Protein modeling to assess the pathogenicity of rare variants of SERPINA1 in patients suspected of having Alpha 1 Antitrypsin Deficiency.

Background: Alpha 1 Antitrypsin (AAT) is a key serum proteinase inhibitor encoded by SERPINA1. Sequence variants of the gene can cause Alpha 1 Antitrypsin Deficiency (AATD), a condition associated with lung and liver disease. The majority of AATD cases are caused by the 'Z' and 'S' variants - single-nucleotide variations (SNVs) that result in amino acid substitutions of E342K and E264V.

Development of Level A in vitro-in vivo correlations for peptide loaded PLGA microspheres.

Peptide loaded PLGA microsphere products are more complex in terms of manufacturing, drug release characteristics as well as release mechanism compared to small molecule loaded PLGA microsphere products. This is due to the complex structure of peptides, their hydrophilicity, charged state, large size and potential for instability. Moreover, therapeutic peptides are highly potent and therefore, any unintended change in the microsphere release profile may lead to undesirable side effects and toxicity.

Characterization of branched poly(lactide-co-glycolide) polymers used in injectable, long-acting formulations.

Poly(lactide-co-glycolide) (PLGA) has been used in many injectable, long-acting depot formulations. Despite frequent use of PLGA, however, its characterization has been limited to measuring its molecular weight, lactide:glycolide (L:G) ratio, and end-group. These conventional methods are not adequate for characterization of unique PLGA polymers, such as branched PLGA.

Complex sameness: Separation of mixed poly(lactide-co-glycolide)s based on the lactide:glycolide ratio.

Poly (lactide-co-glycolide) (PLGA) has been used for making injectable, long-acting depot formulations for the last three decades. An in depth understanding of PLGA polymers is critical for development of depot formulations as their properties control drug release kinetics. To date, about 20 PLGA-based formulations have been approved by the U.

Early Cerebral Vein After Endovascular Ischemic Stroke Treatment Predicts Symptomatic Reperfusion Hemorrhage.

Background And Purpose: Parenchymal hemorrhage (PH) after endovascular mechanical thrombectomy in acute ischemic stroke leads to worse outcomes. Better clinical and imaging biomarkers of symptomatic reperfusion PH are needed to identify patients at risk. We identified clinical and imaging predictors of reperfusion PH after endovascular mechanical thrombectomy with attention to early cerebral veins (ECVs) on postreperfusion digital subtraction angiography.

Reduced Intravoxel Incoherent Motion Microvascular Perfusion Predicts Delayed Cerebral Ischemia and Vasospasm After Aneurysm Rupture.

Background And Purpose: Proximal artery vasospasm and delayed cerebral ischemia (DCI) after cerebral aneurysm rupture result in reduced cerebral perfusion and microperfusion and significant morbidity and mortality. Intravoxel incoherent motion (IVIM) magnetic resonance imaging extracts microvascular perfusion information from a multi-b value diffusion-weighted sequence. We determined whether decreased IVIM perfusion may identify patients with proximal artery vasospasm and DCI.

Right Ventricular Myofilament Functional Differences in Humans With Systemic Sclerosis-Associated Versus Idiopathic Pulmonary Arterial Hypertension.

Background: Patients with systemic sclerosis (SSc)-associated pulmonary arterial hypertension (PAH) have a far worse prognosis than those with idiopathic PAH (IPAH). In the intact heart, SSc-PAH exhibits depressed rest and reserve right ventricular (RV) contractility compared with IPAH. We tested whether this disparity involves underlying differences in myofilament function.

Prospective study of lung function and abdominal aortic aneurysm risk: The Atherosclerosis Risk in Communities study.

Background And Aims: No prospective study has investigated whether individuals with respiratory impairments, including chronic obstructive pulmonary disease (COPD) and restrictive lung disease (RLD), are at increased risk of abdominal aortic aneurysm (AAA). We aimed to prospectively investigate whether those respiratory impairments are associated with increased AAA risk.

Methods: In 1987-1989, the Atherosclerosis Risk in Communities (ARIC) study followed 14,269 participants aged 45-64 years, without a history of AAA surgery, through 2011.

Patient Outcomes and Cerebral Infarction after Ruptured Anterior Communicating Artery Aneurysm Treatment.

Background And Purpose: Anterior communicating artery aneurysm rupture and treatment is associated with high rates of dependency, which are more severe after clipping compared with coiling. To determine whether ischemic injury might account for these differences, we characterized cerebral infarction burden, infarction patterns, and patient outcomes after surgical or endovascular treatment of ruptured anterior communicating artery aneurysms.

Materials And Methods: We performed a retrospective cohort study of consecutive patients with ruptured anterior communicating artery aneurysms.

Genetic and Pharmacologic Inactivation of ANGPTL3 and Cardiovascular Disease.

Background: Loss-of-function variants in the angiopoietin-like 3 gene (ANGPTL3) have been associated with decreased plasma levels of triglycerides, low-density lipoprotein (LDL) cholesterol, and high-density lipoprotein (HDL) cholesterol. It is not known whether such variants or therapeutic antagonism of ANGPTL3 are associated with a reduced risk of atherosclerotic cardiovascular disease.

Methods: We sequenced the exons of ANGPTL3 in 58,335 participants in the DiscovEHR human genetics study.

Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E.

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE.

"Should Patients With Substance Use Disorders Be Prescribed Benzodiazepines?" No.

Patients with substance use disorders (SUDs) should not use benzodiazepines to treat anxiety, insomnia, or anything else, for the same reasons that they should not drink any alcohol or use other drugs, regardless of their primary drug used. Once the addiction "switch" is thrown on, it never again goes off. This question has additional relevance today because in 2016, the US Food and Drug Administration put black box warnings on all benzodiazepines and opioid analgesics about the serious risks associated with their concomitant use.

Restriction Spectrum Imaging Improves Risk Stratification in Patients with Glioblastoma.

Background And Purpose: ADC as a marker of tumor cellularity has been promising for evaluating the response to therapy in patients with glioblastoma but does not successfully stratify patients according to outcomes, especially in the upfront setting. Here we investigate whether restriction spectrum imaging, an advanced diffusion imaging model, performed after an operation but before radiation therapy, could improve risk stratification in patients with newly diagnosed glioblastoma relative to ADC.

Materials And Methods: Pre-radiation therapy diffusion-weighted and structural imaging of 40 patients with glioblastoma were examined retrospectively.

Evaluation of Cell Therapy on Exercise Performance and Limb Perfusion in Peripheral Artery Disease: The CCTRN PACE Trial (Patients With Intermittent Claudication Injected With ALDH Bright Cells).

Background: Atherosclerotic peripheral artery disease affects 8% to 12% of Americans >65 years of age and is associated with a major decline in functional status, increased myocardial infarction and stroke rates, and increased risk of ischemic amputation. Current treatment strategies for claudication have limitations. PACE (Patients With Intermittent Claudication Injected With ALDH Bright Cells) is a National Heart, Lung, and Blood Institute-sponsored, randomized, double-blind, placebo-controlled, phase 2 exploratory clinical trial designed to assess the safety and efficacy of autologous bone marrow-derived aldehyde dehydrogenase bright (ALDHbr) cells in patients with peripheral artery disease and to explore associated claudication physiological mechanisms.

Right Ventricular Functional Reserve in Pulmonary Arterial Hypertension.

Background: Right ventricular (RV) functional reserve affects functional capacity and prognosis in patients with pulmonary arterial hypertension (PAH). PAH associated with systemic sclerosis (SSc-PAH) has a substantially worse prognosis than idiopathic PAH (IPAH), even though many measures of resting RV function and pulmonary vascular load are similar. We therefore tested the hypothesis that RV functional reserve is depressed in SSc-PAH patients.

Restriction spectrum imaging predicts response to bevacizumab in patients with high-grade glioma.

Background: Diffusion-weighted imaging has shown initial promise for evaluating response to bevacizumab in patients with high-grade glioma (HGG). However, it is well recognized that the apparent diffusion coefficient (ADC) is influenced by bevacizumab-induced reductions in edema, which may limit its prognostic value. We demonstrate that an advanced diffusion-weighted imaging technique, restriction spectrum imaging (RSI), improves the evaluation of response to bevacizumab because unlike ADC, RSI is not affected by resolution of edema.

Randomized Trial of Reduced-Nicotine Standards for Cigarettes.

Background: The Food and Drug Administration can set standards that reduce the nicotine content of cigarettes.

Methods: We conducted a double-blind, parallel, randomized clinical trial between June 2013 and July 2014 at 10 sites. Eligibility criteria included an age of 18 years or older, smoking of five or more cigarettes per day, and no current interest in quitting smoking.

A science based approach to topical drug classification system (TCS).

The Biopharmaceutics Classification System (BCS) for oral immediate release solid drug products has been very successful; its implementation in drug industry and regulatory approval has shown significant progress. This has been the case primarily because BCS was developed using sound scientific judgment. Following the success of BCS, we have considered the topical drug products for similar classification system based on sound scientific principles.

Brain endoplasmic reticulum stress mechanistically distinguishes the saline-intake and hypertensive response to deoxycorticosterone acetate-salt.

Endoplasmic reticulum stress has become an important mechanism in hypertension. We examined the role of endoplasmic reticulum stress in mediating the increased saline-intake and hypertensive effects in response to deoxycorticosterone acetate (DOCA)-salt. Intracerebroventricular delivery of the endoplasmic reticulum stress-reducing chemical chaperone tauroursodeoxycholic acid did not affect the magnitude of hypertension, but markedly decreased saline-intake in response to DOCA-salt.

Development of performance matrix for generic product equivalence of acyclovir topical creams.

The effect of process variability on physicochemical characteristics and in vitro performance of qualitatively (Q1) and quantitatively (Q2) equivalent generic acyclovir topical dermatological creams was investigated to develop a matrix of standards for determining their in vitro bioequivalence with reference listed drug (RLD) product (Zovirax®). A fractional factorial design of experiment (DOE) with triplicate center point was used to create 11 acyclovir cream formulations with manufacturing variables such as pH of aqueous phase, emulsification time, homogenization speed, and emulsification temperature. Three more formulations (F-12-F-14) with drug particle size representing RLD were also prepared where the pH of the final product was adjusted.

Generic development of topical dermatologic products: formulation development, process development, and testing of topical dermatologic products.

This review presents considerations which can be employed during the development of a semi-solid topical generic product. This includes a discussion on the implementation of quality by design concepts during development to ensure the generic drug product has similar desired quality attributes to the reference-listed drug (RLD) and ensure batch to batch consistency through commercial production. This encompasses the concept of reverse-engineering to copy the RLD as a strategy during product development to ensure qualitative (Q1) and quantitative (Q2) formulation similarity, as well as similarity in formulation microstructure (Q3).

The 1.9Å crystal structure of Prp20p from Saccharomyces cerevisiae and its binding properties to Gsp1p and histones.

Prp20p is the homolog of mammalian RCC1 (regulator of chromosome condensation 1) in Saccharomyces cerevisiae, which acts as the guanine nucleotide exchange factor (GEF) for Gsp1p (yeast Ran). Prp20p plays multiple roles in mRNA metabolism, nucleocytoplasmic transport and mitosis regulation. Prp20p also functions as a linker between chromatin and nuclear pore complex (NPC) which regulates the NPC-mediated boundary activity (BA).

A new apparatus for the lengthening of legs : Frank D. Dickson MD, Rex L. Diveley MD (1893-1980). The 15th president of the AAOS 1947 (RLD).

Rexford L. Diveley was born in Bazine, Kansas, in 1892, to the owner of a variety store. The family moved to the Oklahoma Territory (which had been opened for settlement in 1890).

Impaired lung function and lung cancer incidence in a cohort of Swedish construction workers.

Background: Although impaired lung function in general has been associated with an increased risk of lung cancer, past studies typically have not attempted to investigate separately the obstructive and restrictive components of respiratory impairment. To deal with this question further, data from a large (n = 176 997) cohort of male Swedish construction workers, for whom spirometry measurements before follow-up were available, were analysed.

Methods: Cancer incidence for 1971-2001 was obtained through linkage with the national cancer registry.