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Dacheng Ma, Shuguang Peng, Weiren Huang, Zhiming Cai, Zhen Xie
Nuclease dead Cas9 (dCas9) has been widely used for modulating gene expression by fusing with different activation or repression domains. However, delivery of the CRISPR/Cas system fused with variant effector domains in a single adeno-associated virus (AAV) remains challenging due to the payload limit. Here, we engineered a set of downsized variants of Cas9 including Staphylococcus aureus Cas9 (SaCas9) that retained DNA binding activity by deleting conserved functional domains. We demonstrated that fusing FokI nuclease domain to the N-terminal of the minimal SaCas9 (mini-SaCas9) or to the middle of the split mini-SaCas9 can trigger efficient DNA cleavage...
March 21, 2018: ACS Synthetic Biology
Dennis A Smith, Timothy Hammond, Thomas A Baillie
While simple O- (ether-linked) and N-glucuronide drug conjugates generally are unreactive and considered benign from a safety perspective, the acyl glucuronides that derive from metabolism of carboxylic acid-containing xenobiotics can exhibit a degree of chemical reactivity that is dependent upon their molecular structure. As a result, concerns have arisen over the safety of acyl glucuronides as a class, several members of which have been implicated in the toxicity of their respective parent drugs. However, direct evidence in support of these claims remains sparse, and due to frequently encountered species differences in the systemic exposure to acyl glucuronides (both of parent drug and oxidized derivatives thereof), coupled with their instability in aqueous media and potential to undergo chemical rearrangement (acyl migration), qualification of these conjugates by traditional safety assessment methods can be very challenging...
March 20, 2018: Drug Metabolism and Disposition: the Biological Fate of Chemicals
Laura Arkwright, Susan Edgar, James Debenham
BACKGROUND: Despite increasing workforce numbers, new graduate physiotherapists are reporting short career intentions due to low job satisfaction. Job satisfaction improves retention among allied health professionals, however we have limited understanding of its influence specific to physiotherapists. OBJECTIVES: The aim of this study was to explore factors contributing to the job satisfaction of musculoskeletal physiotherapists working in private practice across different career stages (new graduates, graduates, postgraduates, and owners) in Western Australia...
March 10, 2018: Musculoskeletal Science & Practice
Laura M Wagner, Mary A Dolansky, Robert Englander
BACKGROUND: Further efforts are warranted to identify innovative approaches to best implement competencies in nursing education. To bridge the gap between competency-based education, practice, and implementation of knowledge, skills, and attitudes, one emerging approach is entrustable professional activities (EPAs). PURPOSE: The objective of this study was to introduce the concept of EPAs as a framework for curriculum and assessment in graduate nursing education and training...
November 22, 2017: Nursing Outlook
Yuhong Xiang, Jean Donley, Elena Seletskaia, Sonal Shingare, John Kamerud, Boris Gorovits
In ligand binding assays (LBA), the concentration to response data is a nonlinear relationship driven by the law of mass action. Four parameter logistic (4PL) and five parameter logistic (5PL) curve fitting models are two widely accepted and validated models for LBA calibration curve data. Selection of the appropriate regression model and weighting function are key components of LBA development. Assessment of selected model and weighting function should be performed during assay development and confirmed later during validation...
March 13, 2018: AAPS Journal
Ryan H Belcher, David W Molter, Steven L Goudy
Despite humanitarian otolaryngology groups traveling in record numbers to resource-limited areas treating pediatric otolaryngology disease processes and training local providers, there remains a large burden of unmet needs. There is a meager amount of published information that comes from the developing world from an otolaryngology standpoint. As would be expected, the little information that does comes involves some of the most common pediatric otolaryngology diseases and surgical burdens including childhood hearing loss, otitis media, adenotonsillectomies, airway obstructions requiring tracheostomies, foreign body aspirations, and craniomaxillofacial surgeries, including cleft lip and palate...
March 7, 2018: Otolaryngologic Clinics of North America
Mahipal G Sinnollareddy, Michael S Roberts, Jeffrey Lipman, Sandra L Peake, Jason A Roberts
Background: Piperacillin is a β-lactam penicillin antibiotic commonly used for the empirical therapy of sepsis and other hospital-acquired infections. However, knowledge regarding the effect of sustained low-efficiency diafiltration (SLED-f), a technique increasingly being used in ICUs, on piperacillin pharmacokinetics (PK) and dosing in critically ill patients is lacking. Objectives: To describe the PK of piperacillin during SLED-f and compare the results with those reported for other forms of renal replacement therapies...
March 1, 2018: Journal of Antimicrobial Chemotherapy
Hyoungkyu Kim, Anthony G Hudetz, Joseph Lee, George A Mashour, UnCheol Lee
The integrated information theory (IIT) proposes a quantitative measure, denoted as Φ, of the amount of integrated information in a physical system, which is postulated to have an identity relationship with consciousness. IIT predicts that the value of Φ estimated from brain activities represents the level of consciousness across phylogeny and functional states. Practical limitations, such as the explosive computational demands required to estimate Φ for real systems, have hindered its application to the brain and raised questions about the utility of IIT in general...
2018: Frontiers in Human Neuroscience
Romina Mariano, Eoin P Flanagan, Brain G Weinshenker, Jacqueline Palace
Every neurologist will be familiar with the patient with atypical spinal cord disease and the challenges of taking the diagnosis forward. This is predominantly because of the limited range of possible clinical and investigation findings making most individual features non-specific. The difficulty in obtaining a tissue diagnosis further contributes and patients are often treated empirically based on local prevalence and potential for reversibility. This article focuses on improving the diagnosis of adult non-traumatic, non-compressive spinal cord disorders...
March 2, 2018: Practical Neurology
Melinda Raab, Carl J Dunst, Deborah W Hamby
AIM: The purpose of the study was to isolate the sources of variations in the rates of response-contingent learning among young children with multiple disabilities and significant developmental delays randomly assigned to contrasting types of early childhood intervention. METHOD: Multilevel, hierarchical linear growth curve modelling was used to analyze four different measures of child response-contingent learning where repeated child learning measures were nested within individual children (Level-1), children were nested within practitioners (Level-2), and practitioners were nested within the contrasting types of intervention (Level-3)...
February 27, 2018: Research in Developmental Disabilities
Yiyi Chu, Ying Yuan
BACKGROUND: The basket trial evaluates the treatment effect of a targeted therapy in patients with the same genetic or molecular aberration, regardless of their cancer types. Bayesian hierarchical modeling has been proposed to adaptively borrow information across cancer types to improve the statistical power of basket trials. Although conceptually attractive, research has shown that Bayesian hierarchical models cannot appropriately determine the degree of information borrowing and may lead to substantially inflated type I error rates...
February 1, 2018: Clinical Trials: Journal of the Society for Clinical Trials
Adamasco Cupisti, Csaba P Kovesdy, Claudia D'Alessandro, Kamyar Kalantar-Zadeh
Whereas the adequate intake of potassium is relatively high in healthy adults, i.e., 4.7 g per day, a dietary potassium restriction of usually less than 3 g per day is recommended in the management of patients with reduced kidney function, especially those who tend to develop hyperkalaemia including patients who are treated with angiotensin pathway modulators. Most potassium-rich foods are considered heart-healthy nutrients with high fibre, high anti-oxidant vitamins and high alkali content such as fresh fruits and vegetables; hence, the main challenge of dietary potassium management is to maintain high fibre intake and a low net fixed-acid load, because constipation and metabolic acidosis are per se major risk factors for hyperkalaemia...
February 25, 2018: Nutrients
Mark C Liszewski, Edward Y Lee
OBJECTIVE: Lung disease is a common indication for newborns to require medical attention, and neonatal chest radiographs are among the most common studies interpreted by pediatric radiologists. Radiographic features of many neonatal lung disorders overlap, and it may be difficult to differentiate among conditions. CONCLUSION: This review presents an up-to-date practical approach to the radiologic diagnosis of neonatal lung disorders, with a focus on pattern recognition and consideration of clinical history, patient age, and symptoms...
February 28, 2018: AJR. American Journal of Roentgenology
Grace H Elta, Brintha K Enestvedt, Bryan G Sauer, Anne Marie Lennon
Pancreatic cysts are very common with the majority incidentally identified. There are several types of pancreatic cysts; some types can contain cancer or have malignant potential, whereas others are benign. However, even the types of cysts with malignant potential rarely progress to cancer. At the present time, the only viable treatment for pancreatic cysts is surgical excision, which is associated with a high morbidity and occasional mortality. The small risk of malignant transformation, the high risks of surgical treatment, and the lack of high-quality prospective studies have led to contradictory recommendations for their immediate management and for their surveillance...
February 27, 2018: American Journal of Gastroenterology
Lori Berard, Noreen Antonishyn, Kathryn Arcudi, Sarah Blunden, Alice Cheng, Ronald Goldenberg, Stewart Harris, Shelley Jones, Upender Mehan, James Morrell, Robert Roscoe, Rick Siemens, Michael Vallis, Jean-François Yale
It is currently estimated that 11 million Canadians are living with diabetes or prediabetes. Although hyperglycemia is associated with serious complications, it is well established that improved glycemic control reduces the risk of microvascular complications and can also reduce cardiovascular (CV) complications over the long term. The UKPDS and ADVANCE landmark trials have resulted in diabetes guidelines recommending an A1C target of ≤ 7.0% for most patients or a target of ≤ 6.5% to further reduce the risk of nephropathy and retinopathy in those with type 2 diabetes (T2D), if it can be achieved safely...
February 23, 2018: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
Arne Reimers, Jon Andsnes Berg, Margrete Larsen Burns, Eylert Brodtkorb, Svein I Johannessen, Cecilie Johannessen Landmark
Background and objective: Laboratories sometimes use different reference ranges for the same antiepileptic drug (AED), particularly for new and poorly investigated drugs. This may contribute to misunderstandings, concerns or inappropriate dose changes, which in turn may affect therapeutic effect, drug safety or treatment adherence. Therefore, the Norwegian Association of Clinical Pharmacology wished to update and harmonize the reference ranges for AEDs and establish national guidelines for Norway...
2018: Drug Design, Development and Therapy
Sanjay Kalra, Suresh K Sharma
The elderly are an important and distinct yet heterogeneous group of persons living with diabetes. The elderly have a unique biomedical, psychological, and social constitution. Their needs are different from those of younger adults. This implies that special care must be taken while evaluating and planning their nursing and management. Diabetes management in the elderly should focus on prevention and limitation of geriatric syndromes (medical conditions encountered in elderly persons), hypoglycemia (low blood glucose), and neurocognitive dysfunction (impairment in the functioning of the nervous system and brain)...
February 19, 2018: Diabetes Therapy: Research, Treatment and Education of Diabetes and related Disorders
Marcos Pereira Estellita Lins, Sergio Orlando Antoun Netto, Maria Stella de Castro Lobo
The integration of quantitative indicators with qualitative descriptions of context is a noticeable demand from many different scientific disciplines, since it contributes to linking theoretical and practical approaches to problem solving. Amongst them are the problem structuring methods, systems thinking and multimethodology. This work presents a mixed quantitative and qualitative methodological approach to aid formulation and structuring of performance measurement of health care in 5565 Brazilian municipalities...
February 19, 2018: Health Care Management Science
Juliano Lara Fernandes
MRI is a key tool in the current management of patients with thalassemia. Given its capability of assessing iron overload in different organs noninvasively and without contrast, it has significant advantages over other metrics, including serum ferritin. Liver iron concentration can be measured either with relaxometry methods T2*/T2 or signal intensity ratio techniques. Myocardial iron can be assessed in the same examination through T2* imaging. In this review, we focus on showing how MRI evaluates iron in both organs and the clinical applications as well as practical approaches to using this tool by clinicians taking care of patients with thalassemia...
April 2018: Hematology/oncology Clinics of North America
P Ethicist
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February 1, 2018: Journal of Empirical Research on Human Research Ethics: JERHRE
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