Management of Children With Chronic Wet Cough and Protracted Bacterial Bronchitis CHEST Guideline and Expert Panel Report

BACKGROUND: Wet or productive cough is common in children with chronic cough. We formulated recommendations based on systematic reviews related to the management of chronic wet cough in children (aged METHODS: We used the CHEST expert cough panel\u27s protocol for systematic reviews and the American College of Chest Physicians (CHEST) methodologic guidelines and GRADE framework (the Grading of Recommendations Assessment, Development and Evaluation). Data from the systematic reviews in conjunction with patients\u27 values and preferences and the clinical context were used to form recommendations. Delphi methodology was used to obtain consensus for the recommendations/suggestions made. RESULTS: Combining data from the systematic reviews, we found high-quality evidence in children aged 4 weeks\u27 duration) wet/productive cough that using appropriate antibiotics improves cough resolution, and further investigations (eg, flexible bronchoscopy, chest CT scans, immunity tests) should be undertaken when specific cough pointers (eg, digital clubbing) are present. When the wet cough does not improve following 4 weeks of antibiotic treatment, there is moderate-quality evidence that further investigations should be considered to look for an underlying disease. New recommendations include the recognition of the clinical diagnostic entity of protracted bacterial bronchitis. CONCLUSIONS: Compared with the 2006 Cough Guidelines, there is now high-quality evidence for some, but not all, aspects of the management of chronic wet cough in specialist settings. However, further studies (particularly in primary health) are required

Comparative population structure of <i>Plasmodium malariae</i> and <i>Plasmodium falciparum</i> under different transmission settings in Malawi

&lt;b&gt;Background:&lt;/b&gt; Described here is the first population genetic study of Plasmodium malariae, the causative agent of quartan malaria. Although not as deadly as Plasmodium falciparum, P. malariae is more common than previously thought, and is frequently in sympatry and co-infection with P. falciparum, making its study increasingly important. This study compares the population parameters of the two species in two districts of Malawi with different malaria transmission patterns - one seasonal, one perennial - to explore the effects of transmission on population structures. &lt;BR/&gt; &lt;b&gt;Methods:&lt;/b&gt; Six species-specific microsatellite markers were used to analyse 257 P. malariae samples and 257 P. falciparum samples matched for age, gender and village of residence. Allele sizes were scored to within 2 bp for each locus and haplotypes were constructed from dominant alleles in multiple infections. Analysis of multiplicity of infection (MOI), population differentiation, clustering of haplotypes and linkage disequilibrium was performed for both species. Regression analyses were used to determine association of MOI measurements with clinical malaria parameters. &lt;BR/&gt; &lt;b&gt;Results:&lt;/b&gt; Multiple-genotype infections within each species were common in both districts, accounting for 86.0% of P. falciparum and 73.2% of P. malariae infections and did not differ significantly with transmission setting. Mean MOI of P. falciparum was increased under perennial transmission compared with seasonal (3.14 vs 2.59, p = 0.008) and was greater in children compared with adults. In contrast, P. malariae mean MOI was similar between transmission settings (2.12 vs 2.11) and there was no difference between children and adults. Population differentiation showed no significant differences between villages or districts for either species. There was no evidence of geographical clustering of haplotypes. Linkage disequilibrium amongst loci was found only for P. falciparum samples from the seasonal transmission setting. &lt;BR/&gt; &lt;b&gt;Conclusions:&lt;/b&gt; The extent of similarity between P. falciparum and P. malariae population structure described by the high level of multiple infection, the lack of significant population differentiation or haplotype clustering and lack of linkage disequilibrium is surprising given the differences in the biological features of these species that suggest a reduced potential for out-crossing and transmission in P. malariae. The absence of a rise in P. malariae MOI with increased transmission or a reduction in MOI with age could be explained by differences in the duration of infection or degree of immunity compared to P. falciparum

Genetic Variants Associated With Development of TMD and Its Intermediate Phenotypes: The Genetic Architecture of TMD in the OPPERA Prospective Cohort Study

Genetic risk factors are believed to combine with environmental exposures and contribute to risk of developing temporomandibular disorder (TMD). In this prospective cohort study, 2,737 people without TMD were assessed for common genetic variation in 358 genes known to contribute to nociceptive pathways, inflammation, and affective distress. During a median follow-up period of 2.8 years, 260 people developed first-onset TMD. Hazard ratios (HRs) were computed as measures of association between 2,924 single nucleotide polymorphisms (SNPs) and TMD incidence. After correction for multiple testing, no single SNP was significantly associated with risk of onset TMD. However, several SNPs exceeded Bonferroni correction for multiple comparison or false discovery rate thresholds (FDR=0.05, 0.1, or 0.2) for association with intermediate phenotypes shown to be predictive of TMD onset. Non-specific orofacial symptoms were associated with voltage-gated sodium channel, type 1 alpha subunit (SCN1A, rs6432860, p=2.77×10−5) and angiotensin-I converting enzyme 2 (ACE2, rs1514280, p=4.86×10−5), global psychological symptoms with prostaglandin-endoperoxide synthase 1 (PTGS1, rs3842803, p=2.79×10−6), stress and negative affectivity with amyloid-β (A4) precursor protein (APP, rs466448, p=4.29×10−5), and heat pain temporal summation with multiple PDZ domain protein (MPDZ, rs10809907, p=3.05×10−5). The use of intermediate phenotypes for complex pain diseases revealed new genetic pathways influencing risk of TMD

Three major haplotypes of the β2 adrenergic receptor define psychological profile, blood pressure, and the risk for development of a common musculoskeletal pain disorder

Adrenergic receptor β2 (ADRB2) is a primary target for epinephrine. It plays a critical role in mediating physiological and psychological responses to environmental stressors. Thus, functional genetic variants of ADRB2 will be associated with a complex array of psychological and physiological phenotypes. These genetic variants should also interact with environmental factors such as physical or emotional stress to produce a phenotype vulnerable to pathological states. In this study, we determined whether common genetic variants of ADRB2 contribute to the development of a common chronic pain condition that is associated with increased levels of psychological distress and low blood pressure, factors which are strongly influenced by the adrenergic system. We genotyped 202 female subjects and examined the relationships between three major ADRB2 haplotypes and psychological factors, resting blood pressure, and the risk of developing a chronic musculoskeletal pain condition - Temporomandibular Joint Disorder (TMD). We propose that the first haplotype codes for lower levels of ADRB2 expression, the second haplotype codes for higher ADRB2 expression, and the third haplotype codes for higher receptor expression and rapid agonist-induced internalization. Individuals who carried one haplotype coding for high and one coding for low ADRB2 expression displayed the highest positive psychological traits, had higher levels of resting arterial pressure, and were about 10 times less likely to develop TMD. Thus, our data suggest that either positive or negative imbalances in ADRB2 function increase the vulnerability to chronic pain conditions such as TMD through different etiological pathways that imply the need for tailored treatment options

People of the British Isles: preliminary analysis of genotypes and surnames in a UK control population

There is a great deal of interest in fine scale population structure in the UK, both as a signature of historical immigration events and because of the effect population structure may have on disease association studies. Although population structure appears to have a minor impact on the current generation of genome-wide association studies, it is likely to play a significant part in the next generation of studies designed to search for rare variants. A powerful way of detecting such structure is to control and document carefully the provenance of the samples involved. Here we describe the collection of a cohort of rural UK samples (The People of the British Isles), aimed at providing a well-characterised UK control population that can be used as a resource by the research community as well as providing fine scale genetic information on the British population. So far, some 4,000 samples have been collected, the majority of which fit the criteria of coming from a rural area and having all four grandparents from approximately the same area. Analysis of the first 3,865 samples that have been geocoded indicates that 75% have a mean distance between grandparental places of birth of 37.3km, and that about 70% of grandparental places of birth can be classed as rural. Preliminary genotyping of 1,057 samples demonstrates the value of these samples for investigating fine scale population structure within the UK, and shows how this can be enhanced by the use of surnames

MRI observations at return to play of clinically recovered hamstring injuries

Background: Previous studies have shown that MRI of fresh hamstring injuries have diagnostic and prognostic value. The clinical relevance of MRI at return to play (RTP) has not been clarified yet. The aim of this study is to describe MRI findings of clinically recovered hamstring injuries in amateur, elite and professional athletes that were cleared for RTP. Methods: We obtained MRI of 53 consecutive athletes with hamstring injuries within 5 days of injury and within 3 days of RTP. We assessed the following parameters: injured muscle, grading of injury, presence and extent of intramuscular signal abnormality. We recorded reinjuries within 2 months of RTP. Results: MRIs of the initial injury showed 27 (51%) grade 1 and 26 (49%) grade 2 injuries. Median time to RTP was 28 days (range 12-76). On MRI at RTP 47 athletes (89%) had intramuscular increased signal intensity on fluid-sensitive sequences with a mean longitudinal length of 77 mm (±53) and a median cross-sectional area of 8% (range 0-90%) of the total muscle area. In 22 athletes (42%) there was abnormal intramuscular low-signal intensity. We recorded five reinjuries. Conclusions: 89% of the clinically recovered hamstring injuries showed intramuscular increased signal intensity on fluid-sensitive sequences on MRI. Normalisation of this increased signal intensity seems not required for a successful RTP. Low-signal intensity suggestive of newly developed fibrous tissues is observed in one-third of the clinically recovered hamstring injuries on MRI at RTP, but its clinical relevance and possible association with increased reinjury risk has to be determined

Potential Genetic Risk Factors for Chronic TMD: Genetic Associations from the OPPERA Case Control Study

Genetic factors play a role in the etiology of persistent pain conditions, putatively by modulating underlying processes such as nociceptive sensitivity, psychological well-being, inflammation, and autonomic response. However, to date, only a few genes have been associated with temporomandibular disorders (TMD). This study evaluated 358 genes involved in pain processes, comparing allelic frequencies between 166 cases with chronic TMD and 1442 controls enrolled in the OPPERA (Orofacial Pain: Prospective Evaluation and Risk Assessment) study cooperative agreement. To enhance statistical power, 182 TMD cases and 170 controls from a similar study were included in the analysis. Genotyping was performed using the Pain Research Panel, an Affymetrix gene chip representing 3295 single nucleotide polymorphisms, including ancestry-informative markers that were used to adjust for population stratification. Adjusted associations between genetic markers and TMD case status were evaluated using logistic regression. The OPPERA findings provided evidence supporting previously-reported associations between TMD and two genes: HTR2A and COMT. Other genes were revealed as potential new genetic risk factors for TMD, including NR3C1, CAMK4, CHRM2, IFRD1, and GRK5. While these findings need to be replicated in independent cohorts, the genes potentially represent important markers of risk for TMD and they identify potential targets for therapeutic intervention

Prenatal diagnosis and linkage disequilibrium with cystic fibrosis for markers surrounding D7S8

Three polymorphic DNA markers surrounding the D7S8 locus were tested for their usefulness in the diagnosis of cystic fibrosis (CF) by linkage analysis. The markers correspond to the loci D7S424 and D7S426. These polymorphisms were studied by centers in the U.S., the United Kingdom, the Netherlands, and Italy, using samples from populations throughout Europe and North America. The additional information provided by these probes increased the heterogeneity of the region from 50% to 58% and was essential for a completely informative diagnosis in one family. A very high degree of linkage disequilibrium was found between these markers, which span a distance of approximately 250kb. In addition, linkage disequilibrium with CF was noted. Significant heterogeneity of linkage disequilibrium was found among the populations, both for the marker-marker pairs and between the markers and CF.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/47627/1/439_2004_Article_BF00206745.pd

New genetic loci implicated in fasting glucose homeostasis and their impact on type 2 diabetes risk.

Levels of circulating glucose are tightly regulated. To identify new loci influencing glycemic traits, we performed meta-analyses of 21 genome-wide association studies informative for fasting glucose, fasting insulin and indices of beta-cell function (HOMA-B) and insulin resistance (HOMA-IR) in up to 46,186 nondiabetic participants. Follow-up of 25 loci in up to 76,558 additional subjects identified 16 loci associated with fasting glucose and HOMA-B and two loci associated with fasting insulin and HOMA-IR. These include nine loci newly associated with fasting glucose (in or near ADCY5, MADD, ADRA2A, CRY2, FADS1, GLIS3, SLC2A2, PROX1 and C2CD4B) and one influencing fasting insulin and HOMA-IR (near IGF1). We also demonstrated association of ADCY5, PROX1, GCK, GCKR and DGKB-TMEM195 with type 2 diabetes. Within these loci, likely biological candidate genes influence signal transduction, cell proliferation, development, glucose-sensing and circadian regulation. Our results demonstrate that genetic studies of glycemic traits can identify type 2 diabetes risk loci, as well as loci containing gene variants that are associated with a modest elevation in glucose levels but are not associated with overt diabetes