Early Stages of Ex Vivo Collagen Glycation Disrupt the Cellular Interaction and Its Remodeling by Mesenchymal Stem Cells-Morphological and Biochemical Evidence.

Mesenchymal stem cells (MSCs), pivotal for tissue repair, utilize collagen to restore structural integrity in damaged tissue, preserving its organization through concomitant remodeling. The non-enzymatic glycation of collagen potentially compromises MSC communication, particularly upon advancing the process, underlying various pathologies such as late-stage diabetic complications and aging. However, an understanding of the impact of early-stage collagen glycation on MSC interaction is lacking. This study examines the fate of in vitro glycated rat tail collagen (RTC) upon exposure to glucose for 1 or 5 days in contact with MSCs. Utilizing human adipose tissue-derived MSCs (ADMSCs), we demonstrate their significantly altered interaction with glycated collagen, characterized morphologically by reduced cell spreading, diminished focal adhesions formation, and attenuated development of the actin cytoskeleton. The morphological findings were confirmed by ImageJ 1.54g morphometric analysis with the most significant drop in the cell spreading area (CSA), from 246.8 µm2 for the native collagen to 216.8 µm2 and 163.7 µm2 for glycated ones, for 1 day and 5 days, respectively, and a similar trend was observed for cell perimeter 112.9 µm vs. 95.1 µm and 86.2 µm, respectively. These data suggest impaired recognition of early glycated collagen by integrin receptors. Moreover, they coincide with the reduced fibril-like reorganization of adsorbed FITC-collagen (indicating impaired remodeling) and a presumed decreased sensitivity to proteases. Indeed, confirmatory assays reveal diminished FITC-collagen degradation for glycated samples at 1 day and 5 days by attached cells (22.8 and 30.4%) and reduced proteolysis upon exogenous collagenase addition (24.5 and 40.4%) in a cell-free system, respectively. The mechanisms behind these effects remain uncertain, although differential scanning calorimetry confirms subtle structural/thermodynamic changes in glycated collagen.

Altered Mesenchymal Stem Cells Mechanotransduction from Oxidized Collagen: Morphological and Biophysical Observations.

Extracellular matrix (ECM) provides various mechanical cues that are able to affect the self-renewal and differentiation of mesenchymal stem cells (MSC). Little is known, however, how these cues work in a pathological environment, such as acute oxidative stress. To better understand the behavior of human adipose tissue-derived MSC (ADMSC) in such conditions, we provide morphological and quantitative evidence for significantly altered early steps of mechanotransduction when adhering to oxidized collagen (Col-Oxi). These affect both focal adhesion (FA) formation and YAP/TAZ signaling events. Representative morphological images show that ADMSCs spread better within 2 h of adhesion on native collagen (Col), while they tended to round up on Col-Oxi. It also correlates with the lesser development of the actin cytoskeleton and FA formation, confirmed quantitatively by morphometric analysis using ImageJ. As shown by immunofluorescence analysis, oxidation also affected the ratio of cytosolic-to-nuclear YAP/TAZ activity, concentrating in the nucleus for Col while remaining in the cytosol for Col-Oxi, suggesting abrogated signal transduction. Comparative Atomic Force Microscopy (AFM) studies show that native collagen forms relatively coarse aggregates, much thinner with Col-Oxi, possibly reflecting its altered ability to aggregate. On the other hand, the corresponding Young's moduli were only slightly changed, so viscoelastic properties cannot explain the observed biological differences. However, the roughness of the protein layer decreased dramatically, from RRMS equal to 27.95 ± 5.1 nm for Col to 5.51 ± 0.8 nm for Col-Oxi (p < 0.05), which dictates our conclusion that it is the most altered parameter in oxidation. Thus, it appears to be a predominantly topographic response that affects the mechanotransduction of ADMSCs by oxidized collagen.

Development of a measure of collective efficacy within personal networks: A complement to self-efficacy in self-management support?

OBJECTIVE: To develop and evaluate the Collective Efficacy of Networks (CENS) questionnaire to measure perceived collective efficacy within personal social networks. METHODS: A mixed methods approach was used, guided by theory and with extensive input from adults with long-term conditions who completed the initial questionnaire (n = 78) with test-retest assessed at 2 weeks (n = 68). A second sample (n = 85) completed a postal questionnaire including CENS, theoretically linked constructs (self-efficacy, social support) and health outcomes (loneliness, mental and physical health). RESULTS: Principal components analysis demonstrated a two-factor structure with 12-items selected to represent Network responsiveness (8 items, Cronbach's alpha = 0.896) and Access to collective efficacy (4 items, Cronbach's alpha = .773). Good test-retest reliability was established for both subscales (ricc = .793-.853). Network responsiveness was associated with self-efficacy (r = 342, p = . < 001) and social support (r = .407, p < .001) and predicted reduced loneliness. Access to collective efficacy significantly predicted better mental health; the predictive validity of the subscales improved when combined with self-efficacy. CONCLUSION: The CENS is an acceptable and psychometrically robust measure of collective efficacy in personal social networks. PRACTICE IMPLICATIONS: Measuring collective efficacy with self-efficacy will provide useful information for researchers and policymakers interested in capacity for self-management and social determinants of behaviour change.

Correction: The ICE-AKI study: Impact analysis of a Clinical prediction rule and Electronic AKI alert in general medical patients.

[This corrects the article DOI: 10.1371/journal.pone.0200584.].

The ICE-AKI study: Impact analysis of a Clinical prediction rule and Electronic AKI alert in general medical patients.

BACKGROUND: Acute kidney injury (AKI) is assoicated with high mortality and measures to improve risk stratification and early identification have been urgently called for. This study investigated whether an electronic clinical prediction rule (CPR) combined with an AKI e-alert could reduce hospital-acquired AKI (HA-AKI) and improve associated outcomes. METHODS AND FINDINGS: A controlled before-and-after study included 30,295 acute medical admissions to two adult non-specialist hospital sites in the South of England (two ten-month time periods, 2014-16); all included patients stayed at least one night and had at least two serum creatinine tests. In the second period at the intervention site a CPR flagged those at risk of AKI and an alert was generated for those with AKI; both alerts incorporated care bundles. Patients were followed-up until death or hospital discharge. Primary outcome was change in incident HA-AKI. Secondary outcomes in those developing HA-AKI included: in-hospital mortality, AKI progression and escalation of care. On difference-in-differences analysis incidence of HA-AKI reduced (odds ratio [OR] 0.990, 95% CI 0.981-1.000, P = 0.049). In-hospital mortality in HA-AKI cases reduced on difference-in-differences analysis (OR 0.924, 95% CI 0.858-0.996, P = 0.038) and unadjusted analysis (27.46% pre vs 21.67% post, OR 0.731, 95% CI 0.560-0.954, P = 0.021). Mortality in those flagged by the CPR significantly reduced (14% pre vs 11% post intervention, P = 0.008). Outcomes for community-acquired AKI (CA-AKI) cases did not change. A number of process measures significantly improved at the intervention site. Limitations include lack of randomization, and generalizability will require future investigation. CONCLUSIONS: In acute medical admissions a multi-modal intervention, including an electronically integrated CPR alongside an e-alert for those developing HA-AKI improved in-hospital outcomes. CA-AKI outcomes were not affected. The study provides a template for investigations utilising electronically generated prediction modelling. Further studies should assess generalisability and cost effectiveness. TRIAL REGISTRATION: Clinicaltrials.org NCT03047382.

"Velcro-type" crackles predict specific radiologic features of fibrotic interstitial lung disease.

BACKGROUND: "Velcro-type" crackles on chest auscultation are considered a typical acoustic finding of Fibrotic Interstitial Lung Disease (FILD), however whether they may have a role in the early detection of these disorders has been unknown. This study investigated how "Velcro-type" crackles correlate with the presence of distinct patterns of FILD and individual radiologic features of pulmonary fibrosis on High Resolution Computed Tomography (HRCT). METHODS: Lung sounds were digitally recorded from subjects immediately prior to undergoing clinically indicated chest HRCT. Audio files were independently assessed by two chest physicians and both full volume and single HRCT sections corresponding to the recording sites were extracted. The relationships between audible "Velcro-type" crackles and radiologic HRCT patterns and individual features of pulmonary fibrosis were investigated using multivariate regression models. RESULTS: 148 subjects were enrolled: bilateral "Velcro-type" crackles predicted the presence of FILD at HRCT (OR 13.46, 95% CI 5.85-30.96, p < 0.001) and most strongly the Usual Interstitial Pneumonia (UIP) pattern (OR 19.8, 95% CI 5.28-74.25, p < 0.001). Extent of isolated reticulation (OR 2.04, 95% CI 1.62-2.57, p < 0.001), honeycombing (OR 1.88, 95% CI 1.24-2.83, < 0.01), ground glass opacities (OR 1.74, 95% CI 1.29-2.32, p < 0.001) and traction bronchiectasis (OR 1.55, 95% CI 1.03-2.32, p < 0.05) were all independently associated with the presence of "Velcro-type" crackles. CONCLUSIONS: "Velcro-type" crackles predict the presence of FILD and directly correlate with the extent of distinct radiologic features of pulmonary fibrosis. Such evidence provides grounds for further investigation of lung sounds as an early identification tool in FILD.

Successfully implementing and embedding guidelines to improve the nutrition and growth of preterm infants in neonatal intensive care: a prospective interventional study.

OBJECTIVES: We aimed to improve the nutritional care of preterm infants by developing a complex (multifaceted) intervention intended to translate current evidence into practice. We used the sociological framework of Normalization Process Theory (NPT), to guide implementation in order to embed the new practices into routine care. DESIGN: A prospective interventional study with a before and after methodology. PARTICIPANTS: Infants <30 weeks gestation or <1500 g at birth. SETTING: Tertiary neonatal intensive care unit. INTERVENTIONS: The intervention was introduced in phases: phase A (control period, January-August 2011); phase B (partial implementation; improved parenteral and enteral nutrition solutions, nutrition team, education, August-December 2011); phase C (full implementation; guidelines, screening tool, 'nurse champions', January-December 2012); phase D (postimplementation; January-June 2013). Bimonthly audits and staff NPT questionnaires were used to measure guideline compliance and 'normalisation', respectively. NPT Scores were used to guide implementation in real time. Data on nutrient intakes and growth were collected continuously. RESULTS: There were 52, 36, 75 and 35 infants in phases A, B, C and D, respectively. Mean guideline compliance exceeded 75% throughout the intervention period, peaking at 85%. Guideline compliance and NPT scores both increased over time, (r=0.92 and 0.15, p<0.03 for both), with a significant linear association between the two (r=0.21, p<0.01). There were significant improvements in daily protein intake and weight gain between birth and discharge in phases B and Ccompared with phase A (p<0.01 for all), which were sustained into phase D. CONCLUSIONS: NPT and audit results suggest that the intervention was rapidly incorporated into practice, with high guideline compliance and accompanying improvements in protein intake and weight gain. NPT appears to offer an effective way of implementing new practices such that they lead to sustained changes in care. Complex interventions based on current evidence can improve both practice and clinical outcomes.

Systematic review of prognostic prediction models for acute kidney injury (AKI) in general hospital populations.

OBJECTIVE: Critically appraise prediction models for hospital-acquired acute kidney injury (HA-AKI) in general populations. DESIGN: Systematic review. DATA SOURCES: Medline, Embase and Web of Science until November 2016. ELIGIBILITY: Studies describing development of a multivariable model for predicting HA-AKI in non-specialised adult hospital populations. Published guidance followed for data extraction reporting and appraisal. RESULTS: 14 046 references were screened. Of 53 HA-AKI prediction models, 11 met inclusion criteria (general medicine and/or surgery populations, 474 478 patient episodes) and five externally validated. The most common predictors were age (n=9 models), diabetes (5), admission serum creatinine (SCr) (5), chronic kidney disease (CKD) (4), drugs (diuretics (4) and/or ACE inhibitors/angiotensin-receptor blockers (3)), bicarbonate and heart failure (4 models each). Heterogeneity was identified for outcome definition. Deficiencies in reporting included handling of predictors, missing data and sample size. Admission SCr was frequently taken to represent baseline renal function. Most models were considered at high risk of bias. Area under the receiver operating characteristic curves to predict HA-AKI ranged 0.71-0.80 in derivation (reported in 8/11 studies), 0.66-0.80 for internal validation studies (n=7) and 0.65-0.71 in five external validations. For calibration, the Hosmer-Lemeshow test or a calibration plot was provided in 4/11 derivations, 3/11 internal and 3/5 external validations. A minority of the models allow easy bedside calculation and potential electronic automation. No impact analysis studies were found. CONCLUSIONS: AKI prediction models may help address shortcomings in risk assessment; however, in general hospital populations, few have external validation. Similar predictors reflect an elderly demographic with chronic comorbidities. Reporting deficiencies mirrors prediction research more broadly, with handling of SCr (baseline function and use as a predictor) a concern. Future research should focus on validation, exploration of electronic linkage and impact analysis. The latter could combine a prediction model with AKI alerting to address prevention and early recognition of evolving AKI.

The Resolution of Oculomotor Nerve Palsy Caused by Unruptured Posterior Communicating Artery Aneurysms: A Cohort Study and Narrative Review.

OBJECTIVE: Recovery of oculomotor nerve palsy after microsurgical and endovascular treatment has been studied in numerous small series of predominantly ruptured aneurysms. Little consideration has been given to the distinction between ruptured and unruptured aneurysms. This study examines the influence of treatment modality on oculomotor palsy recovery as a result of unruptured posterior communicating artery aneurysms. METHODS: Patients who presented between 2003 and 2015 with an oculomotor palsy secondary to an unruptured posterior communicating artery aneurysm were identified from the hospital database. A keyword search for "posterior communicating artery aneurysm" and "oculomotor nerve palsy OR third nerve palsy" using the PubMed database was performed for the narrative review. RESULTS: The cohort study and narrative review identified 15 and 179 eligible patients, respectively. Surgically treated patients in the cohort study did not have a significantly better rate of complete palsy resolution than those who had been coiled (P = 0.08). In the review, clipping of the aneurysm resulted in a higher rate of complete palsy resolution (70.0%; 95% confidence interval [CI], 60.7%-79.3%) than did coiling (46.5%; 95% CI, 36.0%-57.0%). Patients who presented with an aneurysm <7 mm had a higher rate of complete palsy resolution compared with aneurysms >7 mm (68.6%; 95% CI, 57.7%-79.5% vs. 44.3%; 95% CI, 32.7%-55.9%). Patients presenting with a complete palsy (49.4%; 95% CI, 38.6%-60.2%) had a lower rate of recovery than did those with a partial palsy (71.4%; 95% CI, 60.2%-82.6%). CONCLUSIONS: In this narrative review, surgical clipping of unruptured posterior communicating artery aneurysms was associated with a higher rate of associated oculomotor palsy recovery than was endovascular treatment.

Physical activity levels in locally advanced rectal cancer patients following neoadjuvant chemoradiotherapy and an exercise training programme before surgery: a pilot study.

BACKGROUND: The aim of this pilot study was to measure changes in physical activity level (PAL) variables, as well as sleep duration and efficiency in people with locally advanced rectal cancer (1) before and after neoadjuvant chemoradiotherapy (CRT) and (2) after participating in a pre-operative 6-week in-hospital exercise training programme, following neoadjuvant CRT prior to major surgery, compared to a usual care control group. METHODS: We prospectively studied 39 consecutive participants (27 males). All participants completed standardised neoadjuvant CRT: 23 undertook a 6-week in-hospital exercise training programme following neoadjuvant CRT. These were compared to 16 contemporaneous non-randomised participants (usual care control group). All participants underwent a continuous 72-h period of PA monitoring by SenseWear biaxial accelerometer at baseline, immediately following neoadjuvant CRT (week 0), and at week 6 (following the exercise training programme). RESULTS: Of 39 recruited participants, 23 out of 23 (exercise) and 10 out of 16 (usual care control) completed the study. In all participants (n = 33), there was a significant reduction from baseline (pre-CRT) to week 0 (post-CRT) in daily step count: median (IQR) 4966 (4435) vs. 3044 (3265); p < 0.0001, active energy expenditure (EE) (kcal): 264 (471) vs. 154 (164); p = 0.003, and metabolic equivalent (MET) (1.3 (0.6) vs. 1.2 (0.3); p = 0.010). There was a significant improvement in sleep efficiency (%) between week 0 and week 6 in the exercise group compared to the usual care control group (80 (13) vs. 78 (15) compared to (69 ((24) vs. 76 (20); p = 0.022), as well as in sleep duration and lying down time (p < 0.05) while those in active EE (kcal) (152 (154) vs. 434 (658) compared to (244 (198) vs. 392 (701) or in MET (1.3 (0.4) vs. 1.5 (0.5) compared to (1.1 (0.2) vs. 1.5 (0.5) were also of importance but did not reach statistical significance (p > 0.05). An apparent improvement in daily step count and overall PAL in the exercise group was not statistically significant. CONCLUSIONS: PAL variables, daily step count, EE and MET significantly reduced following neoadjuvant CRT in all participants. A 6-week pre-operative in-hospital exercise training programme improved sleep efficiency, sleep duration and lying down time when compared to participants receiving usual care. TRIAL REGISTRATION: Clinicaltrials.gov NCT01325909.

Assessing the growth of preterm infants using detailed anthropometry.

AIM: Preterm infants display altered body composition compared to term infants, and weight gain is a crude indicator body composition. Childhood mid-upper arm circumference (MUAC) is a measure of nutritional status. This study investigates MUAC and mid-thigh circumference (MTC) to monitor growth in preterm infants. METHODS: Preterm infants (<30-week gestation) were recruited. MUAC, MTC, weight, length and head circumference (HC) were measured at recruitment and weekly intervals until discharge. Descriptive, correlation and regression analyses were used. RESULTS: Ninety-three infants were recruited. Median measurement duration was eight weeks (1-19). Median gestational age was 27 weeks (23-29). Analysis by curve estimation displayed a mean increase of 2.58 mm/week (left MUAC) (p ≤ 0.0001), 2.56 mm/week (right MUAC) (p ≤ 0.0001), 4.16 mm/week (left MTC) (p ≤ 0.0001), 4.20 mm/week (right MTC) (p ≤ 0.0001). Coefficients of determination (R2 ) were calculated using a growth regression model for MUAC and MTC (0.866-0.917); measures were comparable to growth modelling of weight (0.913), length (0.945) and HC (0.928). High concordance between left and right MUAC and MTC generated a Pearson's correlation coefficient of 0.999 (MUAC) (p ≤ 0.001) and 0.994 (MTC) (p ≤ 0.001). CONCLUSION: Data demonstrate the potential utility of MUAC and MTC as additional measures of growth in preterm infants that are reproducible over time. There is potential to gain insights to improve lean-mass accretion in preterm infants.

Identifying Risk of Future Asthma Attacks Using UK Medical Record Data: A Respiratory Effectiveness Group Initiative.

BACKGROUND: Asthma attacks are common, serious, and costly. Individual factors associated with attacks, such as poor symptom control, are not robust predictors. OBJECTIVE: We investigated whether the rich data available in UK electronic medical records could identify patients at risk of recurrent attacks. METHODS: We analyzed anonymized, longitudinal medical records of 118,981 patients with actively treated asthma (ages 12-80 years) and 3 or more years of data. Potential risk factors during 1 baseline year were evaluated using univariable (simple) logistic regression for outcomes of 2 or more and 4 or more attacks during the following 2-year period. Predictors with significant univariable association (P < .05) were entered into multiple logistic regression analysis with backward stepwise selection of the model including all significant independent predictors. The predictive accuracy of the multivariable models was assessed. RESULTS: Independent predictors associated with future attacks included baseline-year markers of attacks (acute oral corticosteroid courses, emergency visits), more frequent reliever use and health care utilization, worse lung function, current smoking, blood eosinophilia, rhinitis, nasal polyps, eczema, gastroesophageal reflux disease, obesity, older age, and being female. The number of oral corticosteroid courses had the strongest association. The final cross-validated models incorporated 19 and 16 risk factors for 2 or more and 4 or more attacks over 2 years, respectively, with areas under the curve of 0.785 (95% CI, 0.780-0.789) and 0.867 (95% CI, 0.860-0.873), respectively. CONCLUSIONS: Routinely collected data could be used proactively via automated searches to identify individuals at risk of recurrent asthma attacks. Further research is needed to assess the impact of such knowledge on clinical prognosis.

A validation of the National Early Warning Score to predict outcome in patients with COPD exacerbation.

BACKGROUND: The National Early Warning Score (NEWS), proposed as a standardised track and trigger system, may perform less well in acute exacerbation of COPD (AECOPD). This study externally validated NEWS and modifications (Chronic Respiratory Early Warning Score (CREWS) and Salford-NEWS) in AECOPD. METHODS: An observational cohort study (2012-2014, two UK acute medical units (AMUs)), compared AECOPD (2361 admissions, 942 individuals, International Statistical Classification of Diseases and Related Health Problems-10 J40-J44 codes) with AMU patients (37 109 admissions, 20 415 individuals). OUTCOME: In-hospital mortality prediction was done by admission NEWS, CREWS and Salford-NEWS assessed by discrimination (area under receiver operating characteristic curves (AUROCs)) and calibration (plots and Hosmer-Lemeshow (H-L) goodness-of-fit). RESULTS: Median admission NEWS in AECOPD was 4 (IQR 2-6) versus 1 (0-3) in AMUs (p≤0.001), despite mortality of 4.5% in both. AECOPD AUROCs were NEWS 0.74 (95% CI 0.66 to 0.82), CREWS 0.72 (0.63 to 0.80) and Salford-NEWS 0.62 (0.53 to 0.70). AMU NEWS AUROC was 0.77 (0.75 to 0.78). At threshold NEWS=5 for AECOPD (44% of admissions), positive predictive value (PPV) of death was 8% (5 to 11) and negative predictive value (NPV) was 98% (97 to 99) versus AMU patients PPV of 17% (16 to 19) and NPV of 97% (97 to 97). For NEWS in AECOPD H-L p value=0.202. CONCLUSION: This first validation of the NEWS in AECOPD found modest discrimination to predict mortality. Lower specificity of NEWS in patients with AECOPD versus other AMU patients reflects acute and chronic respiratory physiological disturbance (including hypoxia), with resultant low PPV at NEWS=5. CREWS and Salford-NEWS, adjusting for chronic hypoxia, increased the specificity and PPV but there was no gain in discrimination.

Protocol for a multicentre study to assess feasibility, acceptability, effectiveness and direct costs of TRIumPH (Treatment and Recovery In PsycHosis): integrated care pathway for psychosis.

INTRODUCTION: Duration of untreated psychosis (time between the onset of symptoms and start of treatment) is considered the strongest predictor of symptom severity and outcome. Integrated care pathways that prescribe timeframes around access and interventions can potentially improve quality of care. METHODS AND ANALYSIS: A multicentre mixed methods study to assess feasibility, acceptability, effectiveness and analysis of direct costs of an integrated care pathway for psychosis. A pragmatic, non-randomised, controlled trial design is used to compare the impact of Treatment and Recovery In PsycHosis (TRIumPH; Intervention) by comparison between NHS organisations that adopt TRIumPH and those that continue with care as usual (Control). Quantitative and qualitative methods will be used. We will use routinely collected quantitative data and study-specific questionnaires and focus groups to compare service user outcomes, satisfaction and adherence to intervention between sites that adopt TRIumPH versus sites that continue with usual care pathways. SETTING: 4 UK Mental health organisations. Two will implement TRIumPH whereas two will continue care as usual. PARTICIPANTS: Staff, carers, individuals accepted to early intervention in psychosis teams in participating organisations for the study period. INTERVENTION: TRIumPH-Integrated Care Pathway for psychosis that has a holistic approach and prescribes time frames against interventions; developed using intelligence from data; co-produced with patients, carers, clinicians and other stakeholders. OUTCOMES: Feasibility will be assessed through adherence to the process measures. Satisfaction and acceptability will be assessed using questionnaires and focus groups. Effectiveness will be assessed through data collection and evaluation of patient outcomes, including clinical, functional and recovery outcomes, physical health, acute care use. Outcome measures will be assessed at baseline, 12 and 24 months to measure whether there is an effect and if so, whether this is sustained over time. Outcomes measures at the adopter sites will be compared to their own baseline and against comparator sites. ETHICS AND DISSEMINATION: Ethics approval was obtained from East of Scotland Research Ethics Service (REC Ref no: LR/15/ES/0091). The results will be disseminated through publications, conference presentations, reports to the organisation. STUDY REGISTRATION: UK Clinical Research Network Portfolio: 19187.

Early neurological and cognitive impairments in subclinical cerebrovascular disease.

BACKGROUND: The subclinical cerebrovascular disease (SCVD) is an important public health problem with demonstrated prognostic significance for stroke, future cognitive decline, and progression to dementia. The earliest possible detection of the silent presence of SCVD in adults at age at risk with normal functioning is very important for both clinical doctors and scientists. MATERIALS AND METHODS: Seventy-seven adult volunteers, recruited during the years 2005-2007, with mean age 58.7 (standard deviation 5.9) years, were assessed by four subtests from the Cambridge Neuropsychological Test Automated Battery (CANTAB)-Eclipse cognitive assessment system. We used a questionnaire survey for the presence of cerebrovascular risk factors (CVRFs) such as arterial hypertension, smoking and dyslipidemia, among others, as well as instrumental (Doppler examination) and neurological magnetic resonance imaging (MRI) procedures. Descriptive statistics, comparison (t-test, Chi-square) and univariate methods were used as followed by multifactor logistic regression and receiver operating characteristics analyses. RESULTS: The risk factor questionnaire revealed nonspecific symptoms in 44 (67.7%) of the subjects. In 42 (64.6%) of all 65 subjects, we found at least one of the conventional CVRFs. Abnormal findings from the extra- and trans-cranial Doppler examination were established in 38 (58.5%) of all studied volunteers. Thirty-four subjects had brain MRI (52.3%), and abnormal findings were found in 12 (35.3%) of them. Two of the four subtests of CANTAB tool appeared to be potentially promising predictors of the outcome, as found at the univariate analysis (spatial working memory 1 [SWM1] total errors; intra-extra dimensional set 1 [IED1] total errors [adjusted]; IED2 total trials [adjusted]). We established that the best accuracy of 82.5% was achieved by a multifactor interaction logistic regression model, with the role CVRF and combined CANTAB predictor "IED total ratio (errors/trials) × SWM1 total errors" (P = 0.006). CONCLUSIONS: Our results have contributed to the hypothesis that it is possible to identify, by noninvasive methods, subjects at age at risk who have mild degree of cognitive impairment and to establish the significant relationship of this impairment with existing CVRFs, nonspecific symptoms and subclinical abnormal brain Doppler/MRI findings. We created a combined neuropsychological predictor that was able to clearly distinguish between the presence and absence of abnormal Doppler/MRI findings. This pilot prognostic model showed a relatively high accuracy of >80%; therefore, the predictors may serve as biomarkers for SCVD in subjects at age at risk (51-65 years).

Non-specific mechanisms in orthodox and CAM management of low back pain (MOCAM): theoretical framework and protocol for a prospective cohort study.

INTRODUCTION: Components other than the active ingredients of treatment can have substantial effects on pain and disability. Such 'non-specific' components include: the therapeutic relationship, the healthcare environment, incidental treatment characteristics, patients' beliefs and practitioners' beliefs. This study aims to: identify the most powerful non-specific treatment components for low back pain (LBP), compare their effects on patient outcomes across orthodox (physiotherapy) and complementary (osteopathy, acupuncture) therapies, test which theoretically derived mechanistic pathways explain the effects of non-specific components and identify similarities and differences between the therapies on patient-practitioner interactions. METHODS AND ANALYSIS: This research comprises a prospective questionnaire-based cohort study with a nested mixed-methods study. A minimum of 144 practitioners will be recruited from public and private sector settings (48 physiotherapists, 48 osteopaths and 48 acupuncturists). Practitioners are asked to recruit 10-30 patients each, by handing out invitation packs to adult patients presenting with a new episode of LBP. The planned multilevel analysis requires a final sample size of 690 patients to detect correlations between predictors, hypothesised mediators and the primary outcome (self-reported back-related disability on the Roland-Morris Disability Questionnaire). Practitioners and patients complete questionnaires measuring non-specific treatment components, mediators and outcomes at: baseline (time 1: after the first consultation for a new episode of LBP), during treatment (time 2: 2 weeks post-baseline) and short-term outcome (time 3: 3 months post-baseline). A randomly selected subsample of participants in the questionnaire study will be invited to take part in a nested mixed-methods study of patient-practitioner interactions. In the nested study, 63 consultations (21/therapy) will be audio-recorded and analysed quantitatively and qualitatively, to identify communication practices associated with patient outcomes. ETHICS AND DISSEMINATION: The protocol is approved by the host institution's ethics committee and the NHS Health Research Authority Research Ethics Committee. Results will be disseminated via peer-reviewed journal articles, conferences and a stakeholder workshop.

PICADAR: a diagnostic predictive tool for primary ciliary dyskinesia.

Symptoms of primary ciliary dyskinesia (PCD) are nonspecific and guidance on whom to refer for testing is limited. Diagnostic tests for PCD are highly specialised, requiring expensive equipment and experienced PCD scientists. This study aims to develop a practical clinical diagnostic tool to identify patients requiring testing.Patients consecutively referred for testing were studied. Information readily obtained from patient history was correlated with diagnostic outcome. Using logistic regression, the predictive performance of the best model was tested by receiver operating characteristic curve analyses. The model was simplified into a practical tool (PICADAR) and externally validated in a second diagnostic centre.Of 641 referrals with a definitive diagnostic outcome, 75 (12%) were positive. PICADAR applies to patients with persistent wet cough and has seven predictive parameters: full-term gestation, neonatal chest symptoms, neonatal intensive care admittance, chronic rhinitis, ear symptoms, situs inversus and congenital cardiac defect. Sensitivity and specificity of the tool were 0.90 and 0.75 for a cut-off score of 5 points. Area under the curve for the internally and externally validated tool was 0.91 and 0.87, respectively.PICADAR represents a simple diagnostic clinical prediction rule with good accuracy and validity, ready for testing in respiratory centres referring to PCD centres.

An external validation study of a clinical prediction rule for medical patients with suspected bacteraemia.

OBJECTIVE: The objective of this study was to externally validate a clinical prediction rule (CPR)-the 'Shapiro criteria'-to predict bacteraemia in an acute medical unit (AMU). METHODS: Prospectively collected data, retrospectively evaluated over 11 months in an AMU in the UK. From 4810 admissions, 635 patients (13%) had blood cultures (BCs) performed. The 100 cases of true bacteraemia were compared with a randomly selected sample of 100 control cases where BCs were sterile. RESULTS: To predict bacteraemia (at a cut-off score of two points), the Shapiro criteria had a sensitivity of 97% (95% CIs 91% to 99%), specificity 37% (28% to 47%), positive likelihood ratio 1.54 (1.3 to 1.8) and a negative likelihood ratio of 0.08 (0.03 to 0.25). The area under the receiver operating curve was 0.80 (0.74 to 0.86), and the Hosmer-Lemeshow p value was 0.45. CONCLUSIONS: A cut-off score of two points on the Shapiro criteria had high sensitivity to predict bacteraemia in a study of acute general medical admissions. Application of the rule in patients being considered for a BC could identify those at low risk of bacteraemia. Though the model demonstrated good discrimination, the lengthy number of variables (13) and difficulty automating the CPR may limit its use.