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1.  Looking Back, Looking Forward 
PMCID: PMC3921617  PMID: 24753988
Antibiotic resistance; CARE guidelines; case reports; statin guidelines; vitamins; dietary supplements
2.  Antibiotic Use in Children with Acute Respiratory or Ear Infections: Prospective Observational Comparison of Anthroposophic and Conventional Treatment under Routine Primary Care Conditions 
Children with acute respiratory or ear infections (RTI/OM) are often unnecessarily prescribed antibiotics. Antibiotic resistance is a major public health problem and antibiotic prescription for RTI/OM should be reduced. Anthroposophic treatment of RTI/OM includes anthroposophic medications, nonmedication therapy and if necessary also antibiotics. This secondary analysis from an observational study comprised 529 children <18 years from Europe (AT, DE, NL, and UK) or USA, whose caregivers had chosen to consult physicians offering anthroposophic (A-) or conventional (C-) treatment for RTI/OM. During the 28-day follow-up antibiotics were prescribed to 5.5% of A-patients and 25.6% of C-patients (P < 0.001); unadjusted odds ratio for nonprescription in A- versus C-patients 6.58 (95%-CI 3.45–12.56); after adjustment for demographics and morbidity 6.33 (3.17–12.64). Antibiotic prescription rates in recent observational studies with similar patients in similar settings, ranged from 31.0% to 84.1%. Compared to C-patients, A-patients also had much lower use of analgesics, somewhat quicker symptom resolution, and higher caregiver satisfaction. Adverse drug reactions were infrequent (2.3% in both groups) and not serious. Limitation was that results apply to children of caregivers who consult A-physicians. One cannot infer to what extent antibiotics might be avoided in children who usually receive C-treatment, if they were offered A-treatment.
PMCID: PMC4251819  PMID: 25505919
3.  Comparison of breeding value prediction for two traits in a Nellore-Angus crossbred population using different Bayesian modeling methodologies 
Genetics and Molecular Biology  2014;37(4):631-637.
The objectives of this study were to 1) compare four models for breeding value prediction using genomic or pedigree information and 2) evaluate the impact of fixed effects that account for family structure. Comparisons were made in a Nellore-Angus population comprising F2, F3 and half-siblings to embryo transfer F2 calves with records for overall temperament at weaning (TEMP; n = 769) and Warner-Bratzler shear force (WBSF; n = 387). After quality control, there were 34,913 whole genome SNP markers remaining. Bayesian methods employed were BayesB (π̃ = 0.995 or 0.997 for WBSF or TEMP, respectively) and BayesC (π = 0 and π̃), where π̃ is the ideal proportion of markers not included. Direct genomic values (DGV) from single trait Bayesian analyses were compared to conventional pedigree-based animal model breeding values. Numerically, BayesC procedures (using π̃) had the highest accuracy of all models for WBSF and TEMP (ρ̂gĝ = 0.843 and 0.923, respectively), but BayesB had the least bias (regression of performance on prediction closest to 1, β̂y,x = 2.886 and 1.755, respectively). Accounting for family structure decreased accuracy and increased bias in prediction of DGV indicating a detrimental impact when used in these prediction methods that simultaneously fit many markers.
PMCID: PMC4261962  PMID: 25505837
Bayesian inference; crossbred cattle; genomic prediction; model comparison
4.  Clinical presentation of chronic traumatic encephalopathy 
Neurology  2013;81(13):1122-1129.
The goal of this study was to examine the clinical presentation of chronic traumatic encephalopathy (CTE) in neuropathologically confirmed cases.
Thirty-six adult male subjects were selected from all cases of neuropathologically confirmed CTE at the Boston University Center for the Study of Traumatic Encephalopathy brain bank. Subjects were all athletes, had no comorbid neurodegenerative or motor neuron disease, and had next-of-kin informants to provide retrospective reports of the subjects' histories and clinical presentations. These interviews were conducted blind to the subjects' neuropathologic findings.
A triad of cognitive, behavioral, and mood impairments was common overall, with cognitive deficits reported for almost all subjects. Three subjects were asymptomatic at the time of death. Consistent with earlier case reports of boxers, 2 relatively distinct clinical presentations emerged, with one group whose initial features developed at a younger age and involved behavioral and/or mood disturbance (n = 22), and another group whose initial presentation developed at an older age and involved cognitive impairment (n = 11).
This suggests there are 2 major clinical presentations of CTE, one a behavior/mood variant and the other a cognitive variant.
PMCID: PMC3795597  PMID: 23966253
5.  The CARE Guidelines: Consensus-based Clinical Case Reporting Guideline Development 
A case report is a narrative that describes, for medical, scientific, or educational purposes, a medical problem experienced by one or more patients. Case reports written without guidance from reporting standards are insufficiently rigorous to guide clinical practice or to inform clinical study design.
Primary Objective:
Develop, disseminate, and implement systematic reporting guidelines for case reports.
We used a three-phase consensus process consisting of (1) premeeting literature review and interviews to generate items for the reporting guidelines, (2) a face-to-face consensus meeting to draft the reporting guidelines, and (3) postmeeting feedback, review, and pilot testing, followed by finalization of the case report guidelines.
This consensus process involved 27 participants and resulted in a 13-item checklist—a reporting guideline for case reports. The primary items of the checklist are title, key words, abstract, introduction, patient information, clinical findings, timeline, diagnostic assessment, therapeutic interventions, follow-up and outcomes, discussion, patient perspective, and informed consent.
We believe the implementation of the CARE (CAse REport) guidelines by medical journals will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports will inform clinical study design, provide early signals of effectiveness and harms, and improve healthcare delivery.
PMCID: PMC3833570  PMID: 24416692
Case report; case study; EQUATOR Network; patient reports; meaningful use; health research reporting guidelines
6.  Alternative parameterizations of relatedness in whole genome association analysis of pre-weaning traits of Nelore-Angus calves 
Genetics and Molecular Biology  2014;37(3):518-525.
Gestation length, birth weight, and weaning weight of F2 Nelore-Angus calves (n = 737) with designed extensive full-sibling and half-sibling relatedness were evaluated for association with 34,957 SNP markers. In analyses of birth weight, random relatedness was modeled three ways: 1) none, 2) random animal, pedigree-based relationship matrix, or 3) random animal, genomic relationship matrix. Detected birth weight-SNP associations were 1,200, 735, and 31 for those parameterizations respectively; each additional model refinement removed associations that apparently were a result of the built-in stratification by relatedness. Subsequent analyses of gestation length and weaning weight modeled genomic relatedness; there were 40 and 26 trait-marker associations detected for those traits, respectively. Birth weight associations were on BTA14 except for a single marker on BTA5. Gestation length associations included 37 SNP on BTA21, 2 on BTA27 and one on BTA3. Weaning weight associations were on BTA14 except for a single marker on BTA10. Twenty-one SNP markers on BTA14 were detected in both birth and weaning weight analyses.
PMCID: PMC4171760  PMID: 25249774
birth weight; gestation length; weaning weight; Nelore; whole genome association
7.  Parallel Evolution of Streptococcus pneumoniae and Streptococcus mitis to Pathogenic and Mutualistic Lifestyles 
mBio  2014;5(4):e01490-14.
The bacterium Streptococcus pneumoniae is one of the leading causes of fatal infections affecting humans. Intriguingly, phylogenetic analysis shows that the species constitutes one evolutionary lineage in a cluster of the otherwise commensal Streptococcus mitis strains, with which humans live in harmony. In a comparative analysis of 35 genomes, including phylogenetic analyses of all predicted genes, we have shown that the pathogenic pneumococcus has evolved into a master of genomic flexibility while lineages that evolved into the nonpathogenic S. mitis secured harmonious coexistence with their host by stabilizing an approximately 15%-reduced genome devoid of many virulence genes. Our data further provide evidence that interspecies gene transfer between S. pneumoniae and S. mitis occurs in a unidirectional manner, i.e., from S. mitis to S. pneumoniae. Import of genes from S. mitis and other mitis, anginosus, and salivarius group streptococci ensured allelic replacements and antigenic diversification and has been driving the evolution of the remarkable structural diversity of capsular polysaccharides of S. pneumoniae. Our study explains how the unique structural diversity of the pneumococcal capsule emerged and conceivably will continue to increase and reveals a striking example of the fragile border between the commensal and pathogenic lifestyles. While genomic plasticity enabling quick adaptation to environmental stress is a necessity for the pathogenic streptococci, the commensal lifestyle benefits from stability.
One of the leading causes of fatal infections affecting humans, Streptococcus pneumoniae, and the commensal Streptococcus mitis are closely related obligate symbionts associated with hominids. Faced with a shortage of accessible hosts, the two opposing lifestyles evolved in parallel. We have shown that the nonpathogenic S. mitis secured harmonious coexistence with its host by stabilizing a reduced genome devoid of many virulence genes. Meanwhile, the pathogenic pneumococcus evolved into a master of genomic flexibility and imports genes from S. mitis and other related streptococci. This process ensured antigenic diversification and has been driving the evolution of the remarkable structural diversity of capsular polysaccharides of S. pneumoniae, which conceivably will continue to increase and present a challenge to disease prevention.
PMCID: PMC4120201  PMID: 25053789
8.  Profile of Self-Reported Problems with Executive Functioning in College and Professional Football Players 
Journal of Neurotrauma  2013;30(14):1299-1304.
Repetitive mild traumatic brain injury (mTBI), such as that experienced by contact-sport athletes, has been associated with the development of chronic traumatic encephalopathy (CTE). Executive dysfunction is believed to be among the earliest symptoms of CTE, with these symptoms presenting in the fourth or fifth decade of life. The present study used a well-validated self-report measure to study executive functioning in football players, compared to healthy adults. Sixty-four college and professional football players were administered the Behavior Rating Inventory of Executive Function, adult version (BRIEF-A) to evaluate nine areas of executive functioning. Scores on the BRIEF-A were compared to published age-corrected normative scores for healthy adults Relative to healthy adults, the football players indicated significantly more problems overall and on seven of the nine clinical scales, including Inhibit, Shift, Emotional Control, Initiate, Working Memory, Plan/Organize, and Task Monitor. These symptoms were greater in athletes 40 and older, relative to younger players. In sum, football players reported more-frequent problems with executive functioning and these symptoms may develop or worsen in the fifth decade of life. The findings are in accord with a growing body of evidence that participation in football is associated with the development of cognitive changes and dementia as observed in CTE.
PMCID: PMC3713446  PMID: 23421745
chronic traumatic encephalopathy; executive function; football; traumatic brain injury
9.  Self-reported concussion history: impact of providing a definition of concussion 
In recent years, the understanding of concussion has evolved in the research and medical communities to include more subtle and transient symptoms. The accepted definition of concussion in these communities has reflected this change. However, it is unclear whether this shift is also reflected in the understanding of the athletic community.
What is known about the subject
Self-reported concussion history is an inaccurate assessment of someone’s lifetime exposure to concussive brain trauma. However, unfortunately, in many cases it is the only available tool.
We hypothesize that athletes’ self-reported concussion histories will be significantly greater after reading them the current definition of concussion, relative to the reporting when no definition was provided. An increase from baseline to post-definition response will suggest that athletes are unaware of the currently accepted medical definition.
Study design
Cross-sectional study of 472 current and former athletes.
Investigators conducted structured telephone interviews with current and former athletes between January 2010 and January 2013, asking participants to report how many concussions they had received in their lives. Interviewers then read participants a current definition of concussion, and asked them to re-estimate based on that definition.
The two estimates were significantly different (Wilcoxon signed rank test: z=15.636, P<0.001). Comparison of the baseline and post-definition medians (7 and 15, respectively) indicated that the post-definition estimate was approximately twice the baseline. Follow-up analyses indicated that this effect was consistent across all levels of competition examined and across type of sport (contact versus non-contact).
Our results indicate that athletes’ current understandings of concussions are not consistent with a currently accepted medical definition. We strongly recommend that clinicians and researchers preface requests for self-reported concussion history with a definition. In addition, it is extremely important that researchers report the definition they used in published manuscripts of their work.
What this study adds to existing knowledge
Our study shows that unprompted reporting of concussion history produces results that are significantly different from those provided after a definition has been given, suggesting one possible mechanism to improve the reliability of self-reported concussion history across multiple individuals.
PMCID: PMC4019619  PMID: 24891816
concussion; self-report; sports-related concussion
10.  Quantitative analysis of gait and balance response to deep brain stimulation in Parkinson's disease 
Gait & posture  2012;38(1):109-114.
Gait and balance disturbances in Parkinson’s disease (PD) can be debilitating and may lead to increased fall risk. Deep brain stimulation (DBS) is a treatment option once therapeutic benefits from medication are limited due to motor fluctuations and dyskinesia. Optimizing DBS parameters for gait and balance can be significantly more challenging than for other PD motor symptoms. Furthermore, inter-rater reliability of the standard clinical PD assessment scale, Unified Parkinson’s Disease Rating Scale (UPDRS), may introduce bias and washout important features of gait and balance that may respond differently to PD therapies. Study objectives were to evaluate clinician UPDRS gait and balance scoring inter-rater reliability, UPDRS sensitivity to different aspects of gait and balance, and how kinematic features extracted from motion sensor data respond to stimulation. Forty-two subjects diagnosed with PD were recruited with varying degrees of gait and balance impairment. All subjects had been prescribed dopaminergic medication, and twenty subjects had previously undergone DBS surgery. Subjects performed seven items of the gait and balance subset of the UPDRS while wearing motion sensors on the sternum and each heel and thigh. Inter-rater reliability varied by UPDRS item. Correlation coefficients between at least one kinematic feature for six of the seven items and UPDRS were greater than 0.75. Kinematic features improved (p < 0.05) from DBS-OFF to DBS-ON for three UPDRS items. Despite achieving high correlations with the UPDRS, evaluating individual kinematic features may help address inter-rater reliability issues and rater bias associated with focusing on different aspects of a motor task.
PMCID: PMC3596454  PMID: 23218768
11.  Introduction to Health Coaching 
This issue and the July 2013 issue of Global Advances in Health and Medicine on health coaching present a series of original research, reviews, case reports, healthcare policy discussions, editorials, and interviews with some of the leaders in the field. Health coaching has emerged as an important example of global convergence in healthcare and a systems-oriented approach integrated with a team-based approach to healthcare, as evidenced by these articles.
PMCID: PMC3833545  PMID: 24416667
Health coaching; patient-centered care; wellness; prevention
12.  Case Reports in the Era of Clinical Trials 
Once upon a time, case reports were the primary content of scholarly medical journals. Case reports are still common but have come to be viewed more often than not as anecdotes rather than evidence. And even though David Sackett referred to the important link between clinical expertise and external evidence,1 the “gold standard” today is the randomized controlled clinical trial. Why is this?
PMCID: PMC3833525  PMID: 24416660
Case reports; CARE guidelines; clinical trials; evidence
13.  Criteria for the diagnosis of corticobasal degeneration 
Neurology  2013;80(5):496-503.
Current criteria for the clinical diagnosis of pathologically confirmed corticobasal degeneration (CBD) no longer reflect the expanding understanding of this disease and its clinicopathologic correlations. An international consortium of behavioral neurology, neuropsychology, and movement disorders specialists developed new criteria based on consensus and a systematic literature review. Clinical diagnoses (early or late) were identified for 267 nonoverlapping pathologically confirmed CBD cases from published reports and brain banks. Combined with consensus, 4 CBD phenotypes emerged: corticobasal syndrome (CBS), frontal behavioral-spatial syndrome (FBS), nonfluent/agrammatic variant of primary progressive aphasia (naPPA), and progressive supranuclear palsy syndrome (PSPS). Clinical features of CBD cases were extracted from descriptions of 209 brain bank and published patients, providing a comprehensive description of CBD and correcting common misconceptions. Clinical CBD phenotypes and features were combined to create 2 sets of criteria: more specific clinical research criteria for probable CBD and broader criteria for possible CBD that are more inclusive but have a higher chance to detect other tau-based pathologies. Probable CBD criteria require insidious onset and gradual progression for at least 1 year, age at onset ≥50 years, no similar family history or known tau mutations, and a clinical phenotype of probable CBS or either FBS or naPPA with at least 1 CBS feature. The possible CBD category uses similar criteria but has no restrictions on age or family history, allows tau mutations, permits less rigorous phenotype fulfillment, and includes a PSPS phenotype. Future validation and refinement of the proposed criteria are needed.
PMCID: PMC3590050  PMID: 23359374
14.  Identification of a major locus interacting with MC1R and modifying black coat color in an F2 Nellore-Angus population 
In cattle, base color is assumed to depend on the enzymatic activity specified by the MC1R locus, i.e. the extension locus, with alleles coding for black (E D ), red (e), and wild-type (E + ). In most mammals, these alleles are presumed to follow the dominance model of E D  > E +  > e, although exceptions are found. In Bos indicus x Bos taurus F2 cattle, some E D E + heterozygotes are discordant with the dominance series for MC1R and display various degrees of red pigmentation on an otherwise predicted black background. The objective of this study was to identify loci that modify black coat color in these individuals.
Reddening was classified with a subjective scoring system. Interval analyses identified chromosome-wide suggestive (P < 0.05) and significant (P < 0.01) QTL on bovine chromosomes (BTA) 4 and 5, although these were not confirmed using single-marker association or Bayesian methods. Evidence of a major locus (F = 114.61) that affects reddening was detected between 60 and 73 Mb on BTA 6 (Btau4.0 build), and at 72 Mb by single-marker association and Bayesian methods. The posterior mean of the genetic variance for this region accounted for 43.75% of the genetic variation in reddening. This region coincided with a cluster of tyrosine kinase receptor genes (PDGFRA, KIT and KDR). Fitting SNP haplotypes for a 1 Mb interval that contained all three genes and centered on KIT accounted for the majority of the variation attributed to this major locus, which suggests that one of these genes or associated regulatory elements, is responsible for the majority of variation in degree of reddening.
Recombinants in a 5 Mb region surrounding the cluster of tyrosine kinase receptor genes implicated PDGFRA as the strongest positional candidate gene. A higher density marker panel and functional analyses will be required to validate the role of PDGFRA or other regulatory variants and their interaction with MC1R for the modification of black coat color in Bos indicus influenced cattle.
PMCID: PMC3924621  PMID: 24460986
15.  The spectrum of disease in chronic traumatic encephalopathy 
Brain  2012;136(1):43-64.
Chronic traumatic encephalopathy is a progressive tauopathy that occurs as a consequence of repetitive mild traumatic brain injury. We analysed post-mortem brains obtained from a cohort of 85 subjects with histories of repetitive mild traumatic brain injury and found evidence of chronic traumatic encephalopathy in 68 subjects: all males, ranging in age from 17 to 98 years (mean 59.5 years), including 64 athletes, 21 military veterans (86% of whom were also athletes) and one individual who engaged in self-injurious head banging behaviour. Eighteen age- and gender-matched individuals without a history of repetitive mild traumatic brain injury served as control subjects. In chronic traumatic encephalopathy, the spectrum of hyperphosphorylated tau pathology ranged in severity from focal perivascular epicentres of neurofibrillary tangles in the frontal neocortex to severe tauopathy affecting widespread brain regions, including the medial temporal lobe, thereby allowing a progressive staging of pathology from stages I–IV. Multifocal axonal varicosities and axonal loss were found in deep cortex and subcortical white matter at all stages of chronic traumatic encephalopathy. TAR DNA-binding protein 43 immunoreactive inclusions and neurites were also found in 85% of cases, ranging from focal pathology in stages I–III to widespread inclusions and neurites in stage IV. Symptoms in stage I chronic traumatic encephalopathy included headache and loss of attention and concentration. Additional symptoms in stage II included depression, explosivity and short-term memory loss. In stage III, executive dysfunction and cognitive impairment were found, and in stage IV, dementia, word-finding difficulty and aggression were characteristic. Data on athletic exposure were available for 34 American football players; the stage of chronic traumatic encephalopathy correlated with increased duration of football play, survival after football and age at death. Chronic traumatic encephalopathy was the sole diagnosis in 43 cases (63%); eight were also diagnosed with motor neuron disease (12%), seven with Alzheimer’s disease (11%), 11 with Lewy body disease (16%) and four with frontotemporal lobar degeneration (6%). There is an ordered and predictable progression of hyperphosphorylated tau abnormalities through the nervous system in chronic traumatic encephalopathy that occurs in conjunction with widespread axonal disruption and loss. The frequent association of chronic traumatic encephalopathy with other neurodegenerative disorders suggests that repetitive brain trauma and hyperphosphorylated tau protein deposition promote the accumulation of other abnormally aggregated proteins including TAR DNA-binding protein 43, amyloid beta protein and alpha-synuclein.
PMCID: PMC3624697  PMID: 23208308
axonal injury; brain trauma; frontotemporal lobar degeneration; neurodegenerative disorders; traumatic brain injury
16.  02B. Case Reports in an Evidence-based World 
Focus Area: Integrative Approaches to Care
Case reports have helped identify effects from interventions and recognize new or rare diseases. Data from case reports—increasingly published in indexed medical journals—are beginning to be systematically collected and reported. However, the quality of published case reports is uneven. One study evaluated 1316 case reports from four emergency medicine journals and found that more than half failed to provide information related to the primary treatment. Case reports written without reporting guidelines (with the exception of harms) are insufficiently rigorous to guide clinical practice, inform research design, or be aggregated for data analysis. This analysis was conducted to develop and implement systematic reporting guidelines for case reports.
We followed published recommendations for guideline development using a modified Delphi process with (1) a literature review and interviews generating guidelines items, (2) an October 2012 face-to-face consensus meeting to draft reporting guidelines, and (3) post-meeting feedback and guideline finalization.
The CARE (CAse REport) guidelines were developed in a consensus-based process and represent essential information necessary to improve the quality of case reports. These guidelines are generic and will need extensions for specific specialties and purposes. Feedback from use of the guidelines in 2013, though positive, is limited. The analysis of systematically aggregated information from patient encounters may provide scalable, data-driven insights into what works for which patients, transforming how we think about evidence and its creation, diffusion, and use.
PMCID: PMC3875053
17.  Inter- and intra-specific pan-genomes of Borrelia burgdorferi sensu lato: genome stability and adaptive radiation 
BMC Genomics  2013;14:693.
Lyme disease is caused by spirochete bacteria from the Borrelia burgdorferi sensu lato (B. burgdorferi s.l.) species complex. To reconstruct the evolution of B. burgdorferi s.l. and identify the genomic basis of its human virulence, we compared the genomes of 23 B. burgdorferi s.l. isolates from Europe and the United States, including B. burgdorferi sensu stricto (B. burgdorferi s.s., 14 isolates), B. afzelii (2), B. garinii (2), B. “bavariensis” (1), B. spielmanii (1), B. valaisiana (1), B. bissettii (1), and B. “finlandensis” (1).
Robust B. burgdorferi s.s. and B. burgdorferi s.l. phylogenies were obtained using genome-wide single-nucleotide polymorphisms, despite recombination. Phylogeny-based pan-genome analysis showed that the rate of gene acquisition was higher between species than within species, suggesting adaptive speciation. Strong positive natural selection drives the sequence evolution of lipoproteins, including chromosomally-encoded genes 0102 and 0404, cp26-encoded ospC and b08, and lp54-encoded dbpA, a07, a22, a33, a53, a65. Computer simulations predicted rapid adaptive radiation of genomic groups as population size increases.
Intra- and inter-specific pan-genome sizes of B. burgdorferi s.l. expand linearly with phylogenetic diversity. Yet gene-acquisition rates in B. burgdorferi s.l. are among the lowest in bacterial pathogens, resulting in high genome stability and few lineage-specific genes. Genome adaptation of B. burgdorferi s.l. is driven predominantly by copy-number and sequence variations of lipoprotein genes. New genomic groups are likely to emerge if the current trend of B. burgdorferi s.l. population expansion continues.
PMCID: PMC3833655  PMID: 24112474
Borrelia burgdorferi; Lyme borreliosis; Pan-genome; Single-nucleotide polymorphisms; Phylogenetic tree; Genome evolution simulation
18.  Extensively duplicated and transcriptionally active recent lateral gene transfer from a bacterial Wolbachia endosymbiont to its host filarial nematode Brugia malayi 
BMC Genomics  2013;14:639.
Lymphatic filariasis is a neglected tropical disease afflicting more than 120 million people, while another 1.3 billion people are at risk of infection. The nematode worm Brugia malayi is one of the causative agents of the disease and exists in a mutualistic symbiosis with Wolbachia bacteria. Since extensive lateral gene transfer occurs frequently between Wolbachia and its hosts, we sought to measure the extent of such LGT in B. malayi by whole genome sequencing of Wolbachia-depleted worms.
A considerable fraction (at least 115.4-kbp, or 10.6%) of the 1.08-Mbp Wolbachia wBm genome has been transferred to its nematode host and retains high levels of similarity, including 227 wBm genes and gene fragments. Complete open reading frames were transferred for 32 of these genes, meaning they have the potential to produce functional proteins. Moreover, four transfers have evidence of life stage-specific regulation of transcription at levels similar to other nematode transcripts, strengthening the possibility that they are functional.
There is extensive and ongoing transfer of Wolbachia DNA to the worm genome and some transfers are transcribed in a stage-specific manner at biologically relevant levels.
PMCID: PMC3849323  PMID: 24053607
19.  The CARE guidelines: consensus-based clinical case reporting guideline development 
A case report is a narrative that describes, for medical, scientific, or educational purposes, a medical problem experienced by one or more patients. Case reports written without guidance from reporting standards are insufficiently rigorous to guide clinical practice or to inform clinical study design.
Primary Objective. Develop, disseminate, and implement systematic reporting guidelines for case reports.
We used a three-phase consensus process consisting of (1) pre-meeting literature review and interviews to generate items for the reporting guidelines, (2) a face-to-face consensus meeting to draft the reporting guidelines, and (3) post-meeting feedback, review, and pilot testing, followed by finalization of the case report guidelines.
This consensus process involved 27 participants and resulted in a 13-item checklist—a reporting guideline for case reports. The primary items of the checklist are title, key words, abstract, introduction, patient information, clinical findings, timeline, diagnostic assessment, therapeutic interventions, follow-up and outcomes, discussion, patient perspective, and informed consent.
We believe the implementation of the CARE (CAse REport) guidelines by medical journals will improve the completeness and transparency of published case reports and that the systematic aggregation of information from case reports will inform clinical study design, provide early signals of effectiveness and harms, and improve healthcare delivery.
PMCID: PMC3844611  PMID: 24228906
Case report; Case study; EQUATOR Network; Patient reports; Meaningful use; Health research reporting guidelines
20.  Genome Sequences of Two Pathogenic Streptococcus agalactiae Isolates from the One-Humped Camel Camelus dromedarius 
Genome Announcements  2013;1(4):e00515-13.
Streptococcus agalactiae causes a range of clinical syndromes in camels (Camelus dromedarius). We report the genome sequences of two S. agalactiae isolates that induce abscesses in Kenyan camels. These genomes provide novel data on the composition of the S. agalactiae “pan genome” and reveal the presence of multiple genomic islands.
PMCID: PMC3715676  PMID: 23868134
21.  Bacteria-Human Somatic Cell Lateral Gene Transfer Is Enriched in Cancer Samples 
PLoS Computational Biology  2013;9(6):e1003107.
There are 10× more bacterial cells in our bodies from the microbiome than human cells. Viral DNA is known to integrate in the human genome, but the integration of bacterial DNA has not been described. Using publicly available sequence data from the human genome project, the 1000 Genomes Project, and The Cancer Genome Atlas (TCGA), we examined bacterial DNA integration into the human somatic genome. Here we present evidence that bacterial DNA integrates into the human somatic genome through an RNA intermediate, and that such integrations are detected more frequently in (a) tumors than normal samples, (b) RNA than DNA samples, and (c) the mitochondrial genome than the nuclear genome. Hundreds of thousands of paired reads support random integration of Acinetobacter-like DNA in the human mitochondrial genome in acute myeloid leukemia samples. Numerous read pairs across multiple stomach adenocarcinoma samples support specific integration of Pseudomonas-like DNA in the 5′-UTR and 3′-UTR of four proto-oncogenes that are up-regulated in their transcription, consistent with conversion to an oncogene. These data support our hypothesis that bacterial integrations occur in the human somatic genome and may play a role in carcinogenesis. We anticipate that the application of our approach to additional cancer genome projects will lead to the more frequent detection of bacterial DNA integrations in tumors that are in close proximity to the human microbiome.
Author Summary
There are 10× more bacterial cells in the human body than there are human cells that are part of the human microbiome. Many of those bacteria are in constant, intimate contact with human cells. We sought to establish if bacterial cells insert their own DNA into the human genome. Such random mutations could cause disease in the same manner that mutagens like UV rays from the sun or chemicals in cigarettes induce mutations. We detected the integration of bacterial DNA in the human genome more readily in tumors than normal samples. In particular, extensive amounts of DNA with similarity to Acinetobacter DNA were fused to human mitochondrial DNA in acute myeloid leukemia samples. We also identified specific integrations of DNA with similarity to Pseudomonas DNA near the untranslated regulatory regions of four proto-oncogenes. This supports our hypothesis that bacterial integrations occur in the human somatic genome that may potentially play a role in carcinogenesis. Further study in this area may provide new avenues for cancer prevention.
PMCID: PMC3688693  PMID: 23840181
22.  Phenotypic, genomic, and transcriptional characterization of Streptococcus pneumoniae interacting with human pharyngeal cells 
BMC Genomics  2013;14:383.
Streptococcus pneumoniae is a leading cause of childhood morbidity and mortality worldwide, despite the availability of effective pneumococcal vaccines. Understanding the molecular interactions between the bacterium and the host will contribute to the control and prevention of pneumococcal disease.
We used a combination of adherence assays, mutagenesis and functional genomics to identify novel factors involved in adherence. By contrasting these processes in two pneumococcal strains, TIGR4 and G54, we showed that adherence and invasion capacities vary markedly by strain. Electron microscopy showed more adherent bacteria in association with membranous pseudopodia in the TIGR4 strain. Operons for cell wall phosphorylcholine incorporation (lic), manganese transport (psa) and phosphate utilization (phn) were up-regulated in both strains on exposure to epithelial cells. Pneumolysin, pili, stress protection genes (adhC-czcD) and genes of the type II fatty acid synthesis pathway were highly expressed in the naturally more invasive strain, TIGR4. Deletion mutagenesis of five gene regions identified as regulated in this study revealed attenuation in adherence. Most strikingly, ∆SP_1922 which was predicted to contain a B-cell epitope and revealed significant attenuation in adherence, appeared to be expressed as a part of an operon that includes the gene encoding the cytoplasmic pore-forming toxin and vaccine candidate, pneumolysin.
This work identifies a list of novel potential pneumococcal adherence determinants.
PMCID: PMC3708772  PMID: 23758733
Streptococcus pneumoniae; Gene expression; Microarray; Adherence; Invasion; Genome; Mutagenesis; SP_1922; Ply operon
23.  Transcriptional adaptation of pneumococci and human pharyngeal cells in the presence of a virus infection 
BMC Genomics  2013;14:378.
Viral upper respiratory tract infections are associated with increased colonization by Streptococcus pneumoniae but the mechanisms underlying this relationship are unclear. The objective of this study is to describe a comprehensive picture of the cellular interaction between the adhering bacteria and host cells in the presence or absence of a viral co-infection.
Gene expression profiles of Detroit-562 pharyngeal cells, which were either mock-infected or infected with human respiratory syncytial virus (RSV) or human parainfluenza virus 3 (HPIV3), were analyzed using human microarrays. Transcription response of S. pneumoniae strain TIGR4 (serotype 4) in the presence of either mock- or viral-infected cells was analyzed by pneumococcal microarray. Significantly regulated genes were identified by both significance analysis of microarray (SAM) and a ≥ 2-fold change ratio cut-off. The adherence of S. pneumoniae to human pharyngeal cells was significantly augmented in the presence of RSV or HPIV3 infection. Global gene expression profiling of the host cells during infection with RSV or HPIV3 revealed increased transcription of carcinoembryonic antigen-related cell adhesion molecules (CEACAM1), CD47, fibronectin, interferon-stimulated genes and many other host cell adhesion molecules. Pneumococci increased transcription of several genes involved in adhesive functions (psaA, pilus islet), choline uptake and incorporation (lic operon), as well as transport and binding.
We have identified a core transcriptome that represents the basic machinery required for adherence of pneumococci to D562 cells infected or not infected with a virus. These bacterial genes and cell adhesion molecules can potentially be used to control pneumococcal adherence occurring secondary to a viral infection.
PMCID: PMC3681581  PMID: 23742656
Streptococcus pneumoniae; RSV; HPIV3; Gene expression; Microarray; Adherence; Bacterial-viral co-infection
24.  Genomic Insights into the Emerging Human Pathogen Mycobacterium massiliense 
Journal of Bacteriology  2012;194(19):5450.
Mycobacterium massiliense (Mycobacterium abscessus group) is an emerging pathogen causing pulmonary disease and skin and soft tissue infections. We report the genome sequence of the type strain CCUG 48898.
PMCID: PMC3457237  PMID: 22965080
25.  Emergency department diagnosis of a quadriceps intramuscular loculated abscess/pyomyositis using dynamic compression bedside ultrasonography 
A 73-year-old man with a past medical history of myelodysplastic syndrome and recent chemotherapy presented to the emergency department with a 1-week history of progressively increasing left thigh pain and swelling. His physical examination revealed left anterolateral diffuse thigh swelling with no erythema or warmth to palpation. The anterolateral quadriceps was markedly tender to palpation. Emergency department bedside dynamic compression ultrasonography that was performed on the left anterolateral thigh revealed a quadriceps intramuscular abscess with loculated yet movable pus.
Bedside dynamic compression ultrasonography can assist the emergency or critical care physician in the diagnosis of quadriceps intramuscular abscess or pyomyositis.
PMCID: PMC3598820  PMID: 23402374
Ultrasound; Quadriceps intramuscular loculated abscess; Pyomyositis; Emergency department

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