Combating mutations in genetic disease and drug resistance: understanding molecular mechanisms to guide drug design

Introduction: Mutations introduce diversity into genomes, leading to selective changes and driving evolution. These changes have contributed to the emergence of many of the current major health concerns of the 21st century, from the development of genetic diseases and cancers to the rise and spread of drug resistance. The experimental systematic testing of all mutations in a system of interest is impractical and not cost-effective, which has created interest in the development of computational tools to understand the molecular consequences of mutations to aid and guide rational experimentation.

Areas covered: Here, the authors discuss the recent development of computational methods to understand the effects of coding mutations to protein function and interactions, particularly in the context of the 3D structure of the protein.

Expert opinion: While significant progress has been made in terms of innovative tools to understand and quantify the different range of effects in which a mutation or a set of mutations can give rise to a phenotype, a great gap still exists when integrating these predictions and drawing causality conclusions linking variants. This often requires a detailed understanding of the system being perturbed. However, as part of the drug development process it can be used preemptively in a similar fashion to pharmacokinetics predictions, to guide development of therapeutics to help guide the design and analysis of clinical trials, patient treatment and public health policy strategies.     

Longitudinal Stability of Intellectual Functioning in Autism Spectrum Disorder: From Age 3 Through Mid-adulthood

Journal of Autism and Developmental Disorders - Intelligence (IQ) scores are used in educational and vocational planning for individuals with autism spectrum disorder (ASD) yet little is known...     

The Association of the Medicaid 1915(c) Home and Community-Based Services Waivers with Emergency Department Utilization among Youth with Autism Spectrum Disorder

Journal of Autism and Developmental Disorders - Using the 2008–2013 Medicaid Analytic eXtract files, this retrospective cohort study was to evaluate the effect of Medicaid home and...     

Early postoperative voiding dysfunction after insertion of retropubic midurethral tape

Introduction and hypothesis

A significant proportion of patients develop voiding dysfunction after midurethral tape (MUT) insertion, which reduces patient satisfaction. The study’s purpose was to identify predictive factors of voiding dysfunction after a retropubic MUT procedure.

Methods

This was a retrospective study of 100 patients who underwent only a retropubic MUT procedure between January 2010 and December 2011. Early voiding dysfunction was defined when patients required a Foley catheter within 48 h. Data including demographic information, urogenital symptoms, previous surgery, preoperative uroflowmetry and urodynamic parameters were analysed using SPSS v22. Univariate analysis of all demographic variables was performed; those significant at 10 % were entered into a multivariate logistic regression.

Results

Fourteen patients required Foley catheter insertion, with a median age of 58 years (26–83 years), median BMI 28 kg/m² (20–48 kg/m2), and median parity 2 (0–4). Univariate analysis revealed peak flow rate <15 ml/s (OR 3.79; 1.07, 13.4; p?=?0.046), bladder capacity (p?=?0.044), stress incontinence versus mixed or urge incontinence (p?=?0.064) and previous surgery (OR 4.39; 1.34, 14.41; p?=?0.015) to be associated with voiding dysfunction. Multivariate analysis showed only previous pelvic floor surgery to be independently associated (OR 3.76; 1.14, 12.23, p?=?0.029).

Conclusions

Only previous pelvic-floor surgery was found to be a strong predictive factor of voiding dysfunction. The rate of voiding dysfunction was similar to those of published data. Previous studies revealed different predictive factors. A larger cohort is needed to provide a definite answer. Those with previous surgery appear to be those most at risk and pre-surgical counselling for these women could be suggested.

     

Site‐Dependent Reference Point Microindentation Complements Clinical Measures for Improved Fracture Risk Assessment at the Human Femoral Neck

In contrast to traditional approaches to fracture risk assessment using clinical risk factors and bone mineral density (BMD), a new technique, reference point microindentation (RPI), permits direct assessment of bone quality; in vivo tibial RPI measurements appear to discriminate patients with a fragility fracture from controls. However, it is unclear how this relates to the site of the most clinically devastating fracture, the femoral neck, and whether RPI provides information complementary to that from existing assessments. Femoral neck samples were collected at surgery after low‐trauma hip fracture (n = 46; 17 male; aged 83 [interquartile range 77–87] years) and compared, using RPI (Biodent Hfc), with 16 cadaveric control samples, free from bone disease (7 male; aged 65 [IQR 61–74] years). A subset of fracture patients returned for dual‐energy X‐ray absorptiometry (DXA) assessment (Hologic Discovery) and, for the controls, a micro‐computed tomography setup (HMX, Nikon) was used to replicate DXA scans. The indentation depth was greater in femoral neck samples from osteoporotic fracture patients than controls (p < 0.001), which persisted with adjustment for age, sex, body mass index (BMI), and height (p < 0.001) but was site‐dependent, being less pronounced in the inferomedial region. RPI demonstrated good discrimination between fracture and controls using receiver‐operating characteristic (ROC) analyses (area under the curve [AUC] = 0.79 to 0.89), and a model combining RPI to clinical risk factors or BMD performed better than the individual components (AUC = 0.88 to 0.99). In conclusion, RPI at the femoral neck discriminated fracture cases from controls independent of BMD and traditional risk factors but dependent on location. The clinical RPI device may, therefore, supplement risk assessment and requires testing in prospective cohorts and comparison between the clinically accessible tibia and the femoral neck. © 2015 American Society for Bone and Mineral Research.     

Oral contrast for CT in patients with acute non-traumatic abdominal and pelvic pain: what should be its current role?

Positive oral contrast agents, including barium suspensions and water-soluble iodinated solutions, have traditionally been used in conjunction with the CT evaluation of patients with abdominal and pelvic pain. Due to continued advancements in CT technology, and due to increasing obesity and correspondingly a general increase in the intra-abdominal and intra-pelvic fat separating bowel loops in North American patients and in patients in other parts of the world over the past few decades, the ability of radiologists to accurately evaluate the cause of acute symptoms has substantially improved. Recent research and evolving imaging society guidelines/systematic reviews increasingly support performing CT scans of the abdomen and pelvis without the need for positive oral contrast in these types of adult patient populations, in most clinical situations. Increased patient throughput, patient preference, patient safety, and most importantly, retention of high diagnostic accuracy, are reasons for this recent change in practice to routinely omit the use of enteric contrast agents for the majority of patients presenting with acute abdominal and pelvic pain whom are undergoing emergency CT.