Editing aberrant splice sites efficiently restores β-globin expression in β-thalassemia.

The thalassemias are compelling targets for therapeutic genome editing in part because monoallelic correction of a subset of hematopoietic stem cells (HSCs) would be sufficient for enduring disease amelioration. A primary challenge is the development of efficient repair strategies that are effective in HSCs. Here, we demonstrate that allelic disruption of aberrant splice sites, one of the major classes of thalassemia mutations, is a robust approach to restore gene function.

Changes in exhaled 13CO2/12CO2 breath delta value as an early indicator of infection in intensive care unit patients.

Background: We have developed a new, noninvasive predictive marker for onset of infection in surgical intensive care unit (ICU) patients. The exhaled CO2/CO2 ratio, or breath delta value (BDV), has been shown to be an early marker for infection in a proof of concept human study and in animal models of bacterial peritonitis. In these studies, the BDV changes during onset and progression of infection, and these changes precede physiological changes associated with infection.

Toward economic evaluation of the value of vaccines and other health technologies in addressing AMR.

We discuss the need to make economic evaluations of vaccines antimicrobial resistance (AMR)-sensitive and ways to do so. Such AMR-sensitive evaluations can play a role in value-for-money comparisons of different vaccines within a national immunization program, or in comparisons of vaccine-centric and non-vaccine-centric technologies within an anti-AMR program. In general terms, incremental cost-effectiveness ratios and rates of return and their associated decision rules are unaltered by consideration of AMR-related value.

Military-related risk factors in female veterans and risk of dementia.

Objective: To determine whether diagnoses of traumatic brain injury (TBI), posttraumatic stress disorder (PTSD), and depression, alone or in combination, increase dementia risk among older female veterans.

Methods: This cohort study included data from 109,140 female veterans ≥55 years of age receiving care from Veterans Health Administration medical centers in the United States between October 2004 and September 2015 with at least 1 follow-up visit. TBI, PTSD, depression, and medical conditions at study baseline and incident dementia were determined according to ICD-9-CM codes.

The promise and peril of universal health care.

Universal health care (UHC) is garnering growing support throughout the world, a reflection of social and economic progress and of the recognition that population health is both an indicator and an instrument of national development. Substantial human and financial resources will be required to achieve UHC in any of the various ways it has been conceived and defined. Progress toward achieving UHC will be aided by new technologies, a willingness to shift medical tasks from highly trained to appropriately well-trained personnel, a judicious balance between the quantity and quality of health care services, and resource allocation decisions that acknowledge the important role of public health interventions and nonmedical influences on population health.

Target-Directed Self-Assembly of Homodimeric Drugs Against β-Tryptase.

Tryptase, a serine protease released from mast cells, is implicated in many allergic and inflammatory disorders. Human tryptase is a donut-shaped tetramer with the active sites facing inward forming a central pore. Bivalent ligands spanning two active sites potently inhibit this configuration, but these large compounds have poor drug-like properties.

Mild TBI and risk of Parkinson disease: A Chronic Effects of Neurotrauma Consortium Study.

Objective: Our aim was to assess risk of Parkinson disease (PD) following traumatic brain injury (TBI), including specifically mild TBI (mTBI), among care recipients in the Veterans Health Administration.

Methods: In this retrospective cohort study, we identified all patients with a TBI diagnosis in Veterans Health Administration databases from October 2002 to September 2014 and age-matched 1:1 to a random sample of patients without TBI. All patients were aged 18 years and older without PD or dementia at baseline.

Physical characterization and in vivo organ distribution of coated iron oxide nanoparticles.

Citrate-stabilized iron oxide magnetic nanoparticles (MNPs) were coated with one of carboxymethyl dextran (CM-dextran), polyethylene glycol-polyethylene imine (PEG-PEI), methoxy-PEG-phosphate+rutin, or dextran. They were characterized for size, zeta potential, hysteresis heating in an alternating magnetic field, dynamic magnetic susceptibility, and examined for their distribution in mouse organs following intravenous delivery. Except for PEG-PEI-coated nanoparticles, all coated nanoparticles had a negative zeta potential at physiological pH.

Utilization of rehabilitation therapy services in Parkinson disease in the United States.

Objective: To examine rehabilitation therapy utilization for Parkinson disease (PD).

Methods: We identified 174,643 Medicare beneficiaries with a diagnosis of PD in 2007 and followed them through 2009. The main outcome measures were annual receipt of physical therapy (PT), occupational therapy (OT), or speech therapy (ST).

Impact of a Mobile Health Application on User Engagement and Pregnancy Outcomes Among Wyoming Medicaid Members.

Background: Pregnancy and birth outcomes are a critical area of healthcare, yet negative outcomes like C-sections and preterm births remain widespread. Studies show that early and ongoing prenatal care can improve outcomes; however, in-person care is difficult to deliver in rural areas. This article examines the impact of mobile health technology on user engagement and birth outcomes in a Wyoming pilot study.

Functional interrogation of non-coding DNA through CRISPR genome editing.

Methodologies to interrogate non-coding regions have lagged behind coding regions despite comprising the vast majority of the genome. However, the rapid evolution of clustered regularly interspaced short palindromic repeats (CRISPR)-based genome editing has provided a multitude of novel techniques for laboratory investigation including significant contributions to the toolbox for studying non-coding DNA. CRISPR-mediated loss-of-function strategies rely on direct disruption of the underlying sequence or repression of transcription without modifying the targeted DNA sequence.

PET-based Imaging of Chemokine Receptor 2 in Experimental and Disease-related Lung Inflammation.

Purpose To characterize a chemokine receptor type 2 (CCR2)-binding peptide adapted for use as a positron emission tomography (PET) radiotracer for noninvasive detection of lung inflammation in a mouse model of lung injury and in human tissues from subjects with lung disease. Materials and Methods The study was approved by institutional animal and human studies committees. Informed consent was obtained from patients.

Disruption of the GH Receptor Gene in Adult Mice Increases Maximal Lifespan in Females.

GH and IGF-1 are important for a variety of physiological processes including growth, development, and aging. Mice with reduced levels of GH and IGF-1 have been shown to live longer than wild-type controls. Our laboratory has previously found that mice with a GH receptor gene knockout (GHRKO) from conception exhibit low rates of cancer, resistance to diet-induced diabetes, and extension of lifespan.

Fluid Shear Stress Promotes Placental Growth Factor Upregulation in Human Syncytiotrophoblast Through the cAMP-PKA Signaling Pathway.

The effects of fluid shear stress (FSS) on the human syncytiotrophoblast and its biological functions have never been studied. During pregnancy, the syncytiotrophoblast is the main source of placental growth factor (PlGF), a proangiogenic factor involved in the placental angiogenesis and the vascular adaptation to pregnancy. The role of FSS in regulating PlGF expression in syncytiotrophoblasts is unknown.

Increased ratio of circulating neutrophils to monocytes in amyotrophic lateral sclerosis.

Objective: To elucidate amyotrophic lateral sclerosis (ALS) biomarkers and potential mechanisms of disease, we measured immune cell populations in whole blood from a large cohort of patients with ALS.

Methods: Leukocytes were isolated from the blood of 44 control patients and 90 patients with ALS. The percentages and total numbers of each cell population were analyzed using flow cytometry and matched with patient ALS Functional Rating Scale-Revised (ALSFRS-R) score to correlate leukocyte metrics with disease progression.

Creation of an NCI comparative brain tumor consortium: informing the translation of new knowledge from canine to human brain tumor patients.

On September 14-15, 2015, a meeting of clinicians and investigators in the fields of veterinary and human neuro-oncology, clinical trials, neuropathology, and drug development was convened at the National Institutes of Health campus in Bethesda, Maryland. This meeting served as the inaugural event launching a new consortium focused on improving the knowledge, development of, and access to naturally occurring canine brain cancer, specifically glioma, as a model for human disease. Within the meeting, a SWOT (strengths, weaknesses, opportunities, and threats) assessment was undertaken to critically evaluate the role that naturally occurring canine brain tumors could have in advancing this aspect of comparative oncology aimed at improving outcomes for dogs and human beings.

Cardiac-Specific Disruption of GH Receptor Alters Glucose Homeostasis While Maintaining Normal Cardiac Performance in Adult Male Mice.

GH is considered necessary for the proper development and maintenance of several tissues, including the heart. Studies conducted in both GH receptor null and bovine GH transgenic mice have demonstrated specific cardiac structural and functional changes. In each of these mouse lines, however, GH-induced signaling is altered systemically, being decreased in GH receptor null mice and increased in bovine GH transgenic mice.

Haplotyping germline and cancer genomes with high-throughput linked-read sequencing.

Haplotyping of human chromosomes is a prerequisite for cataloguing the full repertoire of genetic variation. We present a microfluidics-based, linked-read sequencing technology that can phase and haplotype germline and cancer genomes using nanograms of input DNA. This high-throughput platform prepares barcoded libraries for short-read sequencing and computationally reconstructs long-range haplotype and structural variant information.

STARD 2015: An Updated List of Essential Items for Reporting Diagnostic Accuracy Studies.

Incomplete reporting has been identified as a major source of avoidable waste in biomedical research. Essential information is often not provided in study reports, impeding the identification, critical appraisal, and replication of studies. To improve the quality of reporting of diagnostic accuracy studies, the Standards for Reporting of Diagnostic Accuracy Studies (STARD) statement was developed.

Effects of TZD Use and Discontinuation on Fracture Rates in ACCORD Bone Study.

Context: In trials, thiazolidinediones (TZDs) increase fracture risk in women, but the effects of discontinuation are unknown.

Objective: The objective was to investigate the effects of TZD use and discontinuation on fractures in women and men.

Design: This was a longitudinal observational cohort study using data from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial bone ancillary study.

Core domain and outcome measurement sets for shoulder pain trials are needed: systematic review of physical therapy trials.

Objectives: To explore the outcome domains and measurement instruments reported in published randomized controlled trials of physical therapy interventions for shoulder pain (rotator cuff disease, adhesive capsulitis, or nonspecific shoulder pain).

Study Design And Setting: We included trials comparing physical therapy to any other intervention for shoulder pain, indexed up to March 2015 in CENTRAL, MEDLINE, EMBASE, or CINAHL Plus. Two authors independently selected trials for inclusion and extracted information on the domains and measurement instruments reported.