Accuracy and economic evaluation of screening tests for undiagnosed COPD among hypertensive individuals in Brazil.

In Brazil, prevalence of diagnosed COPD among adults aged 40 years and over is 16% although over 70% of cases remain undiagnosed. Hypertension is common and well-recorded in primary care, and frequently co-exists with COPD because of common causes such as tobacco smoking, therefore we conducted a cross-sectional screening test accuracy study in nine Basic Health Units in Brazil, among hypertensive patients aged ≥40 years to identify the optimum screening test/combinations to detect undiagnosed COPD. We compared six index tests (four screening questionnaires, microspirometer and peak flow) against the reference test defined as those below the lower limit of normal (LLN-GLI) on quality diagnostic spirometry, with confirmed COPD at clinical review. Of 1162 participants, 6.8% (n = 79) had clinically confirmed COPD. Peak flow had a higher specificity but lower sensitivity than microspirometry (sensitivity 44.3% [95% CI 33.1, 55.9], specificity 95.5% [95% CI 94.1, 96.6]). SBQ performed well compared to the other questionnaires (sensitivity 75.9% [95% CI 65.0, 84.9], specificity 59.2% [95% CI 56.2, 62.1]). A strategy requiring both SBQ and peak flow to be positive yielded sensitivity of 39.2% (95% CI 28.4, 50.9) and specificity of 97.0% (95% CI 95.7, 97.9). The use of simple screening tests was feasible within the Brazilian primary care setting. The combination of SBQ and peak flow appeared most efficient, when considering performance of the test, cost and ease of use (costing £1690 (5554 R$) with 26.7 cases detected per 1,000 patients). However, the choice of screening tests depends on the clinical setting and availability of resources.ISRCTN registration number: 11377960.

Unique and shared systemic biomarkers for emphysema in Alpha-1 Antitrypsin deficiency and chronic obstructive pulmonary disease.

BACKGROUND: Alpha-1 Antitrypsin (AAT) deficiency (AATD), the most common genetic cause of emphysema presents with unexplained phenotypic heterogeneity in affected subjects. Our objectives to identify unique and shared AATD plasma biomarkers with chronic obstructive pulmonary disease (COPD) may explain AATD phenotypic heterogeneity. METHODS: The plasma or serum of 5,924 subjects from four AATD and COPD cohorts were analyzed on SomaScan V4.0 platform. Using multivariable linear regression, inverse variance random-effects meta-analysis, and Least Absolute Shrinkage and Selection Operator (LASSO) regression we tested the association between 4,720 individual proteins or combined in a protein score with emphysema measured by 15th percentile lung density (PD15) or diffusion capacity (DLCO) in distinct AATD genotypes (Pi*ZZ, Pi*SZ, Pi*MZ) and non-AATD, PiMM COPD subjects. AAT SOMAmer accuracy for identifying AATD was tested using receiver operating characteristic curve analysis. FINDINGS: In PiZZ AATD subjects, 2 unique proteins were associated with PD15 and 98 proteins with DLCO. Of those, 68 were also associated with DLCO in COPD also and enriched for three cellular component pathways: insulin-like growth factor, lipid droplet, and myosin complex. PiMZ AATD subjects shared similar proteins associated with DLCO as COPD subjects. Our emphysema protein score included 262 SOMAmers and predicted emphysema in AATD and COPD subjects. SOMAmer AAT level <7.99 relative fluorescence unit (RFU) had 100% sensitivity and specificity for identifying Pi*ZZ, but it was lower for other AATD genotypes. INTERPRETATION: Using SomaScan, we identified unique and shared plasma biomarkers between AATD and COPD subjects and generated a protein score that strongly associates with emphysema in COPD and AATD. Furthermore, we discovered unique biomarkers associated with DLCO and emphysema in PiZZ AATD. FUNDING: This work was supported by a grant from the Alpha-1 Foundation to RPB. COPDGene was supported by Award U01 HL089897 and U01 HL089856 from the National Heart, Lung, and Blood Institute. Proteomics for COPDGene was supported by NIH 1R01HL137995. GRADS was supported by Award U01HL112707, U01 HL112695 from the National Heart, Lung, and Blood Institute, and UL1TRR002535 to CCTSI; QUANTUM-1 was supported by the National Heart Lung and Blood Institute, the Office of Rare Diseases through the Rare Lung Disease Clinical Research Network (1 U54 RR019498-01, Trapnell PI), and the Alpha-1 Foundation. COPDGene is also supported by the COPD Foundation through contributions made to an Industry Advisory Board that has included AstraZeneca, Bayer Pharmaceuticals, Boehringer-Ingelheim, Genentech, GlaxoSmithKline, Novartis, Pfizer, and Sunovion.

Systematic review: the natural history of alpha-1 antitrypsin deficiency, and associated liver disease.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) is estimated to affect three million people worldwide. It causes liver disease in a proportion of carriers of the PiS and PiZ allele due to the formation and retention of polymers within the endoplasmic reticulum of hepatocytes. The reason for this selective penetrance is not known. Although clinical trials are underway, liver transplantation is the only effective treatment for liver disease due to AATD. AIMS: To report the prevalence and natural history of liver disease among individuals with AATD, and assess the outcomes of liver transplantation through systematic review. METHODS: A comprehensive search was conducted across multiple databases. Two independent authors selected the articles and assessed bias using the Newcastle-Ottawa Scale. Data were pooled for analysis, where comparable outcomes were reported. RESULTS: Thirty-five studies were identified related to disease progression and 12 for the treatment of AATD. Seven per cent of children were reported to develop liver cirrhosis, with 16.5% of individuals presenting in childhood requiring liver transplantation. Of those surviving to adulthood, 10.5% had liver cirrhosis and 14.7% required transplantation. Liver transplantation was the only effective treatment reported and outcomes compare favourably to other indications, with 5-year survival reported as over 90% in children and over 80% in adults. DISCUSSION: The clinical course of liver disease in individuals with AATD remains poorly understood, but affects about 10% of those with AATD. More research is required to identify those patients at risk of developing liver disease at an early stage, and to provide alternative treatments to liver transplantation.

Understanding views on everyday use of personal health information: Insights from community dwelling older adults.

BACKGROUND: Older adults apply various strategies to pursue healthy aging, but we know little about their views and use of personal health information to accomplish those ends. METHODS: As a first step in formulating the role of personal health information management (PHIM) in healthy aging, we explored the perspectives of older adults on health and health information used in their everyday lives through four focus groups with 25 community-dwelling adults aged 60 and over. RESULTS: We found that the concept of wellness-the holistic and multidimensional nature of health and wellbeing-plays prominently in how older adults think about health and health information. Participants expressed wellness from a position of personal strength, rather than health-related deficits, by focusing on wellness activities for staying healthy through: (1) personal health practices, (2) social network support, and (3) residential community engagement. CONCLUSION: Although these themes involve personal health information, existing PHIM systems that focus on disease management are generally not designed to support wellness activities. Substantial opportunity exists to fill this wellness support gap with innovative health information technology designed for older adults. Findings carry implications for the design of PHIM tools that support healthy aging and methods for engaging older adults as co-producers of this critical support.

Lung density associates with survival in alpha 1 antitrypsin deficient patients.

INTRODUCTION: CT density correlates with quality of life (QOL) scores and impaired upper zone lung density associates with higher mortality in alpha one antitrypsin deficiency (A1ATD). We hypothesised that decline in CT densitometry would relate to survival or deterioration in QOL in A1ATD. METHODS: All augmentation naïve PiZZ patients in the UK A1ATD registry with ≥ two successive quantitative CT scans were selected. Patients were divided into groups based on CT density decline and the relationship to survival and change in QOL compared by univariate analyses and multivariate Cox regression. Analyses were performed for whole lung, upper zone and lower zone density separately. Exploratory analyses of FEV1 subgroups were conducted. RESULTS: 110 patients were identified; 77 had whole lung and lung zone density recorded on two CT scans, 33 patients had upper zone data only on four scans. Decline in lower zone density associated with survival, even after adjustment for baseline lung density (p = 0.048), however upper zone density and whole lung density decline did not. This difference appeared to be driven by those with FEV1 >30% predicted. CONCLUSION: Rate of change in lung densitometry could predict survival in A1ATD.

PiSZ alpha-1 antitrypsin deficiency (AATD): pulmonary phenotype and prognosis relative to PiZZ AATD and PiMM COPD.

INTRODUCTION: The PiSZ genotype results in less severe deficiency of alpha-1 antitrypsin (AAT) than PiZZ. Less is known about phenotypic and prognostic features. METHODS: We studied 699 PiZZ, 126 PiSZ and 316 PiMM patients. All AAT deficiency (AATD) patients were augmentation naive. PiSZ were compared with PiZZ patients for clinical phenotype at baseline including CT findings, smoke exposure, progression of lung disease and survival. Similarly, PiSZ patients diagnosed as a result of investigation for possible lung disease (lung index cases) were compared with PiMM. Multivariable analytical techniques and matching (PiSZ to PiZZ) were employed to account for demographic differences. RESULTS: Pack-years smoked and FEV1 exhibited a negative correlation in PiSZ and ZZ patients (both r=-0.43), with emphysema and COPD occurring more commonly in PiZZ patients at <20 pack-year exposure. In multivariable analyses, PiSZ patients were less likely to have emphysema (p<0.01) and had better survival than PiZZ (p=0.017), but lung function decline did not differ significantly. 42% of PiSZ patients had upper-zone-dominant emphysema on CT scan. Analyses of AAT level confirmed a critical threshold at 11 µM, particularly with regard to phenotypes classical of PiZZ AATD.Significant baseline differences suggested that PiSZ had presented earlier to health services than PiMM. Once this was accounted for, risk of emphysema did not differ between PiSZ and PiMM although survival was lower in PiMM patients (p<0.01). CONCLUSIONS: PiSZ patients are less susceptible to cigarette smoke than PiZZ. The pattern of emphysema may be similar at diagnosis to usual COPD.

A care-bundles approach to improving standard of care in AECOPD admissions: results of a national project.

This report describes a care bundles implementation project for COPD undertaken during 2013 in England and Wales. High-level data were collected on outcomes of care for 11 748 patients admitted with an acute exacerbation of COPD (AECOPD). Patient-level data on processes and outcomes of care were collected on 3272 COPD admissions, among which 1174 bundles were delivered. Analysis demonstrated a statistically significant reduction in mortality and length of hospital stay from some bundle elements. Outcomes, including bundle completion rates, were better when specialist respiratory review occurred. The results support wider use of care bundles for AECOPD.

Clinical Informatics Fellowship Programs: In Search of a Viable Financial Model: An open letter to the Centers for Medicare and Medicaid Services.

In the US, the new subspecialty of Clinical Informatics focuses on systems-level improvements in care delivery through the use of health information technology (HIT), data analytics, clinical decision support, data visualization and related tools. Clinical informatics is one of the first subspecialties in medicine open to physicians trained in any primary specialty. Clinical Informatics benefits patients and payers such as Medicare and Medicaid through its potential to reduce errors, increase safety, reduce costs, and improve care coordination and efficiency. Even though Clinical Informatics benefits patients and payers, because GME funding from the Centers for Medicare and Medicaid Services (CMS) has not grown at the same rate as training programs, the majority of the cost of training new Clinical Informaticians is currently paid by academic health science centers, which is unsustainable. To maintain the value of HIT investments by the government and health care organizations, we must train sufficient leaders in Clinical Informatics. In the best interest of patients, payers, and the US society, it is therefore critical to find viable financial models for Clinical Informatics fellowship programs. To support the development of adequate training programs in Clinical Informatics, we request that the Centers for Medicare and Medicaid Services (CMS) issue clarifying guidance that would allow accredited ACGME institutions to bill for clinical services delivered by fellows at the fellowship program site within their primary specialty.

Identification of novel vascular targets in lung cancer.

BACKGROUND: Lung cancer remains the leading cause of cancer-related death, largely owing to the lack of effective treatments. A tumour vascular targeting strategy presents an attractive alternative; however, the molecular signature of the vasculature in lung cancer is poorly explored. This work aimed to identify novel tumour vascular targets in lung cancer. METHODS: Enzymatic digestion of fresh tissue followed by endothelial capture with Ulex lectin-coated magnetic beads was used to isolate the endothelium from fresh tumour specimens of lung cancer patients. Endothelial isolates from the healthy and tumour lung tissue were subjected to whole human genome expression profiling using microarray technology. RESULTS: Bioinformatics analysis identified tumour endothelial expression of angiogenic factors, matrix metalloproteases and cell-surface transmembrane proteins. Predicted novel tumour vascular targets were verified by RNA-seq, quantitative real-time PCR analysis and immunohistochemistry. Further detailed expression profiling of STEAP1 on 82 lung cancer patients confirmed STEAP1 as a novel target in the tumour vasculature. Functional analysis of STEAP1 using siRNA silencing implicates a role in endothelial cell migration and tube formation. CONCLUSIONS: The identification of cell-surface tumour endothelial markers in lung is of interest in therapeutic antibody and vaccine development.

The Early Mobility Bundle: a simple enhancement of therapy which may reduce incidence of hospital-acquired pneumonia and length of hospital stay.

BACKGROUND: Early mobility facilitated by physiotherapy has been shown to reduce the incidence of hospital-acquired pneumonia (HAP) in patients with hip fractures but its effect on HAP incidence in medical patients has not yet been studied. AIM: To determine whether early mobility aided by physiotherapy reduces the incidence of HAP and length of stay in patients on medical wards. METHODS: One respiratory and one elderly care medicine ward in one hospital association in Birmingham, UK, received the 'Early Mobility Bundle'. The bundle consisted of extra targeted physiotherapy and collaboration with ward staff to encourage and promote activity. The incidence of HAP, falls, pressure sores, length of stay (LOS) and activity level were then compared to two matched wards within the same hospital association. RESULTS: HAP incidence was significantly lower in the intervention group (P < 0.0001) and remained so after adjusting for confounders (P = 0.001). Activity levels were higher (P = 0.04) and patients' LOS was more likely to fall in the lowest quartile (OR: 1.44; P = 0.009) in the intervention group. There was no significant difference in other outcomes. CONCLUSION: The Early Mobility Bundle demonstrates a promising method to reduce the incidence of HAP and to increase activity in medical inpatients.

Solitons and thermal fluctuations in strongly nonlinear solids.

We study a chain of anharmonic springs with tunable power law interactions as a minimal model to explore the propagation of strongly nonlinear solitary wave excitations in a background of thermal fluctuations. By treating the solitary waves as quasiparticles, we derive an effective Langevin equation and obtain their damping rate and thermal diffusion. These analytical findings compare favorably against numerical results from a Langevin dynamic simulation. In our chains composed of two-sided nonlinear springs, we report the existence of an expansion solitary wave (antisoliton) in addition to the compressive solitary waves observed for noncohesive macroscopic particles.

Genotype and clinical care correlations in craniosynostosis: findings from a cohort of 630 Australian and New Zealand patients.

Craniosynostosis is one of the most common craniofacial disorders encountered in clinical genetics practice, with an overall incidence of 1 in 2,500. Between 30% and 70% of syndromic craniosynostoses are caused by mutations in hotspots in the fibroblast growth factor receptor (FGFR) genes or in the TWIST1 gene with the difference in detection rates likely to be related to different study populations within craniofacial centers. Here we present results from molecular testing of an Australia and New Zealand cohort of 630 individuals with a diagnosis of craniosynostosis. Data were obtained by Sanger sequencing of FGFR1, FGFR2, and FGFR3 hotspot exons and the TWIST1 gene, as well as copy number detection of TWIST1. Of the 630 probands, there were 231 who had one of 80 distinct mutations (36%). Among the 80 mutations, 17 novel sequence variants were detected in three of the four genes screened. In addition to the proband cohort there were 96 individuals who underwent predictive or prenatal testing as part of family studies. Dysmorphic features consistent with the known FGFR1-3/TWIST1-associated syndromes were predictive for mutation detection. We also show a statistically significant association between splice site mutations in FGFR2 and a clinical diagnosis of Pfeiffer syndrome, more severe clinical phenotypes associated with FGFR2 exon 10 versus exon 8 mutations, and more frequent surgical procedures in the presence of a pathogenic mutation. Targeting gene hot spot areas for mutation analysis is a useful strategy to maximize the success of molecular diagnosis for individuals with craniosynostosis.

Critical and umbilical points of a non-Gaussian random field.

Random fields in nature often have, to a good approximation, Gaussian characteristics. For such fields, the number of maxima and minima are the same. Furthermore, the relative densities of umbilical points, topological defects which can be classified into three types, have certain fixed values. Phenomena described by nonlinear laws can, however, give rise to a non-Gaussian contribution, causing a deviation from these universal values. We consider a random surface, whose height is given by a nonlinear function of a Gaussian field. We find that, as a result of the non-Gaussianity, the density of maxima and minima no longer match and we calculate the relative imbalance between the two. We also calculate the change in the relative density of umbilics. This allows us not only to detect a perturbation, but to determine its size as well. This geometric approach offers an independent way of detecting non-Gaussianity, which even works in cases where the field itself can not be probed directly.

Extrema statistics in the dynamics of a non-Gaussian random field.

When the equations that govern the dynamics of a random field are nonlinear, the field can develop with time non-Gaussian statistics even if its initial condition is Gaussian. Here, we provide a general framework for calculating the effect of the underlying nonlinear dynamics on the relative densities of maxima and minima of a two-dimensional field. Using this simple geometrical probe, we can identify the size of the non-Gaussian contributions in the random field, or alternatively the magnitude of the nonlinear terms in the underlying equations of motion. We demonstrate our approach by applying it to an initially Gaussian field that evolves according to the deterministic KPZ equation, which models surface growth and shock dynamics.

SLUG (SNAI2) overexpression in embryonic development.

The Snail-related zinc-finger transcription factor, SLUG (SNAI2), is critical for the normal development of neural crest-derived cells and loss-of-function SLUG mutations have been proven to cause piebaldism and Waardenburg syndrome type 2 in a dose-dependent fashion. However, little is known about the consequences of SLUG overexpression in embryonic development. We report SLUG duplication in a child with a unique de novo 8q11.2-->q13.3 duplication associated with tetralogy of Fallot, submucous cleft palate, renal anomalies, hypotonia and developmental delay. To investigate the effects of Slug overexpression on development, we analyzed mice carrying a Slug transgene. These mice were morphologically normal at birth, inferring that Slug overexpression is not sufficient to cause overt morphogenetic defects. In the adult mice, there was a 20% incidence of sudden death, cardiomegaly and cardiac failure associated with incipient mesenchymal tumorigenesis. These findings, while not directly implicating Slug in congenital and acquired heart disease, raise the possibility that Slug overexpression may contribute to specific cardiac phenotypes and cancer development.

Incontinentia pigmenti case series: clinical spectrum of incontinentia pigmenti in 53 female patients and their relatives.

A retrospective case series of 53 female patients with incontinentia pigmenti (IP) including 28 secondary cases (female relatives of probands) was reviewed and compared with other series in an attempt to estimate more accurately the true disease burden of patients with IP. We found that, while the frequency of the first three cutaneous stages of IP was comparable with previous studies, none of the secondary cases manifested any serious neurological complications but all displayed stage IV pale anhidrotic reticulate lines on their posterior calves. This important clinical feature of IP in secondary cases has previously been under-represented in studies that often involved only paediatric probands. Hence, mildly affected cases of IP are often undiagnosed and under-represented in case series to date, possibly leading to inappropriately high estimates of neurological and eye involvement. With the availability of genetic testing, it is now feasible to confirm the variability of the phenotype and the risk of complications in IP.

Modified electrode placement must be recorded when performing 12-lead electrocardiograms.

BACKGROUND: Local observation has suggested that placing limb leads on the torso when recording the standard 12-lead resting electrocardiogram (ECG) has become commonplace. This non-standard modification has the important advantages of ease and speed of application, and in an emergency may be applied with minimal undressing. Limb movement artefact is also reduced. It is believed that ECGs obtained with torso electrodes are interchangeable with standard ECGs and any minor electrocardiographic variations do not affect diagnostic interpretation. STUDY DESIGN: The study compared 12-lead ECGs in 100 patients during routine electrocardiography, one being taken in the approved way and one taken with modified limb electrodes. RESULTS: It was found that the use of torso leads produced important amplitude and waveform changes associated with a more vertical and rightward shift of the QRS frontal axis, particularly in those with abnormal standard ECGs. Such changes generated important ECG abnormalities in 36% of patients with normal standard ECGs, suggesting "heart disease of electrocardiographic origin". In those with abnormal standard ECGs, moving the limb leads to the torso made eight possible myocardial infarcts appear and five inferior infarcts disappeared. Twelve others developed clinically important T wave or QRS frontal axis changes. CONCLUSIONS: It is vital that ECGs should be acquired in the standard way unless there are particular reasons for not doing so, and that any modification of electrode placement must be reported on the ECG itself. Marking the ECG "torso-positioned limb leads" or "non-standard" should alert the clinician to its limitations for clinical or investigative purposes, as any lead adaptation may modify the tracing and could result in misinterpretation.

De novo interstitial duplication 4(q28.1q35) associated with choanal atresia.

We report a case of direct interstitial duplication of chromosome 4 from 4q28.1 to 4q35 associated with bilateral choanal atresia. The child also had dysmorphic features including a broad nasal bridge, telecanthus, downward slanting palpebral fissures, prominent ears, mild bilateral clinodactyly of the 5th fingers and bilateral hypoplasia of the 2nd-5th toenails. There was also a slightly dilated renal collecting system. At the age of 2.5 years, he had moderate global developmental delay, short, wide and tapering fingers, and short toes with hypoplastic toenails. To our knowledge, this is the second report of choanal atresia in a patient with trisomy 4q involving this region.