In vivo intervertebral disc deformation: intratissue strain patterns within adjacent discs during flexion-extension.

The biomechanical function of the intervertebral disc (IVD) is a critical indicator of tissue health and pathology. The mechanical responses (displacements, strain) of the IVD to physiologic movement can be spatially complex and depend on tissue architecture, consisting of distinct compositional regions and integrity; however, IVD biomechanics are predominately uncharacterized in vivo. Here, we measured voxel-level displacement and strain patterns in adjacent IVDs in vivo by coupling magnetic resonance imaging (MRI) with cyclic motion of the cervical spine. Across adjacent disc segments, cervical flexion-extension of 10° resulted in first principal and maximum shear strains approaching 10%. Intratissue spatial analysis of the cervical IVDs, not possible with conventional techniques, revealed elevated maximum shear strains located in the posterior disc (nucleus pulposus) regions. IVD structure, based on relaxometric patterns of T2 and T1ρ images, did not correlate spatially with functional metrics of strain. Our approach enables a comprehensive IVD biomechanical analysis of voxel-level, intratissue strain patterns in adjacent discs in vivo, which are largely independent of MRI relaxometry. The spatial mapping of IVD biomechanics in vivo provides a functional assessment of adjacent IVDs in subjects, and provides foundational biomarkers for elastography, differentiation of disease state, and evaluation of treatment efficacy.

Patterned enteroscopy balloon design factors influence tissue anchoring.

Balloon-assisted enteroscopy procedures allow visualization and intervention in the small intestine. These balloons anchor an endoscope and/or overtube to the small intestine, allowing endoscopists to plicate the small intestine over the overtube. This procedure can extend examination deeper into the small intestine than the length of the endoscope would allow with direct examination. However, procedures are often prolonged or incomplete due to balloon slippage. Enteroscopy balloons are pressure-limited to ensure patient safety and thus, improving anchoring without increasing pressure is essential. Patterning balloon exteriors with discrete features may enhance anchoring at the tissue-balloon interface. Here, the pattern design space is explored to determine factors that influence tissue anchoring. The anchoring ability of smooth versus balloons with patterned features is investigated by experimentally measuring a peak force required to induce slippage of an inflated balloon inside ex-vivo porcine small intestine. Stiffer materials, low aspect-ratio features, and pattern area/location on the balloons significantly increase peak force compared to smooth silicone balloons. Smooth latex balloons, used for standard enteroscopy, have the lowest peak force. This work demonstrates both a method to pattern curved surfaces and that a balloon with patterned features improves anchoring against a deformable, lubricated tissue interface.

The transition to clinical expert: enhanced decision making for children aged less than 5†years attending the paediatric ED with acute respiratory conditions.

BACKGROUND: Rates of unplanned paediatric admissions are persistently high. Many admissions are short-stay events, lasting less than 48 hours. OBJECTIVE: This qualitative research explores factors that influence clinical decision making in the paediatric ED (PED) for children under 5 attending with acute respiratory conditions, focusing on how management decisions adapt with increasing experience. METHOD: Semi-structured interviews were conducted with 15 PED clinicians (doctors, emergency nurse practitioners and registered nurses) with varying levels of experience in paediatric emergency medicine (PEM), emergency medicine or paediatrics. Audio-recorded interviews were transcribed and analysed thematically. RESULTS: There were clear differences in decision-making approaches between experienced clinicians and junior staff. The latter were more risk adverse, relying heavily on guidelines, set admission criteria, clinical theory and second opinions. This was particularly true for doctors. 'Informal' learning was apparent in accounts from less-experienced doctors and nurses, whereby tacit knowledge and risk management played an increasing role in the development of clinical intuition that permitted rapid assessment and treatment of young patients. CONCLUSIONS: The emergence of intuition entwined with approaches to risk management and the role of these skills in clinical decision making, carry implications for the development of training programmes for clinicians working in PEM. Enhanced training for such groups to permit development of the supplementary skills described in this study could have the ability to improve care delivery and even reduce paediatric admissions.

Colocalization of cellular nanostructure using confocal fluorescence and partial wave spectroscopy.

A new multimodal confocal microscope has been developed, which includes a parallel Partial Wave Spectroscopic (PWS) microscopy path. This combination of modalities allows molecular-specific sensing of nanoscale intracellular structure using fluorescent labels. Combining molecular specificity and sensitivity to nanoscale structure allows localization of nanostructural intracellular changes, which is critical for understanding the mechanisms of diseases such as cancer. To demonstrate the capabilities of this multimodal instrument, we imaged HeLa cells treated with valinomycin, a potassium ionophore that uncouples oxidative phosphorylation. Colocalization of fluorescence images of the nuclei (Hoechst 33342) and mitochondria (anti-mitochondria conjugated to Alexa Fluor 488) with PWS measurements allowed us to detect a significant decrease in nuclear nanoscale heterogeneity (Σ), while no significant change in Σ was observed at mitochondrial sites. In addition, application of the new multimodal imaging approach was demonstrated on human buccal samples prepared using a cancer screening protocol. These images demonstrate that nanoscale intracellular structure can be studied in healthy and diseased cells at molecular-specific sites.

Nanocytological field carcinogenesis detection to mitigate overdiagnosis of prostate cancer: a proof of concept study.

PURPOSE: To determine whether nano-architectural interrogation of prostate field carcinogenesis can be used to predict prognosis in patients with early stage (Gleason 6) prostate cancer (PCa), which is mostly indolent but frequently unnecessarily treated. MATERIALS AND METHODS: We previously developed partial wave spectroscopic microscopy (PWS) that enables quantification of the nanoscale intracellular architecture (20-200 nm length scale) with remarkable accuracy. We adapted this technique to assess prostate needle core biopsies in a case control study from men with Gleason 6 disease who either progressed (n = 20) or remained indolent (n = 18) over a ~3 year follow up. We measured the parameter disorder strength (Ld) characterizing the spatial heterogeneity of the nanoscale cellular structure and nuclear morphology from the microscopically normal mucosa ~150 histologically normal epithelial cells. RESULTS: There was a profound increase in nano-architectural disorder between progressors and non-progressors. Indeed, the Ld from future progressors was dramatically increased when compared to future non-progressors (1±0.065 versus 1.30±0.0614, respectively p = 0.002). The area under the receiver operator characteristic curve (AUC) was 0.79, yielding a sensitivity of 88% and specificity of 72% for discriminating between progressors and non-progressors. This was not confounded by demographic factors (age, smoking status, race, obesity), thus supporting the robustness of the approach. CONCLUSIONS: We demonstrate, for the first time, that nano-architectural alterations occur in prostate cancer field carcinogenesis and can be exploited to predict prognosis of early stage PCa. This approach has promise in addressing the clinically vexing dilemma of management of Gleason 6 PCa and may provide a paradigm for dealing with the larger issue of cancer overdiagnosis.

Complex consultations in primary care: a tool for assessing the range of health problems and issues addressed in general practice consultations.

BACKGROUND: There is an increasing recognition that many consultations in general practice involve several problems covering multiple disease domains. However there is a paucity of reliable tools and techniques to understand and quantify this phenomenon. The objective was to develop a tool that can be used to measure the number and type of problems discussed in primary care consultations. METHODS: Thirteen consultations between general practitioners and patients were initially videoed and reviewed to identify the problems and issues discussed. An iterative process involving a panel of clinicians and researchers and repeated cycles of testing and development was used to develop a measurement proforma and coding manual for assessment of video recorded consultations. The inter-rater reliability of this tool was assessed in 60 consultations. RESULTS: The problems requiring action were usually readily identified. However the different dimensions of the problem and how they were addressed required the identification and definition of 'issues'. A coding proforma was developed that allowed quantification of the numbers and types of health problems and issues discussed. Ten categories of issues were identified and defined. At the consultation level, inter-rater agreements for the number of problems discussed (within ± 1), types of problems and issues were 98.3%, 96.5% and 90% respectively. The tool has subsequently been used to analyse 229 consultations. CONCLUSION: The iterative approach to development of the tool reflected the complexity of doctor-patient interactions. A reliable tool has been developed that can be used to analyse the number and range of problems managed in primary care consultations.

The content of general practice consultations: cross-sectional study based on video recordings.

BACKGROUND: Demographic and policy changes appear to be increasing the complexity of consultations in general practice. AIM: To describe the number and types of problems discussed in general practice consultations, differences between problems raised by patients or doctors, and between problems discussed and recorded in medical records. DESIGN AND SETTING: Cross-sectional study based on video recordings of consultations in 22 general practices in Bristol and North Somerset. METHOD: Consultations were examined between 30 representative GPs and adults making a pre-booked day-time appointment. The main outcome measures were number and types of problems and issues discussed; who raised each problem/issue; consultation duration; whether problems were recorded and coded. RESULTS: Of 318 eligible patients, 229 (72.0%) participated. On average, 2.5 (95% CI = 2.3 to 2.6) problems were discussed in each consultation, with 41% of consultations involving at least three problems. Seventy-two per cent (165/229) of consultations included problems in multiple disease areas. Mean consultation duration was 11.9 minutes (95% CI = 11.2 to 12.6). Most problems discussed were raised by patients, but 43% (99/229) of consultations included problems raised by doctors. Consultation duration increased by 2 minutes per additional problem. Of 562 problems discussed, 81% (n = 455) were recorded in notes, but only 37% (n = 206) were Read Coded. CONCLUSION: Consultations in general practice are complex encounters, dealing with multiple problems across a wide range of disease areas in a short time. Additional problems are dealt with very briefly. GPs, like patients, bring an agenda to consultations. There is systematic bias in the types of problems coded in electronic medical records databases.

Seroprevalence of bactericidal, specific IgG antibodies and incidence of meningitis due to group A Neisseria meningitidis by age in Burkina Faso 2008.

BACKGROUND: We investigated serological correlates of protection against Neisseria meningitidis serogroup A (NmA) in Burkina Faso before the introduction of NmA conjugate vaccine. METHODOLOGY/PRINCIPAL FINDINGS: We collected blood from a representative sample (N = 1022) of Bobo-Dioulasso residents. Sera were evaluated for serum bactericidal antibody (SBA) activity against NmA strains of immunotype L11 (F8238) and L10 (3125) and NmA-specific IgG. Seroprevalence was compared to the age-specific NmA meningitis incidence in Bobo-Dioulasso during March 2007-February 2008. Meningococcal carriage was evaluated in a subset (N = 538). Geometric mean titres (GMT)/concentrations (GMC) of SBA and NmA-specific IgG increased with age, peaking around age 20 years. Overall, 70% of our sample had NmA-specific IgG ≥2 ug/mL. Meningitis incidence was highest in those aged <6 months and 5-19 years. No NmA carriers were found. Compared to the reference strain SBA, GMTs were higher against a locally isolated strain and around 40-fold lower against Dutch strain 3125. CONCLUSIONS/SIGNIFICANCE: This study provides estimates of natural immunity to NmA, according to a variety of antibody measures, which will be helpful in ascertaining antibody persistence after MenAfriVac™ introduction. Age-specific seroprevalence of reference strain SBA titres most likely reflects exposure to meningococci and consecutive reactive immunity. We could not define any serological correlate of protection.

Effects of Parkinson's Disease on Fundamental Frequency Variability in Running Speech.

In Parkinson's Disease (PD), qualitative speech changes such as decreased variation in pitch and loudness are common, but quantitative vocal changes are not well documented. The variability of fundamental frequency (F0) in 32 individuals (23 male) with PD both ON and OFF levodopa medication was compared with 32 age-matched healthy controls (23 male). Participants read a single paragraph and estimates of fundamental frequency (F0) variability were determined for the entire reading passage as well as for the first and last sentences of the passage separately. F0 variability was significantly increased in controls relative to both PD groups and PD patients showed significantly higher F0 variability while ON medication relative to OFF. No significant effect of group was seen in the change in F0 variability from the beginning to the end of the reading passage. Female speakers were found to have higher F0 variability than males. F0 variability was both significantly reduced in PD relative to controls and significantly increased in patients with PD during use of dopaminergic medications. F0 variability changes over the course of reading a paragraph may not be indicative of PD but rather dependent on non-disease factors such as the linguistic characteristics of the text.

Meningococcal carriage by age: a systematic review and meta-analysis.

BACKGROUND: Neisseria meningitidis is an important cause of meningitis and septicaemia, but most infected individuals experience a period of asymptomatic carriage rather than disease. Previous studies have shown that carriage rates vary by age and setting; however, few have assessed carriage across all ages. We aimed to estimate the age-specific prevalence of meningococcal carriage. METHODS: We searched Embase, Medline, Web of Science, the Cochrane Library, and grey literature for papers reporting carriage of N meningitidis in defined age groups in European countries or in countries with a similar epidemiological pattern (where disease caused by serogroups B and C predominates). We used mixed-effects logistic regression with a natural cubic spline to model carriage prevalence as a function of age for studies that were cross-sectional or serial cross-sectional. The model assessed population type, type of swab used, when swabs were plated, use of preheated plates, and time period (decade of study) as fixed effects, with country and study as nested random effects (random intercept). FINDINGS: Carriage prevalence increased through childhood from 4·5% in infants to a peak of 23·7% in 19-year olds and subsequently decreased in adulthood to 7·8% in 50-year olds. The odds of testing positive for carriage decreased if swabs were not plated immediately after being taken compared with if swabs were plated immediately (odds ratio 0·46, 95% CI 0·31-0·68; p = 0·0001). INTERPRETATION: This study provides estimates of carriage prevalence across all ages, which is important for understanding the epidemiology and transmission dynamics of meningococcal infection. FUNDING: None.