A Na2HPO4‐catalyzed four‐component reaction between a ketone, malononitrile, S8 and formamide has been realized for the first time. This reaction provides a concise approach to ...thieno2,3‐dpyrimidin‐4‐amines, previously requiring 5 steps. The utility of this reaction was validated by preparing a multi‐targeted kinase inhibitor and an inhibitor of the NRF2 pathway with excellent atom‐ and step‐economy.
Concise synthesis of thieno2,3‐dpyrimidin‐4‐amines with improved atom economy, increased step economy, enhanced structural diversity, and simplified purification has been realized.
Current guidelines recommend low-molecular-weight heparin for thromboprophylaxis after orthopaedic trauma. However, recent evidence suggests that aspirin is similar in efficacy and safety. To ...understand patients' experiences with these medications, we compared patients' satisfaction and out-of-pocket costs after thromboprophylaxis with aspirin versus low-molecular-weight heparin.
This study was a secondary analysis of the PREVENTion of CLots in Orthopaedic Trauma (PREVENT CLOT) trial, conducted at 21 trauma centers in the U.S. and Canada. We included adult patients with an operatively treated extremity fracture or a pelvic or acetabular fracture. Patients were randomly assigned to receive 30 mg of low-molecular-weight heparin (enoxaparin) twice daily or 81 mg of aspirin twice daily for thromboprophylaxis. The duration of the thromboprophylaxis, including post-discharge prescription, was based on hospital protocols. The study outcomes included patient satisfaction with and out-of-pocket costs for their thromboprophylactic medication measured on ordinal scales.
The trial enrolled 12,211 patients (mean age and standard deviation SD, 45 ± 18 years; 62% male), 9725 of whom completed the question regarding their satisfaction with the medication and 6723 of whom reported their out-of-pocket costs. The odds of greater satisfaction were 2.6 times higher for patients assigned to aspirin than those assigned to low-molecular-weight heparin (odds ratio OR: 2.59; 95% confidence interval CI: 2.39 to 2.80; p < 0.001). Overall, the odds of incurring any out-of-pocket costs for thromboprophylaxis medication were 51% higher for patients assigned to aspirin compared with low-molecular-weight heparin (OR: 1.51; 95% CI: 1.37 to 1.66; p < 0.001). However, patients assigned to aspirin had substantially lower odds of out-of-pocket costs of at least $25 (OR: 0.15; 95% CI: 0.12 to 0.18; p < 0.001).
Use of aspirin substantially improved patients' satisfaction with their medication after orthopaedic trauma. While aspirin use increased the odds of incurring any out-of-pocket costs, it protected against costs of ≥$25, potentially improving health equity for thromboprophylaxis.
Therapeutic Level II . See Instructions for Authors for a complete description of levels of evidence.
Laser-induced breakdown spectroscopy (LIBS) was carried out on twenty-three low to high alloy steel samples to quantify their concentrations of chromium, nickel, and manganese. LIBS spectral data ...were correlated to known concentrations of the samples and three calibration methods were compared. A standard LIBS calibration technique using peak area integration normalized by an internal standard was compared to peak area integration normalized by total light and the multivariate statistical technique of partial least squares. For the partial least squares analysis, the PLS-1 algorithm was used, where a predictive model is generated for each element separately. Partial least squares regression coefficients show that the algorithm correctly identifies the atomic emission peaks of interest for each of the elements. Predictive capabilities of each calibration approach were quantified by calculating the standard and relative errors of prediction. The performance of partial least squares is on par with using iron as an internal standard but has the key advantage that it can be applied to samples where the concentrations of all elements are unknown.
Abstract Our goal was to determine whether genetic variation at genes affecting statin metabolism or targets of statin therapy would influence low density lipoprotein (LDL) cholesterol lowering with ...pravastatin, baseline heart disease, or cardiac endpoints on trial. We examined associations of single nucleotide polymorphisms (SNPs) at the liver X receptor alpha ( LXRA , rs12221497), and the solute carrier organic anion transporter ( SLCO1B1 , rs4149056 and rs2306283) gene loci with these variables. We studied 5411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No relationships between genetic variation at the LXRA gene locus with statin induced LDL lowering response or other parameters were noted. Both the SLCO1B1 rs4149056 (valine for alanine at 174) and the rs2306283 (asparagine for aspartic acid at 130) SNPs affect the amino acid sequence of the SLCO1B1 gene product. No effect of the rs2306283 SNP on any of the variables was noted. However the presence of the rs4149056 SNP was associated with significantly less LDL cholesterol lowering response to pravastatin (wildtype, 71.5% of the population, −37.0%; heterozygotes, 25.8% of the population, −36.0%; and homozygotes, 2.7% of the population, −31.8%, p = 0.003 at 6 months, and p = 0.022 at 12 months). Our data indicate that the presence of the rs4149056 non-synonymous SNP at the SLCO1B1 gene locus can significantly decrease the pravastatin induced LDL cholesterol lowering response.
Abstract Single nucleotide polymorphisms (SNPs) at the KIF6 (kinesin like protein 6, rs20455 or 719Arg), LPA (lipoprotein(a), rs3798220), TAS2R50 (taste receptor type 2, member 50, rs1376251) and ...VAMP8 (vesicle-associated membrane protein 8, rs1010) have previously been associated with low density lipoprotein cholesterol (LDL-C) lowering response to statins, coronary heart disease (CHD) at baseline, or CHD events on trial. We examined SNPs at the KIF6 (rs20455 or 719Arg), LPA (rs3798220), TAS2R50 (rs1376251) and VAMP8 (rs1010) in 5,411 participants in PROSPER (PROspective Study of Pravastatin in the Elderly at Risk) (mean age 75.3 years), who had been randomized to pravastatin 40 mg/day or placebo and were followed for a mean of 3.2 years. No SNP was related to vascular disease at baseline. Only the KIF6 SNP was related to LDL-C lowering with homozygous Arg 719 subjects being significantly less responsive than other groups ( p = 0.025, −34.2 vs. −36.1%). With regard to the primary CHD endpoint on trial (fatal or non-fatal myocardial infarction or stroke), we observed a significant relationship for KIF6 719Arg homozygotes ( p = 0.03, hazards ratio 0.47, 12.8% of the population) in women on pravastatin only, and for TAS2R50 for the AA genotype ( p = 0.03, hazards ratio 1.76, 8.9% of the population), also only in women on pravastatin. Our data indicate that the assessment of KIF6 rs20455 and TAS2R50 rs1376251 genotypes are not useful for predicting statin induced cardiovascular risk reduction in men, but do predict CHD risk reduction in women in this elderly population. However, these differences are no longer significant after correction for multiple comparisons, and we do not recommend the assessment of any of these SNPs in clinical practice.
Purpose
The Primary Immune Deficiency Treatment Consortium (PIDTC) enrolled children with severe combined immunodeficiency (SCID) in a prospective natural history study of hematopoietic stem cell ...transplant (HSCT) outcomes over the last decade. Despite newborn screening (NBS) for SCID, infections occurred prior to HSCT. This study’s objectives were to define the types and timing of infection prior to HSCT in patients diagnosed via NBS or by family history (FH) and to understand the breadth of strategies employed at PIDTC centers for infection prevention.
Methods
We analyzed retrospective data on infections and pre-transplant management in patients with SCID diagnosed by NBS and/or FH and treated with HSCT between 2010 and 2014. PIDTC centers were surveyed in 2018 to understand their practices and protocols for pre-HSCT management.
Results
Infections were more common in patients diagnosed via NBS (55%) versus those diagnosed via FH (19%) (
p
= 0.012). Outpatient versus inpatient management did not impact infections (47% vs 35%, respectively;
p
= 0.423). There was no consensus among PIDTC survey respondents as to the best setting (inpatient vs outpatient) for pre-HSCT management. While isolation practices varied, immunoglobulin replacement and antimicrobial prophylaxis were more uniformly implemented.
Conclusion
Infants with SCID diagnosed due to FH had lower rates of infection and proceeded to HSCT more quickly than did those diagnosed via NBS. Pre-HSCT management practices were highly variable between centers, although uses of prophylaxis and immunoglobulin support were more consistent. This study demonstrates a critical need for development of evidence-based guidelines for the pre-HSCT management of infants with SCID following an abnormal NBS.
Trial Registration
NCT01186913
Purpose
We sought to evaluate the diagnostic performance for coronary artery disease (CAD) of myocardial blood flow (MBF) quantification with
18
F-flurpiridaz PET using motion correction (MC) and ...residual activity correction (RAC).
Methods
In total, 231 patients undergoing same-day pharmacologic rest and stress
18
F-flurpiridaz PET from Phase III Flurpiridaz trial (NCT01347710) were studied. Frame-by-frame MC was performed and RAC was accomplished by subtracting the rest residual counts from the dynamic stress polar maps. MBF and myocardial flow reserve (MFR) were derived with a two-compartment early kinetic model for the entire left ventricle (global), each coronary territory, and 17-segment. Global and minimal values of three territorial (minimal vessel) and segmental estimation (minimal segment) of stress MBF and MFR were evaluated in the prediction of CAD. MBF and MFR were evaluated with and without MC and RAC (1: no MC/no RAC, 2: no MC/RAC, 3: MC/RAC).
Results
The area-under the receiver operating characteristics curve (AUC 95% confidence interval) of stress MBF with MC/RAC was higher for minimal segment (0.89 0.85–0.94) than for minimal vessel (0.86 0.81–0.92,
p
= 0.03) or global estimation (0.81 0.75–0.87,
p
< 0.0001). The AUC of MFR with MC/RAC was higher for minimal segment (0.87 0.81–0.93) than for minimal vessel (0.83 0.76–0.90,
p
= 0.014) or global estimation (0.77 0.69–0.84,
p
< 0.0001). The AUCs of minimal segment stress MBF and MFR with MC/RAC were higher compared to those with no MC/RAC (
p
< 0.001 for both) or no MC/no RAC (
p
< 0.0001 for both).
Conclusions
Minimal segment MBF or MFR estimation with MC and RAC improves the diagnostic performance for obstructive CAD compared to global assessment.
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