Designing an Industrially Scalable, Flow-Based Synthesis for the Production of Nilotinib: Chemical Process Modeling and Economic Analysis

Nilotinib (Tasigna) is a drug used to treat chronic myelogenous leukemia (CML), a disease which currently affects over 100,000 people in the U.S. The drug is manufactured by Novartis and has been one of its most profitable, bringing in a total revenue of well over $2 billion USD in 2016. Novartis’s patent on Tasigna is set to expire in 2023 and cheaper, generic versions of the drug will soon be in great demand. An assessment of Novartis’s existing patent on the synthesis of Tasigna indicates many drawbacks in the current process. Namely, the Novartis synthesis requires multiple days of reaction, nearly a dozen steps, multiple solvent switching processes, and gives very low yields. On the other hand, work published by Buchwald and coworkers has shown an efficient method of synthesizing nilotinib in fewer than four steps, in less than 24 hours, and at >85$250 million USD/year even with a predicted 60% drop in generic drug price factored in. This, we envision, would serve as an important improvement in the efficiency of industrial level synthesis of a life-saving cancer drug

Bounds on the possible evolution of the Gravitational Constant from Cosmological Type-Ia Supernovae

Recent high-redshift Type Ia supernovae results can be used to set new bounds on a possible variation of the gravitational constant $G$. If the local value of $G$ at the space-time location of distant supernovae is different, it would change both the kinetic energy release and the amount of $^{56}$Ni synthesized in the supernova outburst. Both effects are related to a change in the Chandrasekhar mass $M_{Ch} \propto G^{-3/2}$. In addition, the integrated variation of $G$ with time would also affect the cosmic evolution and therefore the luminosity distance relation. We show that the later effect in the magnitudes of Type Ia supernovae is typically several times smaller than the change produced by the corresponding variation of the Chandrasekhar mass. We investigate in a consistent way how a varying $G$ could modify the Hubble diagram of Type Ia supernovae and how these results can be used to set upper bounds to a hypothetical variation of $G$. We find G/G_0 \la 1.1 and G'/G \la 10^{-11} yr^{-1} at redshifts $z\simeq 0.5$. These new bounds extend the currently available constrains on the evolution of $G$ all the way from solar and stellar distances to typical scales of Gpc/Gyr, i.e. by more than 15 orders of magnitudes in time and distance.Comment: 9 pages, 4 figures, Phys. Rev. D. in pres

Somatic complaints and childhood anxiety disorders

RESUMEN. Los síntomas somáticos en niños han sido asociados con trastornos de interiorización, especialmente de ansiedad. Sin embargo, pocos estudios han examinado los síntomas somáticos precisos en trastornos de ansiedad específicos. Desde este estudio cuasi-experimental se examinan el tipo y la frecuencia de síntomas somáticos en niños (n = 178; rango de edad 7¿14 años) con trastorno generalizado de ansiedad (TAG), fobia social (FS), ansiedad de separación (AS) y sin ningún trastorno de ansiedad. Los niños y sus padres, que acudieron en busca de tratamiento, completaron una entrevista diagnóstica estructurada, los niños completaron además la Multidimensional Anxiety Scale for Children (MASC) (March, Parker, Sullivan, Stallings, y Conners). Los niños diagnosticados con un trastorno de ansiedad informaron de síntomas somáticos más frecuentes que aquellos sin trastorno de ansiedad, pero los síntomas somáticos no difirieron entre los principales grupos de trastornos de ansiedad. Los niños con trastornos de ansiedad y depresivos comórbidos manifestaron síntomas somáticos más frecuentemente que aquellos sin trastornos comórbidos. Se discuten los resultados en términos de los síntomas somáticos como a) criterios dentro del sistema diagnóstico, y b) parte del proceso de evitación

Shared-Medical Appointment for Screening and Risk Assessment for Fall Prevention.

Background: The median age of Americans is rising and fall risk increases with age. While the causes of falls are multifactorial, falls risk can be reduced. Only a small percentage of older-adults report being asked about fall risk or falls. The CDC has initiated a Stopping Elderly Accidents, Deaths and Injuries (STEADI) toolkit, but penetration into practice has been slow. To address this, we implemented a Falls Prevention Shared Medical Appointment (SMA) at an academic internal medicine clinic. Methods: Patients were referred to the SMA and scheduled per their preference virtually or in-person. Patients attended a nurse visit for appropriate fallrisk related screening, followed by the SMA with two physicians for review of medical history, fall screening results and implementation of fall reduction strategies. Follow-up survey of the patients assessed program effectiveness. Results: Fifty-two patients were seen/assessed between November 2021 and February 2023 with SMAs ranging from 3 to 5 patients with an average age of 77 (=/- 6.7). Questionnaire self-reported risk factors, self-reported strength, and polypharmacy were associated with objective markers of increased fall risk. Survey results indicate acceptability of this model. Conclusion: Falls prevention SMAs can be effective. More work is needed to further delineate and refine cohort selection

Could vitamin D sufficiency improve the survival of colorectal cancer patients?

PurposeTo determine whether a higher serum 25-hydroxyvitamin D [25(OH)D] concentration at diagnosis is associated with longer survival of colorectal cancer patients.MethodsA meta-analysis was performed of studies of the relationship between 25(OH)D and mortality of patients with colorectal cancer. A random-effects model was used to calculate a pooled hazards ratio. Homogeneity was evaluated through a DerSimonian-Laird test.ResultsHigher serum concentrations of 25(OH)D were associated with lower mortality in patients with colorectal cancer. Patients in the highest quintile of 25(OH)D had 37% lower mortality from colorectal cancer compared to those in the lowest quintile of 25(OH)D (pooled odds ratio=0.63, p<0.0001). Dose-response curves showed lower hazard ratios for mortality with higher serum 25(OH)D through at least 40ng/ml. There were no exceptions.ConclusionsHigher serum 25(OH)D was associated with lower mortality of patients with colorectal cancer. These results suggest that colorectal cancer patients with deficient levels of serum 25(OH)D should have their levels restored to a normal range (30-80ng/ml). This could be done with regular testing of serum 25(OH)D to be confident that an adequate serum level is being maintained. Additional studies would be worthwhile to evaluate confounding or the possibility of reverse causation

Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE.

BackgroundCurrent guidelines do not recommend screening for non-alcoholic fatty liver disease (NAFLD) or advanced fibrosis. Patients with type 2 diabetes mellitus (T2DM) are known to be at increased risk for NAFLD and advanced fibrosis.AimTo assess the feasibility in diabetics in a primary care setting of screening for NAFLD and advanced fibrosis, by using non-invasive magnetic resonance imaging (MRI) to estimate the hepatic proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to estimate hepatic stiffness.MethodsWe performed a cross-sectional analysis of a prospective study that included 100 (53% men) consecutively enrolled diabetics who did not have any other aetiology of liver disease. All patients underwent a standardised research visit, laboratory tests, MRI-PDFF, and MRE.ResultsMean (±s.d.) age and body mass index (BMI) was 59.7 (±11.2) years and 30.8 (±6.5) kg/m(2) , respectively. The prevalence of NAFLD (defined as MRI-PDFF ≥5%) and advanced fibrosis (defined as MRE ≥3.6 kPa) was 65% and 7.1%, respectively. One patient with advanced fibrosis had definite hepatocellular carcinoma. When compared to those without NAFLD, patients with NAFLD were younger (P = 0.028) and had higher mean BMI (P = 0.0008), waist circumference (P < 0.0001) and prevalence of metabolic syndrome (84.6% vs. 40.0%, P < 0.0001). Only 26% of those with NAFLD had elevated alanine aminotransferase.ConclusionsThis proof-of-concept study demonstrates that T2DM has significant rates of both NAFLD and advanced fibrosis. Concomitant screening for NAFLD and advanced fibrosis by using MRI-proton density fat fraction and magnetic resonance elastography in T2DM is feasible and may be considered after validation in a larger cohort

Non-invasive screening of diabetics in primary care for NAFLD and advanced fibrosis by MRI and MRE

© 2015 John Wiley & Sons Ltd. Background Current guidelines do not recommend screening for non-alcoholic fatty liver disease (NAFLD) or advanced fibrosis. Patients with type 2 diabetes mellitus (T2DM) are known to be at increased risk for NAFLD and advanced fibrosis. Aim To assess the feasibility in diabetics in a primary care setting of screening for NAFLD and advanced fibrosis, by using non-invasive magnetic resonance imaging (MRI) to estimate the hepatic proton density fat fraction (MRI-PDFF) and magnetic resonance elastography (MRE) to estimate hepatic stiffness. Methods We performed a cross-sectional analysis of a prospective study that included 100 (53% men) consecutively enrolled diabetics who did not have any other aetiology of liver disease. All patients underwent a standardised research visit, laboratory tests, MRI-PDFF, and MRE. Results Mean (±s.d.) age and body mass index (BMI) was 59.7 (±11.2) years and 30.8 (±6.5) kg/m2, respectively. The prevalence of NAFLD (defined as MRI-PDFF ≥5%) and advanced fibrosis (defined as MRE ≥3.6 kPa) was 65% and 7.1%, respectively. One patient with advanced fibrosis had definite hepatocellular carcinoma. When compared to those without NAFLD, patients with NAFLD were younger (P = 0.028) and had higher mean BMI (P = 0.0008), waist circumference (P < 0.0001) and prevalence of metabolic syndrome (84.6% vs. 40.0%, P < 0.0001). Only 26% of those with NAFLD had elevated alanine aminotransferase. Conclusions This proof-of-concept study demonstrates that T2DM has significant rates of both NAFLD and advanced fibrosis. Concomitant screening for NAFLD and advanced fibrosis by using MRI-proton density fat fraction and magnetic resonance elastography in T2DM is feasible and may be considered after validation in a larger cohort