Busulfan with 400 centigray of total body irradiation and higher dose fludarabine: An alternative regimen for hematopoietic stem cell transplantation in pediatric acute lymphoblastic leukemia.

BACKGROUND: Hematopoietic stem cell transplantation can be curative for children with difficult-to-treat leukemia. The conditioning regimen utilized is known to influence outcomes. We report outcomes of the conditioning regimen used at the Alberta Children's Hospital, consisting of busulfan (with pharmacokinetic target of 3750 µmol*min/L/day ±10%) for 4 days, higher dose (250 mg/m2 ) fludarabine and 400 centigray (cGy) of total body irradiation. PROCEDURE: This retrospective study involved children receiving transplant for acute lymphoblastic leukemia (ALL). It compared children who fell within the target range for busulfan with those who were either not measured or were measured and fell outside this range. All other treatment factors were identical. RESULTS: Twenty-nine children (17 within target) were evaluated. All subjects engrafted neutrophils with a median [interquartile range] time of 14 days [8-30 days]. The cumulative incidence of acute graft-versus-host disease was 44.8% [95% confidence interval, CI: 35.6%-54.0%], while chronic graft-versus-host disease was noted in 16.0% [95% CI: 8.7%-23.3%]. At 2 years, the overall survival was 78.1% [95% CI: 70.8%-86.4%] and event-free survival was 74.7% [95% CI: 66.4%-83.0%]. Cumulative incidence of relapse was 11.3% [95% CI: 5.1%-17.5%]. There were no statistically significant differences in between the group that received targeted busulfan compared with the untargeted group. CONCLUSION: Our conditioning regiment for children with ALL resulted in outcomes comparable to standard treatment with acceptable toxicities and significant reduction in radiation dose. Targeting busulfan dose in this cohort did not result in improved outcomes.

Cutting-edge strategies and critical advancements in characterization and quantification of metabolites concerning translational metabolomics.

Despite remarkable progress in drug discovery strategies, significant challenges are still remaining in translating new insights into clinical applications. Scientists are devising creative approaches to bridge the gap between scientific and translational research. Metabolomics is a unique field among other omics techniques for identifying novel metabolites and biomarkers. Fortunately, characterization and quantification of metabolites are becoming faster due to the progress in the field of orthogonal analytical techniques. This review detailed the advancement in the progress of sample preparation, and data processing techniques including data mining tools, database, and their quality control (QC). Advances in data processing tools make it easier to acquire unbiased data that includes a diverse set of metabolites. In addition, novel breakthroughs including, miniaturization as well as their integration with other devices, metabolite array technology, and crystalline sponge-based method have led to faster, more efficient, cost-effective, and holistic metabolomic analysis. The use of cutting-edge techniques to identify the human metabolite, including biomarkers has proven to be advantageous in terms of early disease identification, tracking the progression of illness, and possibility of personalized treatments. This review addressed the constraints of current metabolomics research, which are impeding the facilitation of translation of research from bench to bedside. Nevertheless, the possible way out from such constraints and future direction of translational metabolomics has been conferred.

Cost-effectiveness of Contemporary Statin Use Guidelines With or Without Coronary Artery Calcium Assessment in African American Individuals.

Importance: Clinical and economic consequences of statin treatment guidelines supplemented by targeted coronary artery calcium (CAC) assessment have not been evaluated in African American individuals, who are at increased risk for atherosclerotic cardiovascular disease and less likely than non-African American individuals to receive statin therapy. Objective: To evaluate the cost-effectiveness of the 2013 American College of Cardiology/American Heart Association (ACC/AHA) guideline without a recommendation for CAC assessment vs the 2018 ACC/AHA guideline recommendation for use of a non-0 CAC score measured on one occasion to target generic-formulation, moderate-intensity statin treatment in African American individuals at risk for atherosclerotic cardiovascular disease. Design, Setting, and Participants: A microsimulation model was designed to estimate life expectancy, quality of life, costs, and health outcomes over a lifetime horizon. African American-specific data from 472 participants in the Jackson Heart Study (JHS) at intermediate risk for atherosclerotic cardiovascular disease and other US population-specific data on individuals from published sources were used. Data analysis was conducted from November 11, 2018, to November 1, 2019. Main Outcomes and Measures: Lifetime costs and quality-adjusted life-years (QALYs), discounted at 3% annually. Results: In a model-based economic evaluation informed in part by follow-up data, the analysis was focused on 472 individuals in the JHS at intermediate risk for atherosclerotic cardiovascular disease; mean (SD) age was 63 (6.7) years. The sample included 243 women (51.5%) and 229 men (48.5%). Of these, 178 of 304 participants (58.6%) who underwent CAC assessment had a non-0 CAC score. In the base-case scenario, implementation of 2013 ACC/AHA guidelines without CAC assessment provided a greater quality-adjusted life expectancy (0.0027 QALY) at a higher cost ($428.97) compared with the 2018 ACC/AHA guideline strategy with CAC assessment, yielding an incremental cost-effectiveness ratio of $158 325/QALY, which is considered to represent low-value care by the ACC/AHA definition. The 2018 ACC/AHA guideline strategy with CAC assessment provided greater quality-adjusted life expectancy at a lower cost compared with the 2013 ACC/AHA guidelines without CAC assessment when there was a strong patient preference to avoid use of daily medication therapy. In probability sensitivity analyses, the 2018 ACC/AHA guideline strategy with CAC assessment was cost-effective compared with the 2013 ACC/AHA guidelines without CAC assessment in 76% of simulations at a willingness-to-pay value of $100 000/QALY when there was a preference to lose 2 weeks of perfect health to avoid 1 decade of daily therapy. Conclusions and Relevance: A CAC assessment-guided strategy for statin therapy appears to be cost-effective compared with initiating statin therapy in all African American individuals at intermediate risk for atherosclerotic cardiovascular disease and may provide greater quality-adjusted life expectancy at a lower cost than a non-CAC assessment-guided strategy when there is a strong patient preference to avoid the need for daily medication. Coronary artery calcium testing may play a role in shared decision-making regarding statin use.

Association of Type of Treatment Facility With Overall Survival After a Diagnosis of Head and Neck Cancer.

Importance: Patients with head and neck cancer receive care at academic comprehensive cancer programs (ACCPs), integrated network cancer programs (INCPs), comprehensive community cancer programs (CCCPs), and community cancer programs (CCPs). The type of treatment facility may be associated with overall survival. Objective: To examine whether type of treatment facility is associated with overall survival after a diagnosis of head and neck cancer. Design, Setting, and Participants: This population-based retrospective cohort study included patients from the National Cancer Database, a prospectively maintained, hospital-based cancer registry of patients treated at more than 1500 US hospitals. Participants were diagnosed with malignant tumors of the head and neck from January 1, 2004, through December 31, 2016. Data were analyzed from May 1 through November 30, 2019. Exposures: Treatment at facilities classified as ACCPs, INCPs, CCCPs, or CCPs. Main Outcomes and Measures: Overall survival after diagnosis and treatment of head and neck cancer was the primary outcome. The secondary outcome was the odds of receiving treatment at ACCPs and INCPs vs CCCPs and CCPs. Multivariable Cox proportional hazards regression and univariable and multivariable logistic regression models were used for analysis. Results: A total of 525 740 patients (368 821 men [70.2%]; mean [SD] age, 63.3 [14.0] years) were diagnosed with malignant tumors of the head and neck during the study period. Among them, 36 595 patients (7.0%) were treated at CCPs; 174 658 (33.2%), at CCCPs; 232 867 (44.3%), at ACCPs; and 57 857 (11.0%), at INCPs. The median survival for patients with aerodigestive cancers was 69.2 (95% CI, 68.6-69.8) months; salivary gland cancers, 107.2 (95% CI, 103.9-110.2) months; and skin cancers, 113.2 (95% CI, 111.4-114.6) months. Improved overall survival was associated with treatment at ACCPs (hazard ratio [HR], 0.89; 95% CI, 0.88-0.91), INCPs (HR, 0.94; 95% CI, 0.92-0.96), and CCCPs (HR, 0.94; 95% CI, 0.92-0.95) compared with CCPs. Compared with patients with private insurance, those with government insurance (odds ratio [OR], 1.35; 95% CI, 1.29-1.41), no insurance (OR, 1.12; 95% CI, 1.09-1.16), or Medicaid (OR, 1.17; 95% CI, 1.14-1.20) were more likely to receive treatment at ACCPs and INCPs, whereas patients with Medicare were less likely to receive treatment at ACCPs and INCPs (OR, 0.95; 95% CI, 0.94-0.97). Compared with white patients, black (OR, 1.55; 95% CI, 1.52-1.59) and Asian (OR, 1.56; 95% CI, 1.49-1.63) patients were more likely to receive care at ACCPs and INCPs. Compared with patients from lower-income areas, patients from high-income areas were more likely to receive treatment at ACCPs and INCPs (OR, 1.25; 95% CI, 1.22-1.28). Conclusions and Relevance: These findings suggest that treatment at ACCPs and INCPs was associated with a better overall survival rate in patients with head and neck cancer. Key social determinants of health such as race/ethnicity, socioeconomic status, and type of insurance were associated with receiving treatment at ACCPs and INCPs.

Effect of Omega-3 Acid Ethyl Esters on Left Ventricular Remodeling After Acute Myocardial Infarction: The OMEGA-REMODEL Randomized Clinical Trial.

BACKGROUND: Omega-3 fatty acids from fish oil have been associated with beneficial cardiovascular effects, but their role in modifying cardiac structures and tissue characteristics in patients who have had an acute myocardial infarction while receiving current guideline-based therapy remains unknown. METHODS: In a multicenter, double-blind, placebo-controlled trial, participants presenting with an acute myocardial infarction were randomly assigned 1:1 to 6 months of high-dose omega-3 fatty acids (n=180) or placebo (n=178). Cardiac magnetic resonance imaging was used to assess cardiac structure and tissue characteristics at baseline and after study therapy. The primary study endpoint was change in left ventricular systolic volume index. Secondary endpoints included change in noninfarct myocardial fibrosis, left ventricular ejection fraction, and infarct size. RESULTS: By intention-to-treat analysis, patients randomly assigned to omega-3 fatty acids experienced a significant reduction of left ventricular systolic volume index (-5.8%, P=0.017), and noninfarct myocardial fibrosis (-5.6%, P=0.026) in comparison with placebo. Per-protocol analysis revealed that those patients who achieved the highest quartile increase in red blood cell omega-3 index experienced a 13% reduction in left ventricular systolic volume index in comparison with the lowest quartile. In addition, patients in the omega-3 fatty acid arm underwent significant reductions in serum biomarkers of systemic and vascular inflammation and myocardial fibrosis. There were no adverse events associated with high-dose omega-3 fatty acid therapy. CONCLUSIONS: Treatment of patients with acute myocardial infarction with high-dose omega-3 fatty acids was associated with reduction of adverse left ventricular remodeling, noninfarct myocardial fibrosis, and serum biomarkers of systemic inflammation beyond current guideline-based standard of care. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00729430.

Regulation of selenocysteine incorporation into the selenium transport protein, selenoprotein P.

Selenoproteins are unique as they contain selenium in their active site in the form of the 21st amino acid selenocysteine (Sec), which is encoded by an in-frame UGA stop codon. Sec incorporation requires both cis- and trans-acting factors, which are known to be sufficient for Sec incorporation in vitro, albeit with low efficiency. However, the abundance of the naturally occurring selenoprotein that contains 10 Sec residues (SEPP1) suggests that processive and efficient Sec incorporation occurs in vivo. Here, we set out to study native SEPP1 synthesis in vitro to identify factors that regulate processivity and efficiency. Deletion analysis of the long and conserved 3'-UTR has revealed that the incorporation of multiple Sec residues is inherently processive requiring only the SECIS elements but surprisingly responsive to the selenium concentration. We provide evidence that processive Sec incorporation is linked to selenium utilization and that reconstitution of known Sec incorporation factors in a wheat germ lysate does not permit multiple Sec incorporation events, thus suggesting a role for yet unidentified mammalian-specific processes or factors. The relationship between our findings and the channeling theory of translational efficiency is discussed.

Comparison of the Treatment Implications of American Society of Hypertension and International Society of Hypertension 2013 and Eighth Joint National Committee Guidelines: an analysis of National Health and Nutrition Examination Survey.

Multiple guidelines and statements related to hypertension have recently been published. Much discord has arisen from discrepant treatment and target systolic blood pressure thresholds for individuals aged 60 to 79 years of <150 mm Hg in the guideline published by members assigned to the Eighth Joint National Committee and <140 mm Hg in a statement by the American Society of Hypertension and International Society of Hypertension 2013. We sought to evaluate the public health implications of these differences using data from the 2005 to 2010 National Health and Nutrition Examination Survey (NHANES) cycles. NHANES is an ongoing survey designed to allow characterization of the US population and subpopulations. We found that only .2.4% (95% confidence interval, 1.5.3.2%) of adults aged 60 to 79 years had indications for antihypertensive treatment under the more stringent American Society of Hypertension and International Society of Hypertension 2013 guideline but not under Eighth Joint National Committee. About 65.7% (95% confidence interval, 62.4.69.0%) of adults aged 60 to 79 years had indications for treatment under both guidelines. Furthermore, those with indications for treatment under American Society of Hypertension and International Society of Hypertension 2013 but not under Eighth Joint National Committee generally had higher systolic blood pressure and less favorable lipid profiles compared with those with indications for treatment under both guidelines. Importantly, a larger group, comprising 21.0% (95% confidence interval, 18.7.23.2%) of adults aged 60 to 79 years, had either untreated or inadequately treated hypertension and represents an important group for continued efforts.

Cytochrome P450 2C epoxygenases mediate photochemical stress-induced death of photoreceptors.

Degenerative loss of photoreceptors occurs in inherited and age-related retinal degenerative diseases. A chemical screen facilitates development of new testing routes for neuroprotection and mechanistic investigation. Herein, we conducted a mouse-derived photoreceptor (661W cell)-based high throughput screen of the Food and Drug Administration-approved Prestwick drug library to identify putative cytoprotective compounds against light-induced, synthetic visual chromophore-precipitated cell death. Different classes of hit compounds were identified, some of which target known genes or pathways pathologically associated with retinitis pigmentosa. Sulfaphenazole (SFZ), a selective inhibitor of human cytochrome P450 (CYP) 2C9 isozyme, was identified as a novel and leading cytoprotective compound. Expression of CYP2C proteins was induced by light. Gene-targeted knockdown of CYP2C55, the homologous gene of CYP2C9, demonstrated viability rescue to light-induced cell death, whereas stable expression of functional CYP2C9-GFP fusion protein further exacerbated light-induced cell death. Mechanistically, SFZ inhibited light-induced necrosis and mitochondrial stress-initiated apoptosis. Light elicited calcium influx, which was mitigated by SFZ. Light provoked the release of arachidonic acid from membrane phospholipids and production of non-epoxyeicosatrienoic acid metabolites. Administration of SFZ further stimulated the production of non-epoxyeicosatrienoic acid metabolites, suggesting a metabolic shift of arachidonic acid under inhibition of the CYP2C pathway. Together, our findings indicate that CYP2C genes play a direct causative role in photochemical stress-induced death of photoreceptors and suggest that the CYP monooxygenase system is a risk factor for retinal photodamage, especially in individuals with Stargardt disease and age-related macular degeneration that deposit condensation products of retinoids.

Preoperative liver reduction utilizing a novel nutritional supplement.

BACKGROUND: One of the most common reasons for conversion in bariatric surgery is hepatomegaly caused by inadequate exposure of the proximal stomach. This study utilizes a novel nutritional supplement with a calorie-restricted diet to reduce liver volume preoperatively. METHODS: A consecutive series of morbidly obese patients consumed a nutritional supplement called Nuvista(®) for 4 weeks preoperatively. Preoperatively, each patient completed baseline demographics, blood work, urine ketone analysis, ultrasonography of the left lateral segment, and multiple questionnaires. At the time of surgery, these studies were repeated. Data were analyzed using a paired t-test and bivariate analysis where appropriate. A P<.05 was considered significant. RESULTS: Four men and 17 women were recruited with a mean preoperative weight and body mass index of 122.7±15.9 kg and 44.5±3.9, respectively. Mean preoperative liver volume of the left lateral segment was 562.5±291.3 cm(3). After 4 weeks of Nuvista, the mean weight and body mass index decreased significantly to 118.9±15.5 kg and 43.1±3.4, respectively (P<.001). The mean liver volume of the left lateral segment was significantly reduced to 299.9±162.1 cm(3) (P<.001). Mean liver reduction was 43.4%±17.2% (13.6%-81.9%, P<.05). Urinary ketone scores did not show any evidence of starvation. No preoperative factors correlated with liver volume reduction. CONCLUSION: Utilizing Nuvista, as part of a preoperative 4-week calorie-restricted regimen, significantly reduced lateral segment liver volume by 43.4%. This preoperative regimen incorporates healthy behavioral changes that are necessary to sustain long-term weight loss.

Screening of Indian aphrodisiac ayurvedic/herbal healthcare products for adulteration with sildenafil, tadalafil and/or vardenafil using LC/PDA and extracted ion LC-MS/TOF.

Ayurvedic/herbal healthcare products are considered safe under the impression that they are derived from natural products. But recently, there have been several reports worldwide on the adulteration of synthetic PDE-5 inhibitors in aphrodisiac herbal formulations. Therefore, the objective of the present study was to explore the presence of synthetic PDE-5 inhibitors (sildenafil, tadalafil and/or vardenafil) in ayurvedic/herbal healthcare products sold in Indian market for aphrodisiac/related uses. In total, 85 herbal formulations (HFs) were included in the study. The formulations were extracted with methanol and subjected to centrifugation. The supernatant was analysed by HPLC and LC-MS/TOF. Early detection of the presence of sildenafil, tadalafil and vardenafil in the herbal samples was done by the study of extracted ion mass chromatograms at the m/z values of respective parent ions, and two prominent fragments of each. In case of sildenafil and tadalafil, adulteration was also detected by comparing the relative retention times (RR(T)) and UV spectra. Further substantiation was done through comparison of accurate mass spectra with those of the two available standards. Of the 85 HFs tested, only one was eventually found to be adulterated with sildenafil. The extent of adulterant in this sample was determined to the therapeutic dose in the formulation. The study thus indicates emergence of the problem of adulteration of Indian herbal products with PDE-5 inhibitors.

Compatibility of atenolol with excipients: LC-MS/TOF characterization of degradation/interaction products, and mechanisms of their formation.

A study was carried out to investigate compatibility of atenolol, a beta(1) blocker, with a variety of pharmaceutical excipients. The binary mixtures (1:1) of atenolol with the excipients were stored for 1 month at 40 degrees C/75% RH. The samples were directly observed for the physical changes, and also analyzed by a validated HPLC method to determine the chemical changes. The study revealed that atenolol was incompatible with ascorbic acid, citric acid and butylated hydroxyanisole. The degradation/interaction products formed in these mixtures were characterized by high resolution mass spectrometric and fragmentation analyses, using a LC-MS/TOF system. The identity of characterized structures was justified through mechanistic explanations.