Symptomatic Skeletal Events and the Use of Bone Health Agents in a Real-World Treated Metastatic Castration Resistant Prostate Cancer Population: Results From the CAPRI-Study in the Netherlands.

BACKGROUND: Patients with metastatic castration resistant prostate cancer (mCRPC) are at risk of symptomatic skeletal events (SSE). Bone health agents (BHA, ie bisphosphonates and denosumab) and new life-prolonging drugs (LPDs) can delay SSEs. The aim of this study is to investigate the use of BHAs in relation to SSEs in treated real-world mCRPC population. PATIENTS AND METHODS: We included patients from the CAPRI registry who were treated with at least one LPD and diagnosed with bone metastases prior to the start of first LPD (LPD1). Outcomes were SSEs (external beam radiation therapy (EBRT) to the bone, orthopedic surgery, pathologic fracture or spinal cord compression) and SSE-free survival (SSE-FS) since LPD1. RESULTS: One-thousand nine hundred and twenty-three patients were included with a median follow-up from LPD1 of 16.7 months. Fifty-two percent (n = 996) started BHA prior or within 4 weeks after the start of LPD1 (early BHA). In total, 41% experienced at least one SSE. SSE incidence rate was 0.29 per patient year for patients without BHA and 0.27 for patients with early BHA. Median SSE-FS from LPD1 was 12.9 months. SSE-FS was longer in patients who started BHA early versus patients without BHA (13.2 vs. 11.0 months, P = .001). CONCLUSION: In a real-world population we observed an undertreatment with BHAs, although patients with early BHA use had lower incidence rates of SSEs and longer SSE-FS. This finding was irrespective of type of SSE and presence of risk factors. In addition to LPD treatment, timely initiation of BHAs is recommended in bone metastatic CRPC-patients with both pain and/or opioid use and prior SSE.

The effects of new life-prolonging drugs for metastatic castration-resistant prostate cancer (mCRPC) patients in a real-world population.

BACKGROUND: In 2004 docetaxel was the first life-prolonging drug (LPD) registered for metastatic castration-resistant prostate cancer (mCRPC) patients. Between 2011 and 2014 new LPDs for mCRPC (cabazitaxel, abiraterone, enzalutamide, and radium-223) were introduced in the Netherlands. The objective of this study is to assess the impact of the introduction of new LPDs on treatment patterns and overall survival (OS) over time. PATIENTS AND METHODS: CRPC patients diagnosed in the years 2010-2016 in the observational, retrospective CAPRI registry (20 hospitals) were included and followed up to 2018. Two subgroups were analyzed: treatment-naïve patients (subgroup 1, n = 3600) and post-docetaxel patients (subgroup 2, n = 1355). RESULTS: In both subgroups, the use of any LPD increased: from 57% (2010-2011) to 69% (2014-2015) in subgroup 1 and from 65% (2011-2012) to 79% (2015-2016) in subgroup 2. Chemotherapy as first mCRPC-treatment (i.e., docetaxel) and first post-docetaxel treatment (i.e., cabazitaxel or docetaxel rechallenge) decreased (46-29% and 20-9% in subgroup 1 and 2, respectively), while the use of androgen-receptor targeting treatments (ART) increased from 11% to 39% and 46% to 64% in subgroup 1 and 2, respectively. In subgroup 1, median OS (mOS) from diagnosis CRPC increased from 28.5 months to 31.0 months (p = 0.196). In subgroup 2, mOS from progression on docetaxel increased from 7.9 months to 12.5 months (p < 0.001). After multiple imputations of missing values, in multivariable cox-regression analysis with known prognostic parameters, the treatment period was independent significant for OS in subgroup 1 (2014-2015 vs. 2010-2011 with HR 0.749, p < 0.001) and subgroup 2 (2015-2016 vs. 2011-2012 with HR 0.811, p = 0.037). CONCLUSION: Since 2010, a larger proportion of mCRPC patients was treated with LPDs, which was related to an increased mOS.

Real-world Outcomes of Sequential Androgen-receptor Targeting Therapies with or Without Interposed Life-prolonging Drugs in Metastatic Castration-resistant Prostate Cancer: Results from the Dutch Castration-resistant Prostate Cancer Registry.

BACKGROUND: Cross resistance between androgen-receptor targeting therapies (ARTs) (abiraterone acetate plus prednisone [ABI+P] or enzalutamide [ENZ]) for treatment of metastatic castration-resistant prostate cancer (mCRPC) may affect responses to second ART (ART2). OBJECTIVE: To establish treatment duration and prostate-specific antigen (PSA) response of ART2 in real-world mCRPC patients treated with or without other life-prolonging drugs (LPDs; ie, docetaxel, cabazitaxel, or radium-223) between ART1 and ART2. DESIGN, SETTING, AND PARTICIPANTS: Castration-resistant prostate cancer patients, diagnosed between 2010 and 2016 were retrospectively registered in Castration-resistant Prostate Cancer Registry (CAPRI). Patients treated with both ARTs were clustered into two subgroups: ART1>ART2 or ART1>LPD>ART2. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Outcomes were ≥50% PSA response and treatment duration of ART2. Descriptive statistics and binary logistic regression after multiple imputations were performed. RESULTS AND LIMITATIONS: A total of 273 patients were included with a median follow-up of 8.4 mo from ART2. Patients with ART1>ART2 were older and had favourable prognostic characteristics at ART2 baseline compared with patients with ART1>LPD>ART2. No differences between ART1>ART2 and ART1>LPD>ART2 were found in PSA response and treatment duration. Multivariate analysis suggested that PSA response of ART2 was less likely in patients with visceral metastases (odds ratio [OR] 0.143, p=0.04) and more likely in patients with a relatively longer duration of androgen-deprivation treatment (OR 1.028, p=0.01) and with ABI + P before ENZ (OR 3.192, p=0.02). A major limitation of this study was missing data, a common problem in retrospective observational research. CONCLUSIONS: The effect of ART2 seems to be low, with a low PSA response rate and a short treatment duration irrespective of interposed chemotherapy or radium-223, especially in patients with short time on castration, visceral disease, and ENZ before ABI+P. PATIENT SUMMARY: We observed no differences in outcomes of patients treated with sequential abiraterone acetate plus prednisone (ABI+P) and enzalutamide (ENZ) with or without interposed chemotherapy or radium-223. In general, outcomes were lower than those in randomised trials, questioning the additional effect of second treatment with ABI+P or ENZ in daily practice.

Second-Line Cabazitaxel Treatment in Castration-Resistant Prostate Cancer Clinical Trials Compared to Standard of Care in CAPRI: Observational Study in the Netherlands.

BACKGROUND: Cabazitaxel has been shown to improve overall survival (OS) in metastatic castration-resistant prostate cancer (mCRPC) patients after docetaxel in the TROPIC trial. However, trial populations may not reflect the real-world population. We compared patient characteristics and outcomes of cabazitaxel within and outside trials (standard of care, SOC). PATIENTS AND METHODS: mCRPC patients treated with cabazitaxel directly after docetaxel therapy before 2017 were retrospectively identified and followed to 2018. Patients were grouped on the basis of treatment within a trial or SOC. Outcomes included OS and prostate-specific antigen (PSA) response. RESULTS: From 3616 patients in the CAPRI registry, we identified 356 patients treated with cabazitaxel, with 173 patients treated in the second line. Trial patients had favorable prognostic factors: fewer symptoms, less visceral disease, lower lactate dehydrogenase, higher hemoglobin, more docetaxel cycles, and longer treatment-free interval since docetaxel therapy. PSA response (≥ 50% decline) was 28 versus 12%, respectively (P = .209). Median OS was 13.6 versus 9.6 months for trial and SOC subgroups, respectively (hazard ratio = 0.73, P = .067). After correction for prognostic factors, there was no difference in survival (hazard ratio = 1.00, P = .999). Longer duration of androgen deprivation therapy treatment, lower lactate dehydrogenase, and lower PSA were associated with longer OS; visceral disease had a trend for shorter OS. CONCLUSION: Patients treated with cabazitaxel in trials were fitter and showed outcomes comparable to registration trials. Conversely, those treated in daily practice showed features of more aggressive disease and worse outcome. This underlines the importance of adequate estimation of trial eligibility and health status of mCRPC patients in daily practice to ensure optimal outcomes.

In vivo models and decision trees for formulation development in early drug development: A review of current practices and recommendations for biopharmaceutical development.

The ability to predict new chemical entity performance using in vivo animal models has been under investigation for more than two decades. Pharmaceutical companies use their own strategies to make decisions on the most appropriate formulation starting early in development. In this paper the biopharmaceutical decision trees available in four EFPIA partners (Bayer, Boehringer Ingelheim, Bristol Meyers Squibb and Janssen) were discussed by 7 companies of which 4 had no decision tree currently defined. The strengths, weaknesses and opportunities for improvement are discussed for each decision tree. Both pharmacokineticists and preformulation scientists at the drug discovery & development interface responsible for lead optimization and candidate selection contributed to an overall picture of how formulation decisions are progressed. A small data set containing compound information from the database designed for the IMI funded OrBiTo project is examined for interrelationships between measured physicochemical, dissolution and relative bioavailability parameters. In vivo behavior of the drug substance and its formulation in First in human (FIH) studies cannot always be well predicted from in vitro and/or in silico tools alone at the time of selection of a new chemical entity (NCE). Early identification of the risks, challenges and strategies to prepare for formulations that provide sufficient preclinical exposure in animal toxicology studies and in FIH clinical trials is needed and represents an essential part of the IMI funded OrBiTo project. This article offers a perspective on the use of in vivo models and biopharmaceutical decision trees in the development of new oral drug products.

Intersegmental strategies in frontal plane in moderately-skilled riders analyzed in ridden and un-mounted situations.

The symmetry of the rider is highly relevant, and in the equestrian community it is generally thought that a symmetrical rider has a better possibility to influence the horse in an optimal way. The aim of the study was to analyse and compare frontal plane kinematics of the core body segments in ten riders while riding and while rocking a balance chair from side-to-side. It was hypothesized that the riders were asymmetrical in relation to their intersegmental strategies when comparing between left and right directions and that individual riders would display the same postural strategies when riding and when rocking the balance chair. Ten moderately-skilled riders wore a full-body marker set that was tracked by a motion capture system as they rocked a balance chair from side to side. Inertial measurement units attached to the head, trunk and pelvis were used to measure the segmental movements while riding in left and right directions. Roll rotation data for head, trunk and pelvis were averaged over available strides/cycles. Results from mixed models showed that the riders were asymmetric when comparing riding in left vs right directions, for example the trunk was rotated 19° to the right on the right circle and 14° to the left on the left circle, on average. Riders adopted the same asymmetrical posture whether they were riding in the left or right direction on straight lines, circles or leg yielding. A significant relationship was found between postural asymmetries when riding and when rocking the balance chair, one degree of pelvis or head roll asymmetry on the chair predicted 2.4 (SE 0.9) degrees of asymmetry while riding. Future studies may investigate the value of seated, off-horse postural training for improving rider symmetry and thereby equestrian performance.

Reducing maternal deaths by skills-and-drills training in managing obstetric emergencies: A before-and-after observational study.

BACKGROUND: The institutional maternal mortality ratio (iMMR) in South Africa (SA) is still unacceptably high. A key recommendation from the National Committee on Confidential Enquiries into Maternal Deaths has been to improve the availability and quality of care for women suffering obstetric emergencies. OBJECTIVES: To determine whether there was a change in the number of maternal deaths and in the iMMR over time that could be attributed to the training of >80% of healthcare professionals by means of a specifically designed emergency obstetric care (EmOC) training programme. METHODS: A before-and-after study was conducted in 12 healthcare districts in SA, with the remaining 40 districts serving as a comparison group. Twelve 'most-in-need' healthcare districts in SA were selected using a composite scoring system. Multiprofessional skills-and-drills workshops were held off-site using the Essential Steps in Managing Obstetric Emergencies and Emergency Obstetric Simulation Training programme. Eighty percent or more of healthcare professionals providing maternity care in each district were trained between October 2012 and March 2015. Institutional births and maternal deaths were assessed for the period January 2011 - December 2016 and a before-and-after-training comparison was made. The number of maternal deaths and the iMMR were used as outcome measures. RESULTS: A total of 3 237 healthcare professionals were trained at 346 workshops. In all, 1 248 333 live births and 2 212 maternal deaths were identified and reviewed for cause of death as part of the SA confidential enquiries. During the same period there were 5 961 maternal deaths and 5 439 870 live births in the remaining 40 districts. Significant reductions of 29.3% in the number of maternal deaths (risk ratio (RR) 0.71, 95% confidence interval (CI) 0.66 - 0.77) and 17.5% in the number of maternal deaths from direct obstetric causes (RR 0.825, 95% CI 0.73 - 0.93) were recorded. When comparing the percentage change in iMMR for equivalent before-and-after periods, there was a greater reduction in all categories of causes of maternal death in the intervention districts than in the comparison districts. CONCLUSIONS: Implementing a skills-and-drills EmOC training package was associated with a significant reduction in maternal deaths.

Midwife-led obstetric units working 'CLEVER': Improving perinatal outcome indicators in a South African health district.

BACKGROUND: South Africa did not meet its Millennium Development Goals with regard to the reduction in maternal and under-5 mortality. Furthermore, many birthing women do not receive intrapartum care with empathy and endure disrespect-ful and abusive care. OBJECTIVES: To implement a multicomponent, context-specific intervention package to change the complex interplay between preventable maternal and perinatal mortality and morbidity and poor clinical governance and supervision in midwife-led labour units. METHODS: A mixed-methods intervention study was conducted in Tshwane District, South Africa, in 10 midwife-led obstetric units (MOUs), from which a purposive sample consisting of five units was selected for the intervention. The intervention took place in three phases: (i) baseline measurement; (ii) implementation of the so-called 'CLEVER' intervention package in the five intervention units, based on the results of the first phase; and (iii) a review of health systems improvements and perinatal outcomes. The intervention had three pillars: (i) feedback of the baseline measurement to the intervention units to raise awareness and solicit participation; (ii) health systems strengthening; and (iii) intensive weekly engagement for 3 months, with further monthly support afterwards. Observation of barriers during baseline activities contributed to the health systems strengthening and improvement strategies during implementation. RESULTS: Perinatal outcome indicators for the year before the intervention were compared with data for the year in which the intervention took place and the year after the intervention. Significant declines were observed in in-facility fresh stillbirths, meconium aspiration and birth asphyxia in the intervention MOUs from 2015 to 2017. The control group showed some decline during the period owing to support from district clinical specialist team members. CONCLUSIONS: CLEVER as a context-specific, multicomponent, clinically focused intervention package may have contributed to improved perinatal morbidity and mortality rates in MOUs.

Obstetrics knowledge and skills training as a catalyst for change.

BACKGROUND: Poor emergency obstetric care has been shown by national confidential enquiries into maternal deaths to contribute to a number of maternal deaths in South Africa. OBJECTIVES: To assess whether a structured training course can improve knowledge and skills and whether this can influence the capacity of a healthcare facility to provide basic and comprehensive emergency obstetric care signal functions. METHODS: A baseline survey was conducted to assess the seven basic emergency obstetric and neonatal care signal functions in 51 community health centres (CHCs) and the nine comprehensive emergency care signal functions in 62 district hospitals (DHs). A re-assessment was conducted 1 year after saturation training had been provided in each district. The delegates were trained using a structured training programme (Essential Steps in Managing Obstetric Emergencies, ESMOE) and their knowledge and skills were tested before and after the training. Saturation training was considered to have been achieved once 80% of the healthcare professionals involved in maternity care had been trained. RESULTS: There was a significant improvement in the knowledge and skills of doctors, namely by 16.8% and 32.8%, respectively, of advanced midwives by 13.7% and 29.0%, and of professional nurses with midwifery by 16.1% and 31.2%. The seven basic emergency care functions improved from 60.8% to 67.8% in the CHCs and from 90.7% to 92.5% in the DHs before and after training. If the two signal functions that are not within the scope of practice of professional nurses with midwifery are excluded (viz. assisted delivery and manual vacuum aspiration), the functionality of CHCs increased from 85.1% to 94.9%. CONCLUSIONS: The ESMOE training programme improved knowledge and skills, but there was a modest improvement in the functionality of the facilities. Improvement in functionality requires changes in the structure of the health system, including changing the scope of practice of professional nurses with midwifery and employing more advanced midwives in CHCs.

Systems thinking: A turning point for improving respectful obstetric care in South African health districts.

Poorly functioning health systems and local health systems barriers affect many women giving birth in low- and middle-income countries. The district clinical specialist teams in South Africa are uniquely positioned to provide facilitation and mentoring during interventions for improving the weak primary healthcare system. To ensure success, four key principles should be considered during scale-up of interventions: systems thinking and awareness of contexts and barriers; a focus on sustainability; harnessing factors known to enhance scalability; and respect for human rights and equity. Asking the right questions about the responsibilities of health systems at the micro-, meso- and macro-levels will benefit scale-up processes and sustain innovative pathways to high-quality obstetric care in communities.

Vertical head and pelvic movement symmetry at the trot in dogs with induced supporting limb lameness.

Compensatory limb loading has been studied in lame dogs; however, little is known about how these compensations relate to motion of the head and pelvis, assessment of which is an important component of lameness examinations. The aim of this study was to describe the patterns of vertical head and pelvic motion symmetry at the trot in dogs with induced supporting limb lameness in the forelimbs or hind limbs. Ten sound dogs were trotted on a treadmill before and after temporary induction of moderate lameness (grade 2/5) in each limb. Reflective markers were located on the head, pelvis and right forelimb, and kinematic data were captured with a motion capture system. Upper body symmetry parameters were calculated, including differences in the highest (HDmax) and in the lowest (HDmin) positions of the head, and in the highest (PDmax) and in the lowest (PDmin) positions of the mid-pelvis, with a value of zero indicating symmetry. The head was lowered more during the sound limb stance phase and lowered less during the lame limb stance phase in supporting forelimb lameness (HDmin: 4.6mm in dogs when sound, -18.3mm when left limb lameness was induced and 20.5mm when right limb lameness was induced). The mid-pelvis was lowered more during the sound limb stance phase and lowered and lifted less during the lame limb stance phase in supporting hind limb lameness (PDmin: 1mm in dogs when sound, -10.1mm in left limb lameness and 8.4mm in right limb lameness). The hip of the lame side, measured at the level of the greater trochanter, had an increased downwards displacement during the lame limb swing phase (-21mm in left hind limb lameness, P=0.005; 23.4mm in right hind limb lameness, P=0.007). Asymmetry in the lowering of the head or mid-pelvis is a more sensitive indicator of supporting forelimb and hind limb lameness, respectively, than asymmetry in the raising of the head. Increased displacement of the hip ('hip drop' of the lame side during its swing phase) is a good indicator of hind limb lameness in dogs.

Comparing subjective and objective evaluation of show jumping competition and warm-up arena surfaces.

The development of safety and quality standards for equestrian surfaces needs to be based on objective, repeatable measurements which allow comparisons between surfaces. These measurements should incorporate the assessment of surface performance by riders. This study provides data from objective and subjective assessment of functional properties of high-level show jumping competition and warm-up arenas. Twenty-five arenas in nine international show jumping events were evaluated by mechanical in-situ testing with a surface tester, rider assessments using visual analogue scales (198 riders provided 749 arena evaluations), descriptions of arena constructions and by laboratory tests of surface material. Mixed models were used to present subjective evaluation of rider perception of the functional properties for each arena while controlling for rider and event. The association between objective and subjective assessments were also explored creating mixed models, controlling for rider and event. Mechanical measurements of impact firmness, and to a lesser extent cushioning and grip, had a significant positive association with the riders' perception. Responsiveness as assessed by the Orono biomechanical surface tester (OBST) was negatively associated with the riders' perceptions, which suggests riders and the OBST had different concepts of this functional property and that further developments of the OBST might be necessary. Objectively measured uniformity showed no useful association with riders' perception. Even though arena assessments were made by top level riders, a substantial inter-rider variation was demonstrated.

Inertial sensor-based system for lameness detection in trotting dogs with induced lameness.

Lameness detection can be challenging in dogs, as reflected in the reported low inter-rater agreement when visually assessing lameness. The aim of this study was to use an inertial sensor-based system to detect and quantify induced distal and proximal limb disturbances mimicking supporting and swinging limb lameness in dogs trotting on a treadmill by measuring vertical head and pelvic movement symmetry. Ten clinically sound dogs were equipped with inertial measurement units that were attached to the head, pelvis and right distal forelimb. Vertical head and pelvic movement symmetry were measured while dogs trotted on a treadmill, before and after the induction of moderate support or swinging fore- and hindlimb lameness. Four symmetry variables were calculated: the differences in displacement between the two lowest and between the two highest values of the head and pelvis per stride, respectively. These variables were defined as minimum head difference (HDmin), maximum head difference (HDmax), minimum pelvic difference (PDmin) and maximum pelvic difference (PDmax). Induction of supporting forelimb and hindlimb lameness produced significant changes in HDmin and PDmin, respectively. Swinging forelimb and hindlimb lameness produced significant changes in HDmax and PDmax, respectively. Additional compensatory ipsilateral forelimb and contralateral hindlimb movements were detected. Based on our findings, inertial sensor-based systems can be used to detect and quantify induced moderate lameness and differentiate between supporting and swinging limb lameness in dogs trotting on a treadmill. Further studies are needed to evaluate this method in dogs presented for clinical lameness evaluation and in overground locomotion.

Dual-modality probe intended for prostate cancer detection combining Raman spectroscopy and tactile resonance technology--discrimination of normal human prostate tissues ex vivo.

Prostate cancer is the most common cancer for men in the western world. For the first time, a dual-modality probe, combining Raman spectroscopy and tactile resonance technology, has been used for assessment of fresh human prostate tissue. The study investigates the potential of the dual-modality probe by testing its ability to differentiate prostate tissue types ex vivo. Measurements on four prostates show that the tactile resonance modality was able to discriminate soft epithelial tissue and stiff stroma (p < 0.05). The Raman spectra exhibited a strong fluorescent background at the current experimental settings. However, stroma could be discerned from epithelia by integrating the value of the spectral background. Combining both parameters by a stepwise analysis resulted in 100% sensitivity and 91% specificity. Although no cancer tissue was analysed, the results are promising for further development of the instrument and method for discriminating prostate tissues and cancer.

Does a magnetic blanket induce changes in muscular blood flow, skin temperature and muscular tension in horses?

REASONS FOR PERFORMING STUDY: Static magnetic blankets are often claimed to induce increases in blood flow, reduce muscle tension and tenderness, and be beneficial in both prevention and treatment of musculoskeletal injuries in horses. However, there are no studies that confirm alleged beneficial effects of magnets on muscles of the back in healthy horses. OBJECTIVES: To investigate whether static magnets sewn into a blanket affect back muscle blood flow, skin temperature, mechanical nociceptive threshold (MNT) and behaviour in healthy horses. STUDY DESIGN: Prospective, randomised, blinded, placebo-controlled crossover study. METHODS: The following outcome measurements of the back of 10 healthy horses were performed; blood flow by photoplethysmography, skin temperature by use of thermistors in conjunction with digital infrared thermography, and MNTs by algometry. The horses' behaviour was filmed during the procedure and scored on an ethogram. Measurements were performed repeatedly for a 30 min baseline period. Thereafter a blanket with active, static magnets (900 gauss) or placebo magnets was placed on the horse and measurements were performed for a 60 min treatment period and a 30 min post treatment period. The study procedure was repeated on the consecutive day, when the horse received the alternative treatment. RESULTS: Blood flow in muscle, skin temperatures, MNTs and behavioural traits did not differ between active and placebo magnetic blankets. Skin temperature increased similarly during both active and placebo blanket treatment. CONCLUSIONS: In healthy horses, magnetic blankets did not induce additional significant effects on muscle blood flow, skin temperature, MNTs and behaviour when compared with nonmagnetic blankets.

Progress with the implementation of kangaroo mother care in four regions in Ghana.

AIM: To measure progress with the implementation of kangaroo mother care (KMC) for low birth-weight (LBW) infants at a health systems level. DESIGN: Action research design, with district and regional hospitals as the unit of analysis. SETTING: Four regions in Ghana, identified by the Ghana Health Service and UNICEF. PARTICIPANTS: Health workers and officials, health care facilities and districts in the four regions. INTERVENTION: A one-year implementation programme with three phases: (1) introduction to KMC, skills development in KMC practice and the management of implementation; (2) advanced skills development for regional steering committee members; and (3) an assessment of progress at the end of the intervention. MAIN OUTCOME MEASURES: Description of practices, services and facilities for KMC and the identification of strengths and challenges. RESULTS: Twenty-six of 38 hospitals (68%) demonstrated sufficient progress with KMC implementation. Half of the hospitals had designated a special ward for KMC. 66% of hospitals used a special record for infants receiving KMC. Two of the main challenges were lack of support for mothers who had to remain with their LBW infants in hospital and no follow-up review services for LBW infants in 39% of hospitals. CONCLUSIONS: It was possible to roll out KMC in Ghana, but further support for the regions is needed to maintain the momentum. Lessons learned from this project could inform further scale-up of KMC and other projects in Ghana.

450K-array analysis of chronic lymphocytic leukemia cells reveals global DNA methylation to be relatively stable over time and similar in resting and proliferative compartments.

In chronic lymphocytic leukemia (CLL), the microenvironment influences gene expression patterns; however, knowledge is limited regarding the extent to which methylation changes with time and exposure to specific microenvironments. Using high-resolution 450K arrays, we provide the most comprehensive DNA methylation study of CLL to date, analyzing paired diagnostic/follow-up samples from IGHV-mutated/untreated and IGHV-unmutated/treated patients (n=36) and patient-matched peripheral blood and lymph node samples (n=20). On an unprecedented scale, we revealed 2239 differentially methylated CpG sites between IGHV-mutated and unmutated patients, with the majority of sites positioned outside annotated CpG islands. Intriguingly, CLL prognostic genes (for example, CLLU1, LPL, ZAP70 and NOTCH1), epigenetic regulator (for example, HDAC9, HDAC4 and DNMT3B), B-cell signaling (for example, IBTK) and numerous TGF-ß and NF-κB/TNF pathway genes were alternatively methylated between subgroups. Contrary, DNA methylation over time was deemed rather stable with few recurrent changes noted within subgroups. Although a larger number of non-recurrent changes were identified among IGHV-unmutated relative to mutated cases over time, these equated to a low global change. Similarly, few changes were identified between compartment cases. Altogether, we reveal CLL subgroups to display unique methylation profiles and unveil methylation as relatively stable over time and similar within different CLL compartments, implying aberrant methylation as an early leukemogenic event.

Assessment of strain and strain rate by two-dimensional speckle tracking in mice: comparison with tissue Doppler echocardiography and conductance catheter measurements.

AIMS: This study was designed in order to compare the strain and strain rate deformation parameters assessed by speckle tracking imaging (STI) with those of tissue Doppler imaging (TDI) and conductance catheter measurements in chronic murine models of left ventricular (LV) dysfunction. METHODS AND RESULTS: Twenty-four male C57BL/6J mice were assigned to wild-type (n = 8), myocardial infarction (n = 8) and transaortic constriction (n = 8) groups. Echocardiographic and conductance measurements were simultaneously performed at rest and during dobutamine infusion (5 µg/kg/min) in all animals 10 weeks post-surgery. The LV circumferential strain (Scirc) and the strain rate (SRcirc) were derived from grey scale and tissue Doppler data at frame rates of 224 and 375 Hz, respectively. Scirc and SRcirc by TDI/STI correlated well with the preload recruitable stroke work (PRSW) (r = -0.64 and -0.71 for TDI; r = -0.46 and -0.50 for STI, P < 0.05). Both modalities showed a good agreement with respect to Scirc and SRcirc (r = 0.60 and r = 0.63, P < 0.05). During stress, however, TDI-estimated Scirc and SRcirc values were predominantly higher than those measured by STI (P < 0.05). The similarity of Scirc and SRcirc measurements with respect to the STI/TDI data was examined by the Bland-Altman analysis. CONCLUSION: In mice, the STI- and TDI-derived strain and strain rate deformation parameters relate closely to intrinsic myocardial function. At low heart rate-to-frame rate ratios (HR/FR), both STI and TDI are equally acceptable for assessing the LV function non-invasively in these animals. At HR/FR (e.g. dobutamine challenge), however, these methods cannot be used interchangeably as STI underestimates S and SR at high values.

Do acetyl salicylic acid and terbutaline in combination increase the probability of a clinical pregnancy in patients undergoing IVF/ICSI?

The present study investigated if acetyl salicylic acid (ASA) and terbutaline in combination increased the clinical pregnancy rate in patients undergoing in vitro fertilisation (IVF)/intra-cytoplasmic sperm injection (ICSI). A randomised controlled trial was designed, in which 167 patients were randomised to taking ASA for 9 weeks after embryo transfer and terbutaline around the time of embryo transfer as adjuvant medication. A total of 112 patients were randomised to no adjuvant medication. The clinical pregnancy rate per controlled ovarian hyperstimulation was 30.5% in the intervention group and 42.0% in the control group. This difference was not statistically significant, and we conclude that ASA and terbutaline in combination do not increase the clinical pregnancy rate after IVF/ICSI treatment.

Combining scanning haptic microscopy and fibre optic Raman spectroscopy for tissue characterization.

The tactile resonance method (TRM) and Raman spectroscopy (RS) are promising for tissue characterization in vivo. Our goal is to combine these techniques into one instrument, to use TRM for swift scanning, and RS for increasing the diagnostic power. The aim of this study was to determine the classification accuracy, using support vector machines, for measurements on porcine tissue and also produce preliminary data on human prostate tissue. This was done by developing a new experimental set-up combining micro-scale TRM-scanning haptic microscopy (SHM)-for assessing stiffness on a micro-scale, with fibre optic RS measurements for assessing biochemical content. We compared the accuracy using SHM alone versus SHM combined with RS, for different degrees of tissue homogeneity. The cross-validation classification accuracy for healthy porcine tissue types using SHM alone was 65-81%, and when RS was added it increased to 81-87%. The accuracy for healthy and cancerous human tissue was 67-70% when only SHM was used, and increased to 72-77% for the combined measurements. This shows that the potential for swift and accurate classification of healthy and cancerous prostate tissue is high. This is promising for developing a tool for probing the surgical margins during prostate cancer surgery.