 intermittent climbing bouts on a Treadwall M6 rotating climbing wall to exhaustion with 20 min recovery between climbs. Heart rate (HR), blood lactate (BL), forearm girth (FG) and hand grip strength (HGS) were recorded.
Results
NZBC extract had no effect on pull-ups but provided a trend for higher HT and significantly improved TCT (+23%) compared to PL (-11%) over three climbs. HR, BL, FG and HGS all indicated that 20 min was insufficient for physiological recovery between the three climbing bouts indicating accumulative fatigue regardless of supplement condition.
Conclusion
Despite indices of progressive fatigue across three bouts of climbing, NZBC extract facilitated not only a maintenance of TCT but an improved climbing endurance as compared with the PL condition. Blackcurrant anthocyanin-derived metabolites seem to affect physiological responses that facilitate sport climbing performance.
•Poly(I:C) molecular weight (MW) and endotoxin vary significantly between suppliers.•MW and endotoxin variability predicts rat maternal IL-6 response and litter size.•MW variability predicts rat ...placental weight.•Poly(I:C) supplier predicts a male-specific reduction in fetal brain weight.
The viral mimetic polyinosinic:polycytidylic acid (poly(I:C)) is increasingly used to induce maternal immune activation (mIA) to model neurodevelopmental disorders (NDDs). Robust and reproducible phenotypes across studies are essential for the generation of models that will enhance our understanding of NDDs and enable the development of improved therapeutic strategies. However, differences in mIA-induced phenotypes using poly(I:C) have been widely observed, and this has prompted the reporting of useful and much needed methodological guidelines. Here, we perform a detailed investigation of molecular weight and endotoxin variations in poly(I:C) procured from two of the most commonly used suppliers, Sigma and InvivoGen. We demonstrate that endotoxin contamination and molecular weight differences in poly(I:C) composition lead to considerable variability in maternal IL-6 response in rats treated on gestational day (GD)15 and impact on fetal outcomes. Specifically, both endotoxin contamination and molecular weight predicted reductions in litter size on GD21. Further, molecular weight predicted a reduction in placental weight at GD21. While fetal body weight at GD21 was not affected by poly(I:C) treatment, male fetal brain weight was significantly reduced by poly(I:C), dependent on supplier. Our data are in agreement with recent reports of the importance of poly(I:C) molecular weight, and extend this work to demonstrate a key role of endotoxin on relevant phenotypic outcomes. We recommend that the source and batch numbers of poly(I:C) used should always be stated and that molecular weight variability and endotoxin contamination should be minimised for more robust mIA modelling.
Aim
Diabetes is associated with a high risk of adverse pregnancy outcomes. Optimal glycaemic control is fundamental and is traditionally monitored with self‐measured glucose profiles and periodic ...HbA1c measurements. We investigated the effectiveness of additional use of retrospective continuous glucose monitoring (CGM) in diabetic pregnancies.
Material and methods
We performed a nationwide multicentre, open label, randomized, controlled trial to study pregnant women with type 1 or type 2 diabetes who were undergoing insulin therapy at gestational age < 16 weeks, or women who were undergoing insulin treatment for gestational diabetes at gestational age < 30 weeks. Women were randomly allocated (1:1) to intermittent use of retrospective CGM or to standard treatment. Glycaemic control was assessed by CGM for 5‐7 days every 6 weeks in the CGM group, while self‐monitoring of blood glucose and HbA1c measurements were applied in both groups. Primary outcome was macrosomia, defined as birth weight above the 90th percentile. Secondary outcomes were glycaemic control and maternal and neonatal complications.
Results
Between July 2011 and September 2015, we randomized 300 pregnant women with type 1 (n = 109), type 2 (n = 82) or with gestational (n = 109) diabetes to either CGM (n = 147) or standard treatment (n = 153). The incidence of macrosomia was 31.0% in the CGM group and 28.4% in the standard treatment group (relative risk RR, 1.06; 95% CI, 0.83‐1.37). HbA1c levels were similar between treatment groups.
Conclusions
In diabetic pregnancy, use of intermittent retrospective CGM did not reduce the risk of macrosomia. CGM provides detailed information concerning glycaemic fluctuations but, as a treatment strategy, does not translate into improved pregnancy outcome.
Survivors of childhood and adolescent cancer are at risk for long-term effects of disease and treatment. The Childhood Cancer Survivor Study assessed overall and cause-specific mortality in a ...retrospective cohort of 20,227 5-year survivors.
Eligible subjects were individuals diagnosed with cancer (from 1970 to 1986) before the age of 21 who had survived 5 years from diagnosis. Underlying cause of death was obtained from death certificates and other sources and coded and categorized as recurrent disease, sequelae of cancer treatment, or non-cancer-related. Age and sex standardized mortality ratios (SMRs) were calculated using United States population mortality data.
The cohort, including 208,947 person-years of follow-up, demonstrated a 10.8-fold excess in overall mortality (95% confidence interval, 10.3 to 11.3). Risk of death was statistically significantly higher in females (SMR = 18.2), individuals diagnosed with cancer before the age of 5 years (SMR = 14.0), and those with an initial diagnosis of leukemia (SMR = 15.5) or CNS tumor (SMR = 15.7). Recurrence of the original cancer was the leading cause of death among 5-year survivors, accounting for 67% of deaths. Statistically significant excess mortality rates were seen due to subsequent malignancies (SMR = 19.4), along with cardiac (SMR = 8.2), pulmonary (SMR = 9.2), and other causes (SMR = 3.3). Treatment-related associations were present for subsequent cancer mortality (radiation, alkylating agents, epipodophyllotoxins), cardiac mortality (chest irradiation, bleomycin), and other deaths (radiation, anthracyclines). No excess mortality was observed for external causes (SMR = 0.8).
While recurrent disease remains a major contributor to late mortality in 5-year survivors of childhood cancer, significant excesses in mortality risk associated with treatment-related complications exist up to 25 years after the initial cancer diagnosis.
Carriers of germline mutations in DNA mismatch repair (MMR) genes have a high risk of colorectal cancer (CRC), but the modifiers of this risk are not well established. We estimated an association ...between body mass index (BMI) in early adulthood and subsequent risk of CRC for carriers and, as a comparison, estimated the association for non-carriers.
A weighted Cox regression was used to analyse height and weight at 20 years reported by 1324 carriers of MMR gene mutations (500 MLH1, 648 MSH2, 117 MSH6 and 59 PMS2) and 1219 non-carriers from the Colon Cancer Family Registry.
During 122,304 person-years of observation, we observed diagnoses of CRC for 659 carriers (50%) and 36 non-carriers (3%). For carriers, the risk of CRC increased by 30% for each 5 kg m(-2) increment in BMI in early adulthood (hazard ratio, HR: 1.30; 95% confidence interval, CI: 1.08-1.58; P=0.01), and increased by 64% for non-carriers (HR: 1.64; 95% CI: 1.02-2.64; P=0.04) after adjusting for sex, country, cigarette smoking and alcohol drinking (and the MMR gene that was mutated in carriers). The difference in HRs for carriers and non-carriers was not statistically significant (P=0.50). For MLH1 and PMS2 (MutLα heterodimer) mutation carriers combined, the corresponding increase was 36% (HR: 1.36; 95% CI: 1.05-1.76; P=0.02). For MSH2 and MSH6 (MutSα heterodimer) mutation carriers combined, the HR was 1.26 (95% CI: 0.96-1.65; P=0.09). There was no significant difference between the HRs for MutLα and MutSα heterodimer carriers (P=0.56).
Body mass index in early adulthood is positively associated with risk of CRC for MMR gene mutation carriers and non-carriers.
Soybean aphid, Aphis glycines Matsumura (Hemiptera: Aphididae), reached damaging levels in 2003 and 2005 in soybean, Glycine max (L.) Merrill, in most northern U.S. states and Canadian provinces, and ...it has become one of the most important pests of soybean throughout the North Central region. A common experimental protocol was adopted by participants in six states who provided data from 19 yield-loss experiments conducted over a 3-yr period. Population doubling times for field populations of soybean aphid averaged 6.8 d plus or minus 0.8 d (mean plus or minus SEM). The average economic threshold (ET) over all control costs, market values, and yield was 273 plus or minus 38 (mean plus or minus 95% confidence interval CI, range 111-567) aphids per plant. This ET provides a 7-d lead time before aphid populations are expected to exceed the economic injury level (EIL) of 674 plus or minus 95 (mean plus or minus 95% CI, range 275-1,399) aphids per plant. Peak aphid density in 18 of the 19 location-years occurred during soybean growth stages R3 (beginning pod formation) to R5 (full size pod) with a single data set having aphid populations peaking at R6 (full size green seed). The ET developed here is strongly supported through soybean growth stage R5. Setting an ET at lower aphid densities increases the risk to producers by treating an aphid population that is growing too slowly to exceed the EIL in 7 d, eliminates generalist predators, and exposes a larger portion of the soybean aphid population to selection by insecticides, which could lead to development of insecticide resistance.
The soybean aphid (Aphis glycines Matsumura) is a threat to soybean production in the Midwestern United States. Varieties containing the Rag1 soybean aphid resistance gene have been released with ...limited success in reducing aphid populations. Furthermore, virulent biotypes occur within North America and challenge the durability of single-gene resistance. Pyramiding resistance genes has the potential to improve aphid population suppression and increase resistance gene durability. Our goal was to determine if a pyramid could provide improved aphid population suppression across a wide range of environments.Weconducted a small-plot field experiment across seven states and three years. We compared soybean near-isolines for the Rag1 or Rag2 gene, and a pyramid line containing both genes for their ability to decrease aphid pressure and protect yield compared with a susceptible line. These lines were evaluated both with and without a neonicitinoid seed treatment. All aphid-resistant lines significantly decreased aphid pressure at all locations but one. The pyramid line experienced lower aphid pressure than both single-gene lines at eight of 23 location-years. Soybean aphids significantly reduced soybean yield for the susceptible line by 14% and for both single-gene lines by 5%; however, no significant yield decrease was observed for the pyramid line. The neonicitinoid seed treatment reduced plant exposure to aphids across all soybean lines, but did not provide significant yield protection for any of the lines. These results demonstrate that pyramiding resistance genes can provide sufficient and consistent yield protection from soybean aphid in North America.
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