Analysis of signal-to-noise behavior in Cartesian continuous sampling sequences: predictions and experimental validation of opportunities for improved image SNR.

Image signal-to-noise ratio (SNR) limits many MRI applications. Here we propose a method to improve SNR based on continuous sampling (CS) during each TR without significant increases in acquisition time. The general concept of CS is defined here as sampling the NMR signal immediately after slice excitation including ramp times, both the dephase and rephase lobes, the phase-encoding (PE) gradient application, and the slice refocusing gradient. This study analyzes several cases of CS and demonstrates a specific case where sampling occurs during an isolated and balanced readout gradient in order to increase SNR in a rectilinear Cartesian sequence without significantly increasing overall acquisition time. The noise correlation consequences of rectilinear CS are mathematically derived and proven through simulation. The SNR improvement of up to approximately 40% measured in both phantom and asymptomatic human volunteer images is comparable to theoretical prediction of increased SNR proportional to the increase in the square root of the sampling time.     

Preterm Birth Among US and Foreign-Born Non-Hispanic Black Birthing Parents in Massachusetts: Variation by Nativity,Region, and Country of Origin

Maternal and Child Health Journal - Foreign-born non-Hispanic Black (NHB) birthing parents are less likely to have a preterm birth (PTB) than US-born NHBs. There is further variation by region and...     

ASO Visual Abstract: Chemotherapy After Diagnosis of Malignant Bowel Obstruction is Associated with Greater Survival for Medicare Patients with Advanced Malignancy

Annals of Surgical Oncology -     

COVID-19 Treatment: Drug Safety Prior to Conception and During Pregnancy and Breastfeeding

In December 2019, a new viral respiratory infection known as coronavirus disease 2019 (COVID-19) was first diagnosed in the city of Wuhan, China. COVID-19 quickly spread across the world, leading the World Health Organization to declare it a pandemic on March 11, 2020. The disease is caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a similar virus to those involved in other epidemics such as severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV). Epidemiological studies have shown that COVID-19 frequently affects young adults of reproductive age and that the elderly and patients with chronic disease have high mortality rates. Little is known about the impact of COVID-19 on pregnancy and breastfeeding. Most COVID-19 cases present with mild flu-like symptoms and only require treatment with symptomatic relief medications, whereas other cases with COVID-19 require treatment in an intensive care unit. There is currently no specific effective treatment for COVID-19. A large number of drugs are being used to fight infection by SARS-CoV-2. Experience with this therapeutic arsenal has been gained over the years in the treatment of other viral, autoimmune, parasitic, and bacterial diseases. Importantly, the search for an effective treatment for COVID-19 cannot expose pregnant women infected with SARS-CoV-2 to the potential teratogenic risks of these drugs. Therefore, it is necessary to determine and understand the safety of anti-COVID-19 therapies prior to conception and during pregnancy and breastfeeding.Key words: COVID-19, SARS-CoV-2, antiviral, pregnancy, breastfeeding     

Confirmation of a major QTL influencing oral morphine intake in C57 and DBA mice using reciprocal congenic strains.

C57BL/6 (B6) and DBA/2 (D2) mice exhibit disparate behavior when tested for voluntary morphine intake in a two-bottle choice drinking paradigm with B6 mice consuming 10 times more drug than D2 mice. Previous genetic mapping studies identified a locus, Mop2, on the proximal part of chromosome 10 that explained over half of the genetic variance in this mouse model of opioid self-administration. We constructed a set of reciprocal congenic strains between B6 and D2 mice in which the proximal portion of chromosome 10 has been introgressed from one strain onto the background of the other. We tested mice from this pair of reciprocal strains together with progenitor B6 and D2 mice in a two-bottle choice drinking paradigm with morphine and quinine. The results showed that introgression of chromosome 10 alleles from the B6 strain onto a D2 genetic background increased voluntary morphine intake four-fold compared to progenitor D2 mice. Preference for morphine was also increased significantly in D2.B6-Mop2 mice compared to progenitor D2 mice. Conversely, introgression of chromosome 10 alleles from the D2 strain onto a B6 genetic background decreased morphine intake by half compared to progenitor B6 mice in B6.D2 -Mop2 mice; however, high morphine preference was maintained in this congenic strain most likely due to strong quinine aversion. When quinine was eliminated from the control bottle, morphine preference in B6.D2-Mop2 mice was decreased significantly relative to B6 and D2.B6-Mop2 mice. Overall, these data confirm the existence of a gene(s) on chromosome 10 proximal to D10Mit124 that has a strong influence on the difference in morphine drinking behavior between B6 and D2 mice.     

The impact of age and comorbidities on practice patterns and outcomes in patients with relapsed/refractory multiple myeloma in the era of novel therapies

Objectives

One-third of patients with multiple myeloma (MM) are diagnosed at age ≥ 75 years. Older patients have increased incidence of cardiovascular disease (CVD) and renal insufficiency (RI), hallmark complications of MM. We examined cumulative incidence of CVD and RI in relapsed/refractory MM (RRMM) and outcomes by age and RI/CVD.

Rituximab pediatric drug development: Pharmacokinetic and pharmacodynamic modeling to inform regulatory approval for rituximab treatment in patients with granulomatosis with polyangiitis or microscopic polyangiitis

Anti‐neutrophil cytoplasmic antibody‐associated vasculitides granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) are rare, potentially organ‐ and life‐threatening autoimmune conditions affecting adult and pediatric patients. An open‐label phase II study was conducted to determine safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA. To determine the selection of an appropriate dose regimen in children for induction and maintenance, a population pharmacokinetic approach was used (nonlinear mixed‐effect modeling), combining pediatric data with data from adults with GPA/MPA. The time course of B‐cell depletion was assessed in both populations. The exposure‐effect relationship was assessed by logistic regression. Twenty‐five pediatric patients (80% female patients; age range, 6–17 years) were enrolled in the trial and received the induction regimen of intravenous rituximab 375 mg/m² weekly for 4 weeks, which resulted in a similar exposure to that of adults. Based on pharmacokinetic modeling, a maintenance dosing regimen of 250 mg/m² administered twice over 14 days followed by 250 mg/m² every 6 months is expected to result in similar rituximab exposure as that of adults receiving the approved maintenance dose of 500 mg administered twice over 14 days followed by 500 mg every 6 months. The time course of B‐cell depletion was similar between the pediatric and adult populations, supporting the similarities in response in both populations and allowing extrapolation to patients less than 6 years old. Using a partial extrapolation approach helped identify safe and effective dosing regimens of rituximab in pediatric patients with GPA/MPA and lead to regulatory approval.

Study Highlights

• WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?

Rituximab was first approved for remission induction in adult patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) and subsequently approved for remission maintenance. The approval of rituximab for pediatric patients was based on the PePRS trial, which used the same induction regimen as adults, whereas the follow‐up treatment and dosing regimen was left to the physician''s discretion.

• WHAT QUESTION DID THIS STUDY ADDRESS?

This open‐label phase II study was conducted to determine dosing regimens of rituximab in pediatric patients with GPA/MPA.

• WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?

Modeling and simulations were used to confirm the dosing regimen used for induction in patients greater than 6 years old, extrapolate to younger patients aged ≥2 to < 6 years and suggest a dosing regimen for follow‐up maintenance treatment in pediatric patients aged ≥2 to <18 years.

• HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?

The work presented here was instrumental in supporting the first approval of rituximab in pediatric patients with GPA/MPA and demonstrates the utility of model‐informed drug development to complement limited clinical trial data.