Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis.

Visceral leishmaniasis causes considerable mortality and morbidity in many parts of the world. There is an urgent need for the development of new, effective treatments for this disease. Here we describe the development of an anti-leishmanial drug-like chemical series based on a pyrazolopyrimidine scaffold. The leading compound from this series (7, DDD853651/GSK3186899) is efficacious in a mouse model of visceral leishmaniasis, has suitable physicochemical, pharmacokinetic and toxicological properties for further development, and has been declared a preclinical candidate. Detailed mode-of-action studies indicate that compounds from this series act principally by inhibiting the parasite cdc-2-related kinase 12 (CRK12), thus defining a druggable target for visceral leishmaniasis.

Pathways to a more peaceful and sustainable world: The transformative power of children in families.

This article provides an overview of selected ongoing international efforts that have been inspired by Edward Zigler's vision to improve programs and policies for young children and families in the United States. The efforts presented are in close alignment with three strategies articulated by Edward Zigler: (a) conduct research that will inform policy advocacy; (b) design, implement, and revise quality early childhood development (ECD) programs; and (c) invest in building the next generation of scholars and advocates in child development. The intergenerational legacy left by Edward Zigler has had an impact on young children not only in the United States, but also across the globe. More needs to be done. We need to work together with a full commitment to ensure the optimal development of each child.

Exploring the association between mental wellbeing, health-related quality of life, family affluence and food choice in adolescents.

Young people choose energy-dense, nutrient-poor diets, yet understanding of potential determinants is limited. Associations between food choices, mental wellbeing, health-related quality of life (HRQoL) and family affluence were explored to identify targets for intervention to promote dietary health and wellbeing in young people. Adolescents were recruited via post-primary schools in the UK and surveyed at two time-points when aged 13-14 years and 15-16 years. The questionnaire enquired about mental wellbeing using the Short Warwick-Edinburgh Mental Wellbeing Scale, HRQoL using the KIDSCREEN-10, socio-economic status using the Family Affluence Scale and food choice by Food Frequency Questionnaire (FFQ). With missing and anomalous cases excluded, the sample comprised 1208 cases. Factor analysis on the FFQ indicated five food choice factors: 'Junk Food'; 'Meat'; 'Healthy Protein'; 'Fruit/Vegetables'; 'Bread/Dairy'. Multivariate regression analysis indicated that frequent consumption of Junk Food was associated with being male and lower mental wellbeing. Frequent Meat intake was associated with being male and with lower HRQoL. Frequent choice of Bread/Dairy foods was more common among males and associated with higher wellbeing and greater affluence. Those who consumed Fruit/Vegetables frequently were more likely to be female, have higher HRQoL, higher mental wellbeing, and greater family affluence. These direct associations endured between time points. The dietary factors were not mutually exclusive. Those who frequently chose Junk Food were less likely to choose Fruit/Vegetables. Frequent choice of Meat was associated with more frequent choice of Junk Food and Healthy Protein. Intervention to improve dietary and psychological health in young people should target males, those in less affluent households, seek to reduce consumption of 'junk' food, and increase fruit and vegetable intake.

Low-field NMR relaxation-exchange measurements for the study of gas admission in microporous solids.

Understanding the uptake and storage of gases by microporous materials is important for our future energy security. As such, we demonstrate here the application of two-dimensional NMR relaxation experiments for probing the admission and corresponding exchange dynamics of methane within microporous zeolites. Specifically, we report low-field (12.7 MHz) 1H NMR relaxation-exchange correlation measurements of methane within commercial LTA zeolites (3A and 4A) at 25 and 35 bar and ambient temperature. Our results demonstrate the clear identification of bulk-pore and pore-pore exchange processes within zeolite 4A, facilitating the calculation and comparison of effective exchange rate dynamics across varying diffusion length scales and gas pressures. Additional data acquired for zeolite 3A reveals the sensitivity of NMR relaxation phenomena to size-exclusive gas admission phenomena, illustrating the potential of benchtop NMR protocols for material screening applications.

Paving the way for the use of the SDQ in economic evaluations of school-based population health interventions: an empirical analysis of the external validity of SDQ mapping algorithms to the CHU9D in an educational setting.

PURPOSE: The Strengths and Difficulties Questionnaire (SDQ) is a behavioural screening tool for children. The SDQ is increasingly used as the primary outcome measure in population health interventions involving children, but it is not preference based; therefore, its role in allocative economic evaluation is limited. The Child Health Utility 9D (CHU9D) is a generic preference-based health-related quality of-life measure. This study investigates the applicability of the SDQ outcome measure for use in economic evaluations and examines its relationship with the CHU9D by testing previously published mapping algorithms. The aim of the paper is to explore the feasibility of using the SDQ within economic evaluations of school-based population health interventions. METHODS: Data were available from children participating in a cluster randomised controlled trial of the school-based roots of empathy programme in Northern Ireland. Utility was calculated using the original and alternative CHU9D tariffs along with two SDQ mapping algorithms. t tests were performed for pairwise differences in utility values from the preference-based tariffs and mapping algorithms. RESULTS: Mean (standard deviation) SDQ total difficulties and prosocial scores were 12 (3.2) and 8.3 (2.1). Utility values obtained from the original tariff, alternative tariff, and mapping algorithms using five and three SDQ subscales were 0.84 (0.11), 0.80 (0.13), 0.84 (0.05), and 0.83 (0.04), respectively. Each method for calculating utility produced statistically significantly different values except the original tariff and five SDQ subscale algorithm. CONCLUSION: Initial evidence suggests the SDQ and CHU9D are related in some of their measurement properties. The mapping algorithm using five SDQ subscales was found to be optimal in predicting mean child health utility. Future research valuing changes in the SDQ scores would contribute to this research.

Eliminating the use of allogeneic blood products in adolescent idiopathic scoliosis surgery.

PURPOSE: The aim of this study was to compare transfusion requirements in patients before and after the introduction of tranexamic acid as standard in patients undergoing spinal surgery for idiopathic scoliosis in a national orthopaedic hospital. METHODS: A retrospective chart review of 56 idiopathic scoliosis patients who underwent posterior spinal instrumentation and fusion between 2009 and 2013 at our institution. Preoperative, intraoperative, and postoperative data were measured. RESULTS: Patients who received tranexamic acid as standard (n = 31) showed a trend towards a decrease in transfusion requirements compared with those who received no tranexamic acid (n = 25). These patients had a statistically significant decrease in operative time (223 vs 188 min, p = 0.005), and estimated intraoperative blood loss was reduced by nearly 50% in the tranexamic acid group. They also had an associated reduced decrease in haemoglobin between preoperative and postoperative levels (4 vs 5 g/dL, p = 0.01). CONCLUSIONS: Since February 2012, no patient has required intraoperative or postoperative allogeneic blood product transfusion in this hospital. The routine use of antifibrinolytic medications in patients undergoing surgery for adolescent idiopathic scoliosis has effectively eliminated the need for allogeneic blood products.

Application of QbD principles for the evaluation of empty hard capsules as an input parameter in formulation development and manufacturing.

Understanding the product and process variable on the final product performance is an essential part of the quality-by-design (QbD) principles in pharmaceutical development. The hard capsule is an established pharmaceutical dosage form used worldwide in development and manufacturing. The empty hard capsules are supplied as an excipient that is filled by pharmaceutical manufacturers with a variety of different formulations and products. To understand the potential variations of the empty hard capsules as an input parameter and its potential impact on the finished product quality, a study was performed investigating the critical quality parameters within and in between different batches of empty hard gelatin capsules. The variability of the hard capsules showed high consistency within the specification of the critical quality parameters. This also accounts for the disintegration times, when automatic endpoint detection was used. Based on these data, hard capsules can be considered as a suitable excipient for product development using QbD principles.

Repair of a large thoracolumbar myelomeningocele with associated lumbar kyphosis.

This report describes a novel method of repair for a large thoracolumbar myelomeningocele with an associated lumbar kyphosis in the neonate. A Caucasian male child was born at term with an antenatal diagnosis of hydrocephalus and spina bifida. Lumbar spine X-ray showed a significant kyphosis at L2-L3 level. Kyphectomy was performed and a cervical plate was used to reduce the gibbus deformity and maintain a rigid construct. Local rotation flaps were elevated and advanced to cover the defect. Wound was well healed at 3-month follow-up and the patient remained shunt-free at 1 year. To our knowledge, this is the first description of myelomeningocele repair with kyphectomy and posterior fixation in a neonate.

Detection of honey adulteration using benchtop 1H NMR spectroscopy.

High magnetic field NMR spectroscopy featuring the use of superconducting magnets is a powerful analytical technique for the detection of honey adulteration. Such high field NMR systems are, however, typically housed in specialised laboratories, require cryogenic coolants, and necessitate specialist training to operate. Benchtop NMR spectrometers featuring permanent magnets are, by comparison, significantly cheaper, more mobile and can be operated with minimal expertise. The lower magnetic fields used in such systems, however, result in limited spectral resolution, which diminishes their ability to perform quantitative composition analysis. These limitations may be overcome by implementing a recently developed field-invariant model-based fitting method which is defined by the underlying quantum mechanical properties of the nuclear spin system; this method is applied here to quantify the sugar composition of honey using benchtop 1H NMR (43 MHz) spectroscopy. The detection of adulteration of 26 honey samples with brown rice syrup is quantitatively demonstrated to a minimum adulterant concentration of 5 wt%. Honey adulteration with corn syrup, glucose syrup and wheat syrup was also quantitatively detected using this approach. Our NMR detection of adulteration was shown to be invariant with time over 60 days of storage.

Comparing the effectiveness of two reciprocal reading comprehension interventions for primary school pupils in disadvantaged schools.

BACKGROUND: Effective reading comprehension teaching is an aspiration of education systems across the world. Teaching incorporating reciprocal reading theory and evidence is an internationally popular approach for improving comprehension. AIMS: This paper uses two large cluster randomized controlled trials of similar reciprocal reading interventions implemented in different ways to compare their effectiveness. SAMPLE: The two interventions had the same teacher professional development, reciprocal reading activities and dosage/exposure, but varied in their implementation, with one delivered as a whole-class ('universal') version for pupils aged 8-9 years and the other a small group ('targeted') version for pupils aged 9-11 years with specific comprehension difficulties. METHODS: Two large-scale cluster RCTs were conducted in 98 schools with N = 3699 pupils in the universal trial and N = 1523 in the targeted trial. RESULTS: Multi-level models showed significant effects for the targeted version of the intervention on pupil reading comprehension (g = .18) and overall reading (g = .14). No significant effects were found for the whole class version. A sub-group analyses of disadvantaged pupils showed the targeted intervention's effects were even larger on reading comprehension (g = .25). CONCLUSIONS: The evidence suggested that this reciprocal reading intervention worked best when implemented in small groups and targeted for pupils with specific comprehension difficulties and particularly for pupils in disadvantaged circumstances. COMMENTS: This evaluation shows that even if a reading comprehension intervention is underpinned by strong theory and evidence-based practice, its effectiveness can still depend on implementation choices.

UPDATED PROTOCOL: Universal school-based programmes for improving social and emotional outcomes in children aged 3-11 years: An evidence and gap map.

This is the protocol for an evidence and gap map. The objective of this EGM is to identify and map all primary studies (including randomised and cluster randomised trials) and systematic reviews on universal, school-based social and emotional learning programmes for young children (3-11 years) to create a live, searchable, and publicly available evidence and gap map.

The readout thickness versus the measured thickness for a range of screen film mammography and full-field digital mammography units.

PURPOSE: To establish a simple method to determine breast readout accuracy on mammography units. METHODS: A thickness measuring device (TMD) was used in conjunction with a breast phantom. This phantom had compression characteristics similar to human female breast tissue. The phantom was compressed, and the thickness was measured using TMD and mammography unit readout. Measurements were performed on a range of screen film mammography (SFM) and full-field digital mammography (FFDM) units (8 units in total; 6 different models/manufacturers) for two different sized paddles and two different compression forces (60 and 100 N). RESULTS: The difference between machine readout and TMD for the breast area, when applying 100 N compression force, for nonflexible paddles was largest for GE Senographe DMR+ (24 cm × 30 cm paddle: +14.3%). For flexible paddles the largest difference occurred for Hologic Lorad Selenia (18 cm × 24 cm paddle: +26.0%). CONCLUSIONS: None of the units assessed were found to have perfect correlation between measured and readout thickness. TMD measures and thickness readouts were different for the duplicate units from two different models/manufacturers.

Determination and confirmation of parent and total ractopamine in bovine, swine, and turkey tissues by liquid chromatography with tandem mass spectrometry: First Action 2011.23.

A candidate method selected by the AOAC Expert Review Panel (ERP) for Ractopamine for determination and confirmation of parent and total ractopamine by LC/MS/MS was validated in a single laboratory for bovine, swine, and turkey tissues. The candidate method utilizes methanol extraction of the tissues, followed by an optional enzymatic hydrolysis for determination of total (parent plus conjugate) ractopamine. A mixed-mode cation exchange SPE cartridge is used to purify the initial extract before LC/MS/MS. Matrix-matched standards and a ractopamine-d6 internal standard are used for quantification of parent and total ractopamine in unknown samples. Validation data demonstrated that mean intertrial recoveries for ractopamine across all concentrations tested ranged from 79.7 to 102.2% for parent ractopamine and from 79.0 to 100.0% when a hydrolysis step was included. Intertrial repeatability precision ranged from 2.44 to 11.1% for parent ractopamine and 4.97 to 15.0% with hydrolysis. Estimated LOD values were below 0.1 ng/g and LOQ values were validated at 0.25x the maximum residue limits. The data satisfy the requirements of the AOAC Stakeholder Panel for Veterinary Drug Residue Methods for single laboratory validation studies. The method was awarded Official Methods of Analysis First Action 2011.23 by the AOAC ERP on Veterinary Drug Residues.

Gluteal compartment syndrome following bone marrow biopsy: a case report.

Compartment syndrome is a well described limb-threatening and potentially life-threatening condition. Compartment syndromes of the upper and lower limbs are well documented in the literature. The gluteal region, however, is often not considered as a compartment despite having three osseofascial boundaries. We report a case of gluteal compartment syndrome which resulted from a bone marrow biopsy. The patient was anticoagulated at the time. The outcome was residual right sided foot drop due to sciatic nerve palsy. This case describes an unusual presentation of a rare condition. Gluteal compartment syndrome is a potential complication of bone marrow biopsy.

A feasibility study of 'The StepSmart Challenge' to promote physical activity in adolescents.

BACKGROUND: Inactive lifestyles are becoming the norm and creative approaches to encourage adolescents to be more physically active are needed. Little is known about how gamification techniques can be used in physical activity interventions for young people. Such approaches may stimulate interest and encourage physical activity behaviour. The study investigated the feasibility of implementing and evaluating a physical activity intervention for adolescents which included gamification techniques within schools. We tested recruitment and retention strategies for schools and participants, the use of proposed outcome measures, and explored intervention acceptability. METHODS: This school-based feasibility study of a randomised cluster trial recruited adolescents aged 12-14 years (n = 224) from five schools (three intervention; two control) in Belfast, Northern Ireland. The 22-week intervention (The StepSmart Challenge) informed by self-determination theory and incorporating gamification strategies involved a school-based pedometer competition. Outcomes, measured at baseline, and post-intervention (at 22 weeks post-baseline and 52 weeks post-baseline) included daily minutes of moderate to vigorous physical activity (MVPA) (measured using ActiGraph accelerometer), mental wellbeing (Warwick-Edinburgh Mental Wellbeing Scale), social support for physical activity, time preference (for delayed and larger rewards or immediate and smaller rewards), pro-social behaviour (Strengths and Difficulties Questionnaire (SDQ)) and the influence of social networks. The intervention's acceptability was explored in focus groups. RESULTS: We invited 14 schools to participate; eight showed interest in participating. We recruited the first five who responded; all five completed the trial. Of the 236 pupils invited, 224 participated (94.9%): 84.8% (190/224) provided valid MVPA (minutes/day) at baseline and 57.2% (123/215) at 52 weeks. All other outcomes were well completed apart from the SDQ (65% at baseline). Qualitative data highlighted that participants and teachers found The StepSmart Challenge to be an acceptable intervention. CONCLUSIONS: The level of interest and high recruitment and retention rates provide support for the feasibility of this trial. The intervention, incorporating gamification strategies and the recruitment methods, using parental opt-out procedures, were acceptable to participants and teachers. Teachers also suggested that the implementation of The StepSmart Challenge could be embedded in a lifelong learning approach to health within the school curriculum. As young people's lives become more intertwined with technology, the use of innovative gamified interventions could be one approach to engage and motivate health behavioural change in this population. TRIAL REGISTRATION: NCT02455986 (date of registration: 28 May 2015).

[The natural history of acetabular development in developmental dysplasia of the hip]. / Gelisimsel kalça displazisinde asetabulum gelisiminin dogal seyri.

Normal hip joint development requires a genetically determined balance of growth between the acetabular and triradiate cartilage, and a well-centered femoral head. It is unclear how and why this delicate balance becomes disrupted, leading to abnormal development of the hip joint. It is known that, without treatment, a certain number of hips will become problematic later in life. This article outlines normal hip joint development and discusses the natural history of acetabular development in developmental dysplasia of the hip (DDH). The natural history of DDH depends on many factors including age of diagnosis, the growth capacity of the involved structures, and the effects of treatment interventions. Early identification and treatment of hip instability maximizes the chance for normal hip development to occur. However, close observation of the child is crucial to identify individuals where normal development is not occurring. Intervention may become necessary in certain situations to positively affect hip joint development.

[The course and treatment of avascular necrosis of the femoral head in developmental dysplasia of the hip]. / Gelisimsel kalça displazisinde femur basi avasküler nekrozunun seyri ve tedavisi.

Proximal femoral growth disturbance, commonly referred to as avascular necrosis (AVN) of the femoral head in the literature, is a potentially devastating complication in the treatment of developmental dysplasia of the hip (DDH). The early onset of debilitating degenerative changes in the hip joint when treatment options are limited remains the biggest fear. Controversy exists regarding the pathophysiology of this disorder, as well as exactly defining and diagnosing this problem. The natural history of AVN in the setting of DDH is very variable. Current practice concentrates primarily on prevention of this disorder, as there are no reliable ways to intervene at an early stage when changes are potentially reversible. Newer techniques using magnetic resonance imaging may have a role in early diagnosis of this condition before irreversible damage has occurred, and allow for interventions that will favorably affect the natural history of AVN. Treatment options for established AVN in DDH concentrate on improving the biomechanics of the proximal femur but unfortunately do not obviate the need for arthrodesis or arthroplasty at a later date.

Identification and characterisation of a salt form of Danirixin with reduced pharmacokinetic variability in patient populations.

The natural variability of gastric pH or gastric acid reducing medications can result in lower and more variable clinical pharmacokinetics for basic compounds in patient populations. Progressing alternative salt forms with improved solubility and dissolution properties can minimise this concern. This manuscript outlines a nonclinical approach comprising multiple biopharmaceutical, in vitro and physiologically based pharmacokinetic model (PBPK) modelling studies to enable selection of an alternative salt form for danirixin (DNX, GSK1325756), a pharmaceutical agent being developed for chronic obstructive pulmonary disease (COPD). The hydrobromide salt of DNX was identified as having superior biopharmaceutical properties compared to the free base (FB) form in clinical development and the impact of switching to the hydrobromide salt (HBr) was predicted by integrating the nonclinical data in a PBPK model (using GastroPlus™) to enable simulation of clinical drug exposure with FB and HBr salts in the absence and presence of a gastric acid reducing comedication (omeprazole, a proton pump inhibitor (PPI)). Subsequent investigation of DNX pharmacokinetics in a Phase 1 clinical study comparing FB with HBr salt forms confirmed that DNX HBr had reduced the variability of drug exposure and that exposure was not affected by PPI co-administration with DNX HBr. This case study therefore adds to the surprisingly few examples of a more soluble salt of a weak base translating to an improvement in human pharmacokinetics and illustrates a clear clinical benefit of salt selection during drug development.