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1.  Hair regrowth in alopecia areata patients following Stem Cell Educator therapy 
BMC Medicine  2015;13:87.
Alopecia areata (AA) is one of the most common autoimmune diseases and targets the hair follicles, with high impact on the quality of life and self-esteem of patients due to hair loss. Clinical management and outcomes are challenged by current limited immunosuppressive and immunomodulating regimens.
We have developed a Stem Cell Educator therapy in which a patient’s blood is circulated through a closed-loop system that separates mononuclear cells from the whole blood, allows the cells to briefly interact with adherent human cord blood-derived multipotent stem cells (CB-SC), and returns the “educated” autologous cells to the patient’s circulation. In an open-label, phase 1/phase 2 study, patients (N = 9) with severe AA received one treatment with the Stem Cell Educator therapy. The median age was 20 years (median alopecic duration, 5 years).
Clinical data demonstrated that patients with severe AA achieved improved hair regrowth and quality of life after receiving Stem Cell Educator therapy. Flow cytometry revealed the up-regulation of Th2 cytokines and restoration of balancing Th1/Th2/Th3 cytokine production in the peripheral blood of AA subjects. Immunohistochemistry indicated the formation of a “ring of transforming growth factor beta 1 (TGF-β1)” around the hair follicles, leading to the restoration of immune privilege of hair follicles and the protection of newly generated hair follicles against autoimmune destruction. Mechanistic studies revealed that co-culture with CB-SC may up-regulate the expression of coinhibitory molecules B and T lymphocyte attenuator (BTLA) and programmed death-1 receptor (PD-1) on CD8β+NKG2D+ effector T cells and suppress their proliferation via herpesvirus entry mediator (HVEM) ligands and programmed death-1 ligand (PD-L1) on CB-SCs.
Current clinical data demonstrated the safety and efficacy of the Stem Cell Educator therapy for the treatment of AA. This innovative approach produced lasting improvement in hair regrowth in subjects with moderate or severe AA.
Trial registration, NCT01673789, 21 August 2012
PMCID: PMC4417286  PMID: 25896390
Alopecia areata; Autoimmune; Stem Cell Educator; Immune modulation; Hair regrowth
2.  The rising tide of polypharmacy and drug-drug interactions: population database analysis 1995–2010 
BMC Medicine  2015;13:74.
The escalating use of prescribed drugs has increasingly raised concerns about polypharmacy. This study aims to examine changes in rates of polypharmacy and potentially serious drug-drug interactions in a stable geographical population between 1995 and 2010.
This is a repeated cross-sectional analysis of community-dispensed prescribing data for all 310,000 adults resident in the Tayside region of Scotland in 1995 and 2010. The number of drug classes dispensed and the number of potentially serious drug-drug interactions (DDIs) in the previous 84 days were calculated, and age-sex standardised rates in 1995 and 2010 compared. Patient characteristics associated with receipt of ≥10 drugs and with the presence of one or more DDIs were examined using multilevel logistic regression to account for clustering of patients within primary care practices.
Between 1995 and 2010, the proportion of adults dispensed ≥5 drugs doubled to 20.8%, and the proportion dispensed ≥10 tripled to 5.8%. Receipt of ≥10 drugs was strongly associated with increasing age (20–29 years, 0.3%; ≥80 years, 24.0%; adjusted OR, 118.3; 95% CI, 99.5–140.7) but was also independently more common in people living in more deprived areas (adjusted OR most vs. least deprived quintile, 2.36; 95% CI, 2.22–2.51), and in people resident in a care home (adjusted OR, 2.88; 95% CI, 2.65–3.13). The proportion with potentially serious drug-drug interactions more than doubled to 13% of adults in 2010, and the number of drugs dispensed was the characteristic most strongly associated with this (10.9% if dispensed 2–4 drugs vs. 80.8% if dispensed ≥15 drugs; adjusted OR, 26.8; 95% CI 24.5–29.3).
Drug regimens are increasingly complex and potentially harmful, and people with polypharmacy need regular review and prescribing optimisation. Research is needed to better understand the impact of multiple interacting drugs as used in real-world practice and to evaluate the effect of medicine optimisation interventions on quality of life and mortality.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0322-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4417329  PMID: 25889849
Drug interactions; Family practice; Physician; Polypharmacy; Prescribing patterns; Primary care
4.  What are the Patterns of Prophylactic Postoperative Oral Antibiotic Use After Foot and Ankle Surgery? 
The CDC estimates 23% of healthcare-associated infections to be surgical site infections, with alarming prevalence of antibiotic-resistant organisms. While there is consensus regarding preoperative prophylaxis, orthopaedic surgeons’ use of prophylactic postoperative oral antibiotics is less defined.
We investigated surgeons’ use of prophylactic postoperative oral antibiotics after elective outpatient foot or ankle procedures, identifying (1) frequency of use, (2) regimen preferences, (3) personal indications, and (4) associated experience and demographics.
Using a cross-sectional survey design, a questionnaire was emailed to all active and candidate members of the American Orthopaedic Foot and Ankle Society. Supplementary questions captured demographic information. We invited 1136 members to participate; 22 addresses produced delivery failure messages, leaving 1114 members as potential participants. After nonresponses and exclusions, 312 (28%) responses were analyzed. Statistical analysis used Pearson’s chi-square test, Fisher’s exact test, and multivariate regression.
The majority (75%) of respondents reported use of prophylactic postoperative oral antibiotics. Most users (69%) prescribed to fewer than 25% of patients, although 16% prescribed for all elective cases. The most frequent regimen was cephalexin 500 mg four times a day (63%) and the most common duration was 5 to 7 days (50%). Surgeons’ most common indications were previous infection (71%), medical comorbidities (65%), and previous wound-healing difficulties (56%). Those who do and do not prescribe prophylactic postoperative oral antibiotics showed no difference in surgical site infection rate or any demographic category.
Surgeons’ reported use of prophylactic postoperative oral antibiotics after elective foot or ankle surgery was common, without demographic association. Commonalities were identified in antibiotic regimen and personal indications for this practice. Comparative clinical studies are warranted to elucidate the efficacy of prophylactic postoperative oral antibiotics and establish evidence-based guidelines for their use.
PMCID: PMC4160501  PMID: 24942966
5.  A Model to Predict Limb Salvage in Severe Combat-related Open Calcaneus Fractures 
Open calcaneus fractures can be limb threatening and almost universally result in some measure of long-term disability. A major goal of initial management in patients with these injuries is setting appropriate expectations and discussing the likelihood of limb salvage, yet there are few tools that assist in predicting the outcome of this difficult fracture pattern.
We developed two decision support tools, an artificial neural network and a logistic regression model, based on presenting data from severe combat-related open calcaneus fractures. We then determined which model more accurately estimated the likelihood of amputation and which was better suited for clinical use.
Injury-specific data were collected from wounded active-duty service members who sustained combat-related open calcaneus fractures between 2003 and 2012. One-hundred fifty-five open calcaneus fractures met inclusion criteria. Median followup was 3.5 years (interquartile range: 1.5, 5.1 years), and amputation rate was 44%. We developed an artificial neural network designed to estimate the likelihood of amputation, using information available on presentation. For comparison, a conventional logistic regression model was developed with variables identified on univariate analysis. We determined which model more accurately estimated the likelihood of amputation using receiver operating characteristic analysis. Decision curve analysis was then performed to determine each model’s clinical utility.
An artificial neural network that contained eight presenting features resulted in smaller error. The eight features that contributed to the most predictive model were American Society of Anesthesiologist grade, plantar sensation, fracture treatment before arrival, Gustilo-Anderson fracture type, Sanders fracture classification, vascular injury, male sex, and dismounted blast mechanism. The artificial neural network was 30% more accurate, with an area under the curve of 0.8 (compared to 0.65 for logistic regression). Decision curve analysis indicated the artificial neural network resulted in higher benefit across the broadest range of threshold probabilities compared to the logistic regression model and is perhaps better suited for clinical use.
This report demonstrates an artificial neural network was capable of accurately estimating the likelihood of amputation. Furthermore, decision curve analysis suggested the artificial neural network is better suited for clinical use than logistic regression. Once properly validated, this may provide a tool for surgeons and patients faced with combat-related open calcaneus fractures in which decisions between limb salvage and amputation remain difficult.
Level of Evidence
Level IV, prognostic study. See Instructions for Authors for a complete description of levels of evidence.
PMCID: PMC4160503  PMID: 24249536
8.  Targeted Muscle Reinnervation: A Novel Approach to Postamputation Neuroma Pain 
Postamputation neuroma pain can prevent comfortable prosthesis wear in patients with limb amputations, and currently available treatments are not consistently effective. Targeted muscle reinnervation (TMR) is a decade-old technique that employs a series of novel nerve transfers to permit intuitive control of upper-limb prostheses. Clinical experience suggests that it may also serve as an effective therapy for postamputation neuroma pain; however, this has not been explicitly studied.
We evaluated the effect of TMR on residual limb neuroma pain in upper-extremity amputees.
We conducted a retrospective medical record review of all 28 patients treated with TMR from 2002 to 2012 at Northwestern Memorial Hospital/Rehabilitation Institute of Chicago (Chicago, IL, USA) and San Antonio Military Medical Center (San Antonio, TX, USA). Twenty-six of 28 patients had sufficient (> 6 months) followup for study inclusion. The amputation levels were shoulder disarticulation (10 patients) and transhumeral (16 patients). All patients underwent TMR for the primary purpose of improved myoelectric control. Of the 26 patients included in the study, 15 patients had evidence of postamputation neuroma pain before undergoing TMR.
Of the 15 patients presenting with neuroma pain before TMR, 14 experienced complete resolution of pain in the transferred nerves, and the remaining patient’s pain improved (though did not resolve). None of the patients who presented without evidence of postamputation neuroma pain developed neuroma pain after the TMR procedure. All 26 patients were fitted with a prosthesis, and 23 of the 26 patients were able to operate a TMR-controlled prosthesis.
None of the 26 patients who underwent TMR demonstrated evidence of new neuroma pain after the procedure, and all but one of the 15 patients who presented with preoperative neuroma pain experienced complete relief of pain in the distribution of the transferred nerves. TMR offers a novel and potentially more effective therapy for the management of neuroma pain after limb amputation.
Level of Evidence
Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence.
PMCID: PMC4160494  PMID: 24562875
9.  Effect of siRNA with an Asymmetric RNA/dTdT Overhang on RNA Interference Activity 
Nucleic Acid Therapeutics  2014;24(5):364-371.
Small interfering RNAs (siRNAs) guide RNA-induced silencing complexes (RISC) to target mRNAs for sequence-specific silencing. A fundamental aspect of this highly coordinated process is a guide strand–specific loading of the siRNA duplex into the RISC for the accurate target recognition, which is currently dictated by certain duplex parameters such as thermodynamics. Here, we show that minor changes in the overhang structure have profound effects on the extent to which the individual strands of the siRNA duplex participate in RNAi activity. We demonstrate that the two strands of the siRNA are similarly eligible for assembly into RISC for the siRNAs with symmetric overhangs, whereas those with asymmetric RNA/deoxythymidine dinucleotide (dTdT) overhangs exhibit a distinct preference in favor of a strand with an RNA overhang that drives a mature RISC affinity to the desired target. We believe that this additional determinant provides a plausible and simple approach for improving the strand selection, thereby considerably increasing a specificity of target silencing.
PMCID: PMC4162433  PMID: 25211666
10.  Are autistic-behaviors in children related to prenatal vitamin use and maternal whole blood folate concentrations? 
Prenatal multivitamin/folic acid supplement use may reduce the risk of autism spectrum disorders. We investigated whether 2nd trimester prenatal vitamin use and maternal whole blood folate (WBF) concentrations were associated with Social Responsiveness Scale (SRS) scores at 4-5 years of age in a prospective cohort of 209 mother-child pairs. After confounder adjustment, children born to women taking prenatal vitamins weekly/daily (n=179) had lower odds of clinically elevated SRS scores (odds ratio:0.26; 95% confidence interval [CI]:0.08, 0.89) than those who rarely/never took them (n=30). WBF concentrations were not associated with SRS scores. The lack of association between WBF and autistic-behaviors may be due to the timing of biomarker measures relative to critical periods of brain development, confounding, or other modifying factors.
PMCID: PMC4167931  PMID: 24710813
Autism spectrum disorders; folate; pregnancy; prenatal vitamins
11.  Cytokine profiles in nasal fluid of patients with seasonal or persistent allergic rhinitis 
New therapeutic approaches with biologic agents such as anti-cytokine antibodies are currently on trial for the treatment of asthma, rhinosinusitis or allergic diseases necessitating patient selection by biomarkers. Allergic rhinitis (AR), affecting about 20 % of the Canadian population, is an inflammatory disease characterised by a disequilibrium of T-lymphocytes and tissue eosinophilia. Aim of the present study was to describe distinct cytokine patterns in nasal secretion between seasonal and perennial AR (SAR/PAR), and healthy controls by comparing cytokines regulating T-cells or stimulating inflammatory cells, and chemokines.
Nasal secretions of 44 participants suffering from SAR, 45 participants with PAR and 48 healthy controls were gained using the cotton wool method, and analysed for IL-1β, IL-4, IL-5, IL-6, IL-10, IL-12, IL-13, IL-17, GM-CSF, G-CSF, IFN-γ, MCP-1, MIP-1α, MIP-1β, eotaxin, and RANTES by Bio-Plex Cytokine Assay as well as for ECP and tryptase by UniCAP-FEIA.
Participants with SAR or PAR presented elevated levels of tryptase, ECP, MCP-1, and MIP-1β, while values of GM-CSF, G-CSF, IL-1β, and IL-6 did not differ from the controls. Increased levels of IL-5, eotaxin, MIP-1α, and IL-17 and decreased levels of IFN-γ, IL-12 and IL-10 were found in SAR only. RANTES was elevated in SAR in comparison to PAR. Interestingly, we found reduced levels of IL-4 in PAR and of IL-13 in SAR.
Elevated levels of proinflammatory cytokines were seen in both disease entities. They were, however, more pronounced in SAR, indicating a higher degree of inflammation. This study suggests a downregulation of TH1 and Treg-lymphocytes and an upregulation of TH17 in SAR. Moreover, the results display a prominent role of eosinophils and mast cells in AR. The observed distinct cytokine profiles in nasal secretion may prove useful as a diagnostic tool helping to match patients to antibody therapies.
PMCID: PMC4580351  PMID: 26401140
Allergic rhinitis; Nasal secretion; Mediators; Cytokines; Chemokines; Interleukins
12.  Olfaction in Aging and Alzheimer's Disease: Event-Related Potentials to a Cross-Modal Odor Recognition Memory Task Discriminate ApoE ε4+ and ApoE ε4− Individuals 
Alzheimer's disease (AD) is a devastating neurodegenerative condition that affects more than 5 million Americans. Currently, a definitive and unequivocal diagnosis of AD can only be confirmed histopathogically via post-mortem autopsy, demonstrating the need for objective measures of cognitive functioning for those at risk for AD. The single most important genetic risk factor of AD is the Apolipoprotein E (ApoE) ε4 allele. The present study investigated olfactory and cognitive processing deficits in ApoE ε4 positive individuals using a cross-modal recognition memory task and an objective electrophysiological measure, the event-related potential (ERP). Ten ε4+ individuals (5 M, 5 F, M = 75.1 yrs) and ten age and gender-matched ε4− individuals (5 M, 5 F, M = 71 yrs) sequentially encoded a set of 16 olfactory stimuli and were subsequently shown names of odors previously presented (targets) or not (foils). EEG activity was recorded from 19 electrodes as participants distinguished targets from foils using a two-button mouse. P3 latencies were significantly longer in ε4+ individuals and intra-class correlations demonstrated differential activity between the two groups. These findings are consistent with a compensatory hypothesis, which posits that non-demented ε4+ individuals will expend greater effort in cognitive processing or engage in alternative strategies and therefore require greater activation of neural tissue or recruitment of different neural populations. The findings also suggest that cross-modal ERP studies of recognition memory discriminate early neurocognitive changes in ApoE ε4+ and ApoE ε4− individuals and may contribute to identifying the phenotype of persons who will develop Alzheimer's Disease.
PMCID: PMC4575288  PMID: 19686207
Aging; Alzheimer's Disease; ApoE ε4; Olfaction; Olfactory Impairment; Smell; Recognition Memory
13.  Complete resolution of a calcifying cystic odontogenic tumor with physiological eruption of a dislocated permanent tooth after marsupialization in a child with a mixed dentition: a case report 
Here, we report the complete resolution of a calcifying cystic odontogenic tumor (CCOT) in the right mandible after marsupialization in an 8-year-old girl with a mixed dentition. Clinical, radiographic, and histopathological findings showed a simple cystic variant of CCOT in the region of the deciduous second molar, with dislocation of the permanent second premolar tooth germ. Initial treatment involved marsupialization, including extraction of the involved deciduous tooth, incision of pathological tissue, and creation of a window in the extraction socket. The crown of the dislocated second premolar was exposed at the base of the cystic cavity after marsupialization. One year and nine months later, complete bone healing and spontaneous eruption of the second premolar were observed, providing evidence of the bone regeneration capacity and tooth germ eruption potential in children. No recurrence was observed after 7 years. The findings from this case suggest that marsupialization can be successfully applied for the treatment of CCOT in children with a mixed dentition.
PMCID: PMC4574018  PMID: 26376974
Calcifying cystic odontogenic tumor; Marsupialization; Pediatric dentistry
14.  Isolation of nanomolar scFvs of non-human primate origin, cross-neutralizing botulinum neurotoxins A1 and A2 by targeting their heavy chain 
BMC Biotechnology  2015;15:86.
Botulism is a naturally occurring disease, mainly caused by the ingestion of food contaminated by the botulinum neurotoxins (BoNTs). Botulinum neurotoxins are the most lethal. They are classified among the six major biological warfare agents by the Centers for Disease Control. BoNTs act on the cholinergic motoneurons, where they cleave proteins implicated in acetylcholine vesicle exocytosis. This exocytosis inhibition induces a flaccid paralysis progressively affecting all the muscles and generally engendering a respiratory distress. BoNTs are also utilized in medicine, mainly for the treatment of neuromuscular disorders, preventing large scale vaccination. Botulism specific treatment requires injections of antitoxins, usually of equine origin and thus poorly tolerated. Therefore, development of human or human-like neutralizing antibodies is of a major interest, and it is the subject of the European framework project called “AntiBotABE”.
In this study, starting from a macaque immunized with the recombinant heavy chain of BoNT/A1 (BoNT/A1-HC), an immune antibody phage-display library was generated and antibody fragments (single chain Fragment variable) with nanomolar affinity were isolated and further characterized. The neutralization capacities of these scFvs were analyzed in the mouse phrenic nerve-hemidiaphragm assay.
After a three-round panning, 24 antibody fragments with affinity better than 10 nM were isolated. Three of them neutralized BoNT/A1 efficiently and two cross-neutralized BoNT/A1 and BoNT/A2 subtypes in the mouse phrenic nerve-hemidiaphragm assay. These are the first monoclonal human-like antibodies cross-neutralizing both BoNT/A1 and BoNT/A2. The antibody A1HC38 was selected for further development, and could be clinically developed for the prophylaxis and treatment of botulism.
Electronic supplementary material
The online version of this article (doi:10.1186/s12896-015-0206-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4574468  PMID: 26382731
Botulinum neurotoxin; Recombinant antibodies; scFv; Neutralizing antibodies; Non-human primates; Clostridium botulinum; AntiBotABE; Macaques; Biological warfare agents
15.  Relationship of Inflammation and Endothelial Dysfunction with Risks to Cardiovascular Disease among People in Inner Mongolia of China* 
To explore the relationship of inflammation and endothelial dysfunction with risks to cardiovascular disease (CVD).
Blood pressure, body weight, body height, waist circumference and lifestyle risk factors were measured and studied among 2589 participants in Inner Mongolia of China, and biomarkers of inflammation and endothelial dysfunction including high-sensitivity C-reactive protein (hsCRP), soluble inter-cellular adhesion molecule-1 (sICAM-1), soluble E-selectin (sE-selectin), and angiotensin II were investigated.
Subjects with metabolic risk factors for CVD had higher levels of hsCRP, sE-selectin and sICAM-1 than those without such risk factors (all P<0.05). Levels of all biomarkers positively and significantly increased with aggregation of the metabolic risk factors among the subjects (all P for trend <0.001). Data from the multivariate analysis showed that participants with high levels of hsCRP [odds ratio (OR): 1.96, 95% confidence interval (CI): 1.52–2.53], sE-selectin (OR: 1.35, 95% CI: 1.05–1.72), and angiotensin II (OR: 1.81, 95% CI: 1.40–2.33) were more likely to develop hypertension; participants with high levels of hsCRP (OR: 2.33, 95% CI: 1.85–2.94), sE-selectin (OR: 1.24, 95% CI: 1.00–1.54), and sICAM-1 (OR: 1.70, 95% CI: 1.30–2.22) were more likely to develop dyslipidemia, and those with high levels of hsCRP (OR: 2.95, 95% CI: 2.27–3.83) and sICAM-1(OR: 2.80, 95% CI: 2.06–3.80) were more likely to develop hyperglycemia.
Biomarkers of inflammation and endothelial dysfunction were separately associated with relevant metabolic risk factors for CVD. And appropriate measures should be taken to control inflammation and improve endothelial function among individuals with different metabolic risk factors for CVD.
PMCID: PMC4569559  PMID: 24215873
Cardiovascular disease; Endothelial dysfunction; Inflammation; Risk factors
17.  Impact of an integrated community case management programme on uptake of appropriate diarrhoea and pneumonia treatments in Uganda: A propensity score matching and equity analysis study 
Pneumonia and diarrhoea disproportionately affect children in resource-poor settings. Integrated community case management (iCCM) involves community health workers treating diarrhoea, pneumonia and malaria. Studies on impact of iCCM on appropriate treatment and its effects on equity in access to the same are limited. The objective of this study was to measure the impact of integrated community case management (iCCM) as the first point of care on uptake of appropriate treatment for children with a classification of pneumonia (cough and fast breathing) and/or diarrhoea and to measure the magnitude and distribution of socioeconomic status related inequality in use of iCCM.
Following introduction of iCCM, data from cross-sectional household surveys were examined for socioeconomic inequalities in uptake of treatment and use of iCCM among children with a classification of pneumonia or diarrhoea using the Erreygers’ corrected concentration index (CCI). Propensity score matching methods were used to estimate the average treatment effects on the treated (ATT) for children treated under the iCCM programme with recommended antibiotics for pneumonia, and ORS plus or minus zinc for diarrhoea.
Overall, more children treated under iCCM received appropriate antibiotics for pneumonia (ATT = 34.7 %, p < 0.001) and ORS for diarrhoea (ATT = 41.2 %, p < 0.001) compared to children not attending iCCM. No such increase was observed for children receiving ORS-zinc combination (ATT = -0.145, p < 0.05).
There were no obvious inequalities in the uptake of appropriate treatment for pneumonia among the poorest and least poor (CCI = -0.070; SE = 0.083). Receiving ORS for diarrhoea was more prevalent among the least poor groups (CCI = 0.199; SE = 0.118). The use of iCCM for pneumonia was more prevalent among the poorest groups (CCI = -0.099; SE = 0.073). The use of iCCM for diarrhoea was not significantly different among the poorest and least poor (CCI = -0.073; SE = 0.085).
iCCM is a potentially equitable strategy that significantly increased the uptake of appropriate antibiotic treatment for pneumonia and ORS for diarrhoea, but not the uptake of zinc for diarrhoea. For maximum impact, interventions increasing zinc uptake should be considered when scaling up iCCM programmes.
PMCID: PMC4559074  PMID: 26337975
Integrated community case management; Pneumonia; Diarrhoea; Equity; Treatment
18.  Transmission characteristics of MERS and SARS in the healthcare setting: a comparative study 
BMC Medicine  2015;13:210.
The Middle East respiratory syndrome (MERS) coronavirus has caused recurrent outbreaks in the Arabian Peninsula since 2012. Although MERS has low overall human-to-human transmission potential, there is occasional amplification in the healthcare setting, a pattern reminiscent of the dynamics of the severe acute respiratory syndrome (SARS) outbreaks in 2003. Here we provide a head-to-head comparison of exposure patterns and transmission dynamics of large hospital clusters of MERS and SARS, including the most recent South Korean outbreak of MERS in 2015.
To assess the unexpected nature of the recent South Korean nosocomial outbreak of MERS and estimate the probability of future large hospital clusters, we compared exposure and transmission patterns for previously reported hospital clusters of MERS and SARS, based on individual-level data and transmission tree information. We carried out simulations of nosocomial outbreaks of MERS and SARS using branching process models rooted in transmission tree data, and inferred the probability and characteristics of large outbreaks.
A significant fraction of MERS cases were linked to the healthcare setting, ranging from 43.5 % for the nosocomial outbreak in Jeddah, Saudi Arabia, in 2014 to 100 % for both the outbreak in Al-Hasa, Saudi Arabia, in 2013 and the outbreak in South Korea in 2015. Both MERS and SARS nosocomial outbreaks are characterized by early nosocomial super-spreading events, with the reproduction number dropping below 1 within three to five disease generations. There was a systematic difference in the exposure patterns of MERS and SARS: a majority of MERS cases occurred among patients who sought care in the same facilities as the index case, whereas there was a greater concentration of SARS cases among healthcare workers throughout the outbreak. Exposure patterns differed slightly by disease generation, however, especially for SARS. Moreover, the distributions of secondary cases per single primary case varied highly across individual hospital outbreaks (Kruskal–Wallis test; P < 0.0001), with significantly higher transmission heterogeneity in the distribution of secondary cases for MERS than SARS. Simulations indicate a 2-fold higher probability of occurrence of large outbreaks (>100 cases) for SARS than MERS (2 % versus 1 %); however, owing to higher transmission heterogeneity, the largest outbreaks of MERS are characterized by sharper incidence peaks. The probability of occurrence of MERS outbreaks larger than the South Korean cluster (n = 186) is of the order of 1 %.
Our study suggests that the South Korean outbreak followed a similar progression to previously described hospital clusters involving coronaviruses, with early super-spreading events generating a disproportionately large number of secondary infections, and the transmission potential diminishing greatly in subsequent generations. Differences in relative exposure patterns and transmission heterogeneity of MERS and SARS could point to changes in hospital practices since 2003 or differences in transmission mechanisms of these coronaviruses.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0450-0) contains supplementary material, which is available to authorized users.
PMCID: PMC4558759  PMID: 26336062
Coronavirus; Exposure pattern; Hospital transmission; MERS; Middle East; Nosocomial; Reproduction number; SARS; South Korea
19.  Food-dependent exercise-induced anaphylaxis to chickpea in a 17-year-old female: a case report 
Food-dependent exercise-induced anaphylaxis is a subtype of anaphylaxis and, although rare, it is an important condition to be familiar with as it can ultimately lead to death.
Case presentation
We present a case of food-dependent exercise-induced anaphylaxis in a 17-year-old white girl due to chickpea. She had a history of anaphylaxis after eating crackers and hummus before exercising. Skin prick testing and serum-specific immunoglobulin E level confirmed chickpea to be the causative allergen.
This case demonstrates the challenge in identifying specific causative food allergens when foods are eaten in combination, when the food is processed, and when cross-reactivity is possible. These challenges add complexity to a condition that is already rare and unfamiliar to some health care providers. We hope that this case will serve as an important reminder that although rare, food-dependent exercise-induced anaphylaxis exists and making a diagnosis can lead to life-saving preventative strategies. As legumes are not a common food associated with food-dependent exercise-induced anaphylaxis, this will add to our current knowledge base in the field of allergy.
PMCID: PMC4559180  PMID: 26334308
20.  Registered report: Inhibition of BET recruitment to chromatin as an effective treatment for MLL-fusion leukemia 
eLife  null;478:529-533.
The Reproducibility Project: Cancer Biology seeks to address growing concerns about reproducibility in scientific research by conducting replications of selected experiments from a number of high-profile papers in the field of cancer biology. The papers, which were published between 2010 and 2012, were selected on the basis of citations and Altmetric scores (Errington et al., 2014). This Registered report describes the proposed replication plan of key experiments from ‘Inhibition of bromodomain and extra terminal (BET) recruitment to chromatin as an effective treatment for mixed-lineage leukemia (MLL)-fusion leukemia’ by Dawson and colleagues, published in Nature in 2011 (Dawson et al., 2011). The experiments to be replicated are those reported in Figures 2A, 3D, 4B, 4D and Supplementary Figures 11A-B and 16A. In this study, BET proteins were demonstrated as potential therapeutic targets for modulating aberrant gene expression programs associated with MLL-fusion leukemia. In Figure 2A, the BET bromodomain inhibitor I-BET151 was reported to suppress growth of cells harboring MLL-fusions compared to those with alternate oncogenic drivers. In Figure 3D, treatment of MLL-fusion leukemia cells with I-BET151 resulted in transcriptional suppression of the anti-apoptotic gene BCL2. Figures 4B and 4D tested the therapeutic efficacy of I-BET151 in vivo using mice injected with human MLL-fusion leukemia cells and evaluated disease progression following I-BET151 treatment. The Reproducibility Project: Cancer Biology is a collaboration between the Center for Open Science and Science Exchange and the results of the replications will be published in eLife.
PMCID: PMC4552956  PMID: 26327698
Reproducibility Project: Cancer Biology; methodology; bromodomain inhibitor; leukemia; human; mouse
21.  An Invitro Comparative Evaluation of Compressive Strength and Antibacterial Activity of Conventional GIC and Hydroxyapatite Reinforced GIC in Different Storage Media 
GIC is the most commonly used restorative material in pediatric dentistry since it has got various advantages like fluoride release, anticariogenic property and chemical adhesion to tooth but a major disadvantage is its contraindication in posterior teeth because of poor mechanical properties.
The purpose of this study is a modest attempt to explore the influence of the addition of 8% hydroxyapatite to conventional GIC on its compressive strength when immersed in different storage media and antibacterial activity.
Materials and Methods
One hundred and twenty six pellets of the specific dimension of 6 x 4 mm were prepared and divided into 6 groups and were immersed in deionized water, artificial saliva, lactic acid solution respectively for three hours everyday over 30 days test period. The compressive strength was measured by using a universal testing machine (AG-50kNG) at cross head of 1mm2/min and strength was determined after 1 day, 7 days, 30 days respectively and the antibacterial activity evaluated against Streptococcus mutans strain in brain heart infusion broth using serial dilution method.
Statistical Analysis
Group wise comparisons were made by one-way ANOVA followed by post-hoc Tukey’s test, Intergroup comparison was done with Mann-Whitney test.
GIC±HAp showed significantly greater antibacterial activity against Streptococcus mutans when compared to GIC group. There was no statistically significant change in the compressive strength among the groups except for group 3 and group 6 when immersed in lactic acid had shown significant difference at the end of 24 hours.
The addition of 8% hydroxyapatite to GIC showed marked increased in the antibacterial activity of the conventional GIC against caries initiating organism without much increase in the compressive strength of the GIC when immersed in the different storage media.
PMCID: PMC4573037  PMID: 26393206
Broth dilution technique; Mechanical properties; Streptococcus mutans; Storage media; Universal testing machine
22.  AB104. Glucose-6 phospate dehydrogenase deficiency among mongolian neonates 
Annals of Translational Medicine  2015;3(Suppl 2):AB104.
Background and objective
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency in humans, affecting 400 million people worldwide and a high prevalence in persons of African, Middle Asian countries. The most common clinical manifestations are neonatal jaundice and acute hemolytic anemia, which is caused by the impairment of erythrocyte’s ability to remove harmful oxidative stress triggered by exogenous agents such as drugs, infection, or fava bean ingestion. Neonatal hyperbilirubinemia caused by G6PD is strongly associated with mortality and long-term neurodevelopmental impairment. The study aims to determine a level of G6PD in healthy neonates.
We obtained blood spot samples from 268 infants around 24-72 hours in their age who has unsuspected intranatal and neonatal disorders. Glucose 6 phosphate dehydrogenase “Perkin Elmer, Finland” level is determined by Victor 2D Fluorometer assay, developing of neonatal jaundice is examined by recall.
The76.5% of all participants (n=205) was assessed 4.36±1.15 Ug/Hb in normal reference range of G6PD, other 23.5% (n=63) was 0.96±0.51 Ug/Hb with G6PD deficiency. In the both sex, 51.5% of male 0.88±0.46 Ug/Hb (n=33) and 47.6% of female (n=30) 0.97±0.55 Ug/Hb was assessed with G6PD deficiency. Developing Jaundice period in number of 63 neonates with G6PD deficiency, 86% of neonates (n=54) was in 1-4 days, 4% of neonates (n=3) was in 5-7 days and there is no sign of jaundice in 9% (n=6). Therefore neonates with G6PD deficiency, 53.9% (n=34) continued jaundice more than two weeks.
G6PD deficiency was determined in male neonates (51.5%) more than female (47.6%). The 76.5% of all participants (n=205) was assessed 4.36±1.15 Ug/Hb in normal reference range of G6PDH other 23.5% (n=63) of all participants was 0.96±0.51 Ug/Hb with G6PD deficiency. It shows that G6PD might be one potential risk of neonatal jaundice and hyperbilirubinemia in neonates in Mongolia.
PMCID: PMC4563546
Neonatal jaundice; enzyme deficiency; newborn screening; neonatal hemolysis
23.  Exploring the barriers to health care and psychosocial challenges in cervical cancer management in Kenya 
Cervical cancer is the most frequent cancer among women aged between 15 years and 44 years in Kenya, resulting in an estimated 4,802 women being diagnosed with cervical cancer and 2,451 dying from the disease annually. It is often detected at its advanced invasive stages, resulting in a protracted illness upon diagnosis. This qualitative study looked at the illness trajectories of women living with cervical cancer enrolled for follow-up care at Kenyatta National Hospital cancer treatment center and the Nairobi Hospice, both in Nairobi county, Kenya. Using the qualitative phenomenological approach, data were collected through 18 in-depth interviews with women living with cervical cancer between April and July 2011. In-depth interviews with their caregivers, key informant interviews with health care workers, and participant observation field notes were used to provide additional qualitative data. These data were analyzed based on grounded theory’s inductive approach. Two key themes on which the data analysis was then anchored were identified, namely, psychosocial challenges of cervical cancer and structural barriers to quality health care. Findings indicated a prolonged illness trajectory with psychosocial challenges, fueled by structural barriers that women were faced with after a cervical cancer diagnosis. To address issues relevant to the increasing numbers of women with cervical cancer, research studies need to include larger samples of these women. Also important are studies that allow in-depth understanding of the experiences of women living with cervical cancer.
PMCID: PMC4556289  PMID: 26346001
qualitative; illness trajectories; women; cervical cancer
24.  Stool microbiota composition is associated with the prospective risk of Plasmodium falciparum infection 
BMC Genomics  2015;16(1):631.
In humans it is unknown if the composition of the gut microbiota alters the risk of Plasmodium falciparum infection or the risk of developing febrile malaria once P. falciparum infection is established. Here we collected stool samples from a cohort composed of 195 Malian children and adults just prior to an intense P. falciparum transmission season. We assayed these samples using massively parallel sequencing of the 16S ribosomal RNA gene to identify the composition of the gut bacterial communities in these individuals. During the ensuing 6-month P. falciparum transmission season we examined the relationship between the stool microbiota composition of individuals in this cohort and their prospective risk of both P. falciparum infection and febrile malaria.
Consistent with prior studies, stool microbial diversity in the present cohort increased with age, although the overall microbiota profile was distinct from cohorts in other regions of Africa, Asia and North America. Age-adjusted Cox regression analysis revealed a significant association between microbiota composition and the prospective risk of P. falciparum infection; however, no relationship was observed between microbiota composition and the risk of developing febrile malaria once P. falciparum infection was established.
These findings underscore the diversity of gut microbiota across geographic regions, and suggest that strategic modulation of gut microbiota composition could decrease the risk of P. falciparum infection in malaria-endemic areas, potentially as an adjunct to partially effective malaria vaccines.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1819-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4546150  PMID: 26296559
Stool microbiota; Gut microbiota; Malaria; 16S rRNA gene sequencing; Plasmodium falciparum; Human; Prospective cohort
25.  Effect of induction therapy on the expression of molecular markers associated with rejection and tolerance 
BMC Nephrology  2015;16:146.
Induction therapy can improve kidney transplantation (KTx) outcomes, but little is known about the mechanisms underlying its effects.
The mRNA levels of T cell-related genes associated with tolerance or rejection (CD247, GZMB, PRF1, FOXP3, MAN1A1, TCAIM, and TLR5) and lymphocyte subpopulations were monitored prospectively in the peripheral blood of 60 kidney transplant recipients before and 7, 14, 21, 28, 60, 90 days, 6 months, and 12 months after KTx. Patients were treated with calcineurin inhibitor-based triple immunosuppression and induction with rabbit anti-thymocyte globulin (rATG, n = 24), basiliximab (n = 17), or without induction (no-induction, n = 19). A generalized linear mixed model with gamma distribution for repeated measures, adjusted for rejection, recipient/donor age and delayed graft function, was used for statistical analysis.
rATG treatment caused an intense reduction in all T cell type population and natural killer (NK) cells within 7 days, then a slow increase and repopulation was observed. This was also noticed in the expression levels of CD247, FOXP3, GZMB, and PRF1. The basiliximab group exhibited higher CD247, GZMB, FOXP3 and TCAIM mRNA levels and regulatory T cell (Treg) counts than the no-induction group. The levels of MAN1A1 and TLR5 mRNA expressions were increased, whereas TCAIM decreased in the rATG group as compared with those in the no-induction group.
The rATG induction therapy was associated with decreased T and NK cell-related transcript levels and with upregulation of two rejection-associated transcripts (MAN1A1 and TLR5) shortly after KTx. Basiliximab treatment was associated with increased absolute number of Treg cells, and increased level of FOXP3 and TCAIM expression.
PMCID: PMC4545708  PMID: 26286066
Basiliximab; FOXP3; Kidney transplantation; rATG; Rejection; Tolerance

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