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1.  Rifampicin-resistant Mycobacterium tuberculosis: susceptibility to isoniazid and other anti-tuberculosis drugs 
Based on data from 14 Supranational Tuberculosis (TB) Reference Laboratories worldwide, the proportion of rifampicin-resistant isolates that were isoniazid-susceptible by phenotypic drug-susceptibility tests varied widely (0.5%–11.6%). Rifampicin-resistant isolates that were isoniazid-susceptible had significantly lower rates of resistance to other first-line and second-line anti-TB drugs (except rifabutin) compared to multidrug-resistant isolates. Rifampicin resistance is not always a good proxy for a presumptive diagnosis of multidrug-resistant tuberculosis, which has implications for use of molecular assays that identify only rifampicin resistance-associated DNA mutations.
PMCID: PMC4593496  PMID: 22640449
tuberculosis; rifampicin resistance; molecular diagnostic tests; drug resistance
2.  New-onset supraventricular arrhythmia during septic shock: prevalence, risk factors and prognosis 
The aims of this study were to prospectively assess the prevalence of sustained (lasting more than 30 s) new-onset supraventricular arrhythmia (NOSVA) during septic shock, identify the associated factors (including septic myocardial dysfunction), and evaluate its impact on hemodynamics and prognosis.
Patients with a diagnosis of septic shock were screened in a medical intensive care unit of a tertiary hospital center in France with a continuous 12-lead EKG for the occurrence of NOSVA. Biological and clinical data (including septic myocardial dysfunction characterized by echocardiography) were collected. We also assessed the hemodynamic tolerance and prognosis of NOSVA.
Among the 71 septic shock episodes assessed during the study, NOSVA occurred in 30 [prevalence of 42 %, 95 % confidence interval (CI) 30–53 %]. Among all recorded factors, only renal failure (as assessed by renal SOFA score at day 1) was associated with NOSVA and this difference persisted by multivariable analysis (odds ratio of 1.29, 95 % CI 1.03–1.62, p = 0.03). There was a significant increase in norepinephrine dosage during the first hour after SVA onset. NOSVA was associated with longer catecholamine use during septic shock as compared with patients in sinus rhythm, whereas ICU mortality was identical between groups.
We found a high prevalence of sustained NOSVA during septic shock. NOSVA was not related to septic myocardial dysfunction, but rather to acute renal failure, raising the hypothesis of an acute renocardiac syndrome.
PMCID: PMC4579158  PMID: 26395899
Arrhythmia; Sepsis; Shock; Myocardial dysfunction
3.  Medicinal plants used to treat the most frequent diseases encountered in Ambalabe rural community, Eastern Madagascar 
Traditional medicine remains the only health care available in many rural areas in Madagascar like the rural community of Ambalabe, located in a very remote area in the eastern part of the country. With limited access to modern medicine, the local population uses medicinal plants to treat most diseases. In this study, we aimed to inventory medicinal plants used by local people and how those relate to the treatment of the most frequent diseases encountered in Ambalabe.
We interviewed participants in order to identify the most frequent diseases in the region and the medicinal plants used to treat them. The local physician was asked about the most frequent diseases, and ethnobotanical surveys to record medicinal plants and their uses, using semi-structured interviews and free listing, were conducted among 193 informants in local villages, of which 54 % were men and 46 % were women, ageing from 16 to 86 years. The local names, the uses of each plant species and the way they are prepared and administered were recorded and accompanied by herbarium specimens for identification. We also interviewed four traditional healers to elicit more details on the preparation and the use of plants.
Our research allowed us to identify six most frequent diseases, namely diarrhea, malaria, stomach-ache, cough, bilharzia and dysentery. Among 209 plant species identified as having medicinal use, 83 species belonging to 49 families and 77 genera were used to treat these diseases. Our analyses highlighted the 11 commonly used species for their treatment, and also 16 species with a high fidelity level (FL ≥ 75 %) for each ailment. Diarrhea is one of the diseases with high number of species recorded.
This study highlighted the closed relationship between people in Ambalabe and plant species, especially when faced with frequent diseases. However, most of the species used were collected in the surroundings of the villages. Few species were from Vohibe forest in which a management system on the use of plant species was already established. Therefore, a sustainable use management should be considered for wild species from which medicinal plants are highly abundant.
Electronic supplementary material
The online version of this article (doi:10.1186/s13002-015-0050-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4570514  PMID: 26369781
Medicinal plants; Madagascar; Ethnobotanical surveys; Frequent diseases; Conservation
4.  Antiretroviral-Free HIV-1 Remission and Viral Rebound Following Allogeneic Stem Cell Transplantation: A Report of Two Cases 
Annals of internal medicine  2014;161(5):319-327.
It is unknown if the reduction in HIV-1 reservoirs observed following allogeneic hematopoietic stem cell transplantation (HSCT) with susceptible donor cells is sufficient to achieve sustained HIV-1 remission.
To characterize HIV-1 reservoirs in blood and tissues, and to perform analytical antiretroviral treatment interruptions to determine the potential for allogeneic HSCT to lead to sustained antiretroviral-free HIV-1 remission.
Characterization of HIV-1 reservoirs and immunity before and after antiretroviral interruption.
Tertiary care center.
Two HIV-infected men with undetectable HIV-1 following allogeneic HSCT for hematologic malignancies.
Quantification of HIV-1 in various tissues after HSCT and the duration of antiretroviral-free HIV-1 remission after treatment interruption.
No HIV-1 was detected from peripheral blood or rectal mucosa prior to analytical treatment interruption. Plasma HIV-1 RNA and cell-associated HIV-1 DNA remained undetectable until 12 to 32 weeks after antiretroviral cessation. Both patients experienced rebound viremia with the development of acute retroviral syndrome within one to two weeks of the most recent negative viral load measurement. One patient developed new efavirenz resistance after re-initiation of antiretroviral therapy. Re-initiation of active therapy led to viral decay and resolution of symptoms in both patients.
The study was limited to 2 patients.
Allogeneic HSCT may lead to loss of detectable HIV-1 from blood and gut tissue and variable periods of antiretroviral-free HIV-1 remission, but viral rebound can occur despite a minimum 3-log10 reduction in reservoir size. Long-lived tissue reservoirs may have contributed to viral persistence. Defining the nature and half-life of such reservoirs is essential in order to achieve durable antiretroviral-free HIV-1 remission.
PMCID: PMC4236912  PMID: 25047577
5.  Personal Protective Equipment for Filovirus Epidemics: A Call for Better Evidence 
The Journal of Infectious Diseases  2015;212(Suppl 2):S98-S100.
Personal protective equipment (PPE) is an important part of worker protection during filovirus outbreaks. The need to protect against a highly virulent fluid-borne pathogen in the tropical environment imposes a heat stress on the wearer that is itself a safety risk. No evidence supports the choice of PPE employed in recent outbreaks, and standard testing procedures employed by the protective garment industry do not well simulate filovirus exposure. Further research is needed to determine the appropriate PPE for filoviruses and the heat stress that it imposes.
PMCID: PMC4564541  PMID: 25821225
Ebola; heat stress disorders; hemorrhagic fever; protective clothing
6.  A Practical Guide to Immunoassay Method Validation 
Biochemical markers have a central position in the diagnosis and management of patients in clinical medicine, and also in clinical research and drug development, also for brain disorders, such as Alzheimer’s disease. The enzyme-linked immunosorbent assay (ELISA) is frequently used for measurement of low-abundance biomarkers. However, the quality of ELISA methods varies, which may introduce both systematic and random errors. This urges the need for more rigorous control of assay performance, regardless of its use in a research setting, in clinical routine, or drug development. The aim of a method validation is to present objective evidence that a method fulfills the requirements for its intended use. Although much has been published on which parameters to investigate in a method validation, less is available on a detailed level on how to perform the corresponding experiments. To remedy this, standard operating procedures (SOPs) with step-by-step instructions for a number of different validation parameters is included in the present work together with a validation report template, which allow for a well-ordered presentation of the results. Even though the SOPs were developed with the intended use for immunochemical methods and to be used for multicenter evaluations, most of them are generic and can be used for other technologies as well.
PMCID: PMC4541289  PMID: 26347708
immunoassays; method validation; precision; limits of quantitation; robustness
7.  Ilizarov bone transport as a treatment of congenital pseudarthrosis of the tibia: a long-term follow-up study 
Most studies on congenital pseudarthrosis of the tibia (CPT) report on the short-term union rate and refracture rate but do not take into account the long-term outcome. This review includes patients treated with an Ilizarov bone transport, who all reached skeletal maturity. It describes long-term results and highlights any prognostic factors that could predict the final outcome.
The records of patients with CPT treated with an Ilizarov bone transport in our institution were retrospectively evaluated.
A total of 12 consecutive patients were studied. The mean follow-up was 24.5 years (range 6–39 years). Primary consolidation was seen in ten patients (83 %). Half of these patients had a refracture. At final follow-up, eight patients experienced union and four remained un-united, of whom one had an amputation.
The present data confirm a good primary healing rate. However, tibial union at final follow-up was only seen in 67 %, indicating that refracture is the main issue. United bone is often of inferior biological and mechanical quality, so lifetime protection with intramedullary devices, braces or a combination of both is recommended.
PMCID: PMC4549345  PMID: 26266468
Congenital pseudarthrosis of the tibia; Ilizarov bone transport; Neurofibromatosis
8.  2D–3D radiograph to cone-beam computed tomography (CBCT) registration for C-arm image-guided robotic surgery 
C-arm radiographs are commonly used for intraoperative image guidance in surgical interventions. Fluoroscopy is a cost-effective real-time modality, although image quality can vary greatly depending on the target anatomy. Cone-beam computed tomography (CBCT) scans are sometimes available, so 2D–3D registration is needed for intra-procedural guidance. C-arm radiographs were registered to CBCT scans and used for 3D localization of peritumor fiducials during a minimally invasive thoracic intervention with a da Vinci Si robot.
Intensity-based 2D–3D registration of intraoperative radiographs to CBCT was performed. The feasible range of X-ray projections achievable by a C-arm positioned around a da Vinci Si surgical robot, configured for robotic wedge resection, was determined using phantom models. Experiments were conducted on synthetic phantoms and animals imaged with an OEC 9600 and a Siemens Artis zeego, representing the spectrum of different C-arm systems currently available for clinical use.
The image guidance workflow was feasible using either an optically tracked OEC 9600 or a Siemens Artis zeego C-arm, resulting in an angular difference of Δθ : ~ 30°. The two C-arm systems provided TREmean ≤ 2.5 mm and TREmean ≤ 2.0 mm, respectively (i.e., comparable to standard clinical intraoperative navigation systems).
C-arm 3D localization from dual 2D–3D registered radiographs was feasible and applicable for intraoperative image guidance during da Vinci robotic thoracic interventions using the proposed workflow. Tissue deformation and in vivo experiments are required before clinical evaluation of this system.
PMCID: PMC4476946  PMID: 25503592
2D–3D registration; Intraoperative fluoroscopy; Robotic surgery; Image guidance
9.  Iron Overload in Allogeneic Hematopoietic Cell Transplantation Outcome: A Meta-Analysis 
An elevated ferritin before allogeneic hematopoietic cell transplantation (HCT) is an adverse prognostic factor for overall survival (OS) and non-relapse mortality (NRM). Because ferritin is an imperfect surrogate of iron stores, the prognostic role of iron overload remains unclear. We conducted a patient-level meta-analysis of 4 studies that used magnetic resonance imaging to estimate pre-HCT liver iron content (LIC). An elevated LIC was not associated with a significant increase in mortality: the hazard ratio (HR) for mortality associated with LIC>7 mg/gdw (primary endpoint) was 1.4 (p=0.18). In contrast, ferritin >1000 ng/ml was a significant prognostic factor (HR for mortality 1.7, p=0.036). There was, however, no significant association between ferritin>2500 and mortality. This meta-analysis suggests that iron overload, as assessed by LIC, is not a strong prognostic factor for OS in a general adult HCT population. Our data also suggest that ferritin is an inadequate surrogate for iron overload in HCT.
PMCID: PMC4099413  PMID: 24769316
10.  Adaptation Genomics of a Small-Colony Variant in a Pseudomonas chlororaphis 30-84 Biofilm 
The rhizosphere-colonizing bacterium Pseudomonas chlororaphis 30-84 is an effective biological control agent against take-all disease of wheat. In this study, we characterize a small-colony variant (SCV) isolated from a P. chlororaphis 30-84 biofilm. The SCV exhibited pleiotropic phenotypes, including small cell size, slow growth and motility, low levels of phenazine production, and increased biofilm formation and resistance to antimicrobials. To better understand the genetic alterations underlying these phenotypes, RNA and whole-genome sequencing analyses were conducted comparing an SCV to the wild-type strain. Of the genome's 5,971 genes, transcriptomic profiling indicated that 1,098 (18.4%) have undergone substantial reprograming of gene expression in the SCV. Whole-genome sequence analysis revealed multiple alterations in the SCV, including mutations in yfiR (cyclic-di-GMP production), fusA (elongation factor), and cyoE (heme synthesis) and a 70-kb deletion. Genetic analysis revealed that the yfiR locus plays a major role in controlling SCV phenotypes, including colony size, growth, motility, and biofilm formation. Moreover, a point mutation in the fusA gene contributed to kanamycin resistance. Interestingly, the SCV can partially switch back to wild-type morphologies under specific conditions. Our data also support the idea that phenotypic switching in P. chlororaphis is not due to simple genetic reversions but may involve multiple secondary mutations. The emergence of these highly adherent and antibiotic-resistant SCVs within the biofilm might play key roles in P. chlororaphis natural persistence.
PMCID: PMC4292466  PMID: 25416762
11.  Medicinal plants sold in the markets of Antananarivo, Madagascar 
This study focuses on the large outdoor markets of the capital of Madagascar, Antananarivo. As the largest metropolitan area in Madagascar with a population of nearly two million, the region has great capacity for consumption of medicinal plant remedies despite numerous pharmacies. Medicinal plant use spans all socioeconomic levels, and the diverse metropolitan population allows us to study a wide variety of people who consume these plants for medical purposes. The purpose of this study is to identify and generate a list of medicinal plants sold in the traditional markets with a focus on those collected in the forests around Antananarivo, get an idea of the quantities of medicinal plants sold in the markets around Antananarivo, and assess the economy of the medicinal plant markets.
In order to determine which medicinal plants are most consumed in Antananarivo, ethnobotanical enquiries were conducted in the five main markets of the capital city. Ethnobotanical surveys were conducted with medicinal plant traders, suppliers, harvesters and cultivators, with voucher specimens created from the plants discussed. Trade circuit information was established and the income generated by the trade of some of the species was assessed.
The inventory of the Antananarivo markets resulted in a list of 89 commercialized plant species. Ten of the 89 were mentioned by 60-100 % of vendors. Profitability for vendors is high and competitive with other salaried positions within Antananarivo. Transportation costs are also high and therefore lower profitability for other members in the supply chain.
The markets of Antananarivo have always played a vital cultural role in the lives of urban Malagasy, but our study shows they also play an economic role not only for urban residents but rural harvesters as well. Continued research and monitoring of the non-timber forest products trade in Antananarivo is needed to better understand the impact of trade on the wild plant populations.
PMCID: PMC4517502  PMID: 26216098
Madagascar; Urban market; Medicinal plants
12.  Can Whole-Body Cryotherapy with Subsequent Kinesiotherapy Procedures in Closed Type Cryogenic Chamber Improve BASDAI, BASFI, and Some Spine Mobility Parameters and Decrease Pain Intensity in Patients with Ankylosing Spondylitis? 
BioMed Research International  2015;2015:404259.
The present study investigated whether whole-body cryotherapy (WBC) procedures could potentially have more beneficial effects on index of BASDAI and BASFI, pain intensity, and spine mobility parameters: Ott test, modified Schober test, chest expansion in ankylosing spondylitis (AS) patients, than kinesiotherapy procedures used separately. AS patients were exposed to a cycle of WBC procedures lasting 3 minutes a day, with a subsequent 60 minutes of kinesiotherapy or 60 minutes of kinesiotherapy only, for 10 consecutive days excluding weekend. After the completion of the cycle of WBC procedures with subsequent kinesiotherapy in the AS patients, BASDAI index decreased about 40% in comparison with the input value, whereas in the group of patients who received only kinesiotherapy it decreased only about 15% in comparison with the input value. After the completion of the treatment in the WBC group, BASFI index decreased about 30% in comparison with the input value, whereas in the kinesiotherapy group it only decreased about 16% in comparison with the input value. The important conclusion was that, in WBC group with subsequent kinesiotherapy, we observed on average about twice better results than in the group treated only by kinesiotherapy.
PMCID: PMC4529896  PMID: 26273618
13.  Features of human scabies in resource-limited settings: the Cameroon case 
BMC Dermatology  2015;15:12.
The persistent high prevalence of human scabies, especially in low- and middle-income countries prompted us to research the sociodemographic profile of patients suffering from it, and its spreading factors in Cameroon, a resource-poor setting.
We conducted a cross-sectional survey from October 2011 to September 2012 in three hospitals located in Yaoundé, Cameroon, and enrolled patients diagnosed with human scabies during dermatologists’ consultations who volunteered to take part in the study.
We included 255 patients of whom 158 (62 %) were male. Age ranged from 0 to 80 years old with a median of 18 (Inter quartile range: 3–29) years. One to eight persons of our patients’ entourage exhibited pruritus (mean = 2.1 ± 1.8). The number of persons per bed/room varied from 1 to 5 (mean = 2.1 ± 0.8). The first dermatologist’s consultation occurred 4 to 720 days after the onset of symptoms (mean = 77.1 ± 63.7). The post-scabies pruritus (10.2 % of cases) was unrelated to the complications observed before correct treatment (all p values > 0.05), mainly impetiginization (7.1 %) and eczematization (5.9 %).
Human scabies remains preponderant in our milieu. Populations should be educated on preventive measures in order to avoid this disease, and clinicians’ knowledges must be strengthened for its proper diagnosis and management.
PMCID: PMC4512092  PMID: 26201604
Human scabies; Contagiousness; Post-scabies pruritus; Cameroon
14.  PD-1 Blockade with Nivolumab in Relapsed or Refractory Hodgkin's Lymphoma 
The New England journal of medicine  2014;372(4):311-319.
Preclinical studies suggest that Reed–Sternberg cells exploit the programmed death 1 (PD-1) pathway to evade immune detection. In classic Hodgkin's lymphoma, alterations in chromosome 9p24.1 increase the abundance of the PD-1 ligands, PD-L1 and PD-L2, and promote their induction through Janus kinase (JAK)–signal transducer and activator of transcription (STAT) signaling. We hypothesized that nivolumab, a PD-1–blocking antibody, could inhibit tumor immune evasion in patients with relapsed or refractory Hodgkin's lymphoma.
In this ongoing study, 23 patients with relapsed or refractory Hodgkin's lymphoma that had already been heavily treated received nivolumab (at a dose of 3 mg per kilogram of body weight) every 2 weeks until they had a complete response, tumor progression, or excessive toxic effects. Study objectives were measurement of safety and efficacy and assessment of the PDL1 and PDL2 (also called CD274 and PDCD1LG2, respectively) loci and PD-L1 and PD-L2 protein expression.
Of the 23 study patients, 78% were enrolled in the study after a relapse following autologous stem-cell transplantation and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed–Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.
Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin's lymphoma. (Funded by Bristol-Myers Squibb and others; number, NCT01592370.)
PMCID: PMC4348009  PMID: 25482239
15.  Subject-Specific Planning of Femoroplasty: A Combined Evolutionary Optimization and Particle Diffusion Model Approach 
Journal of biomechanics  2014;47(10):2237-2243.
A potential effective treatment for prevention of osteoporotic hip fractures is augmentation of the mechanical properties of the femur by injecting it with agents such as (PMMA) bone cement – femoroplasty. The operation, however, is only in research stage and can benefit substantially from computer planning and optimization. We report the results of computational planning and optimization of the procedure for biomechanical evaluation. An evolutionary optimization method was used to optimally place the cement in finite element (FE) models of seven osteoporotic bone specimens. The optimization, with some inter-specimen variations, suggested that areas close to the cortex in the superior and inferior of the neck and supero-lateral aspect of the greater trochanter will benefit from augmentation. We then used a particle-based model for bone cement diffusion simulation to match the optimized pattern, taking into account the limitations of the actual surgery, including limited volume of injection to prevent thermal necrosis. Simulations showed that the yield load can be significantly increased by more than 30%, using only 9ml of bone cement. This increase is comparable to previous literature reports where gross filling of the bone was employed instead, using more than 40ml of cement. These findings, along with the differences in the optimized plans between specimens, emphasize the need for subject-specific models for effective planning of femoral augmentation.
PMCID: PMC4096901  PMID: 24856887
Femoroplasty; PMMA Cement; Finite Element; Optimization; Planning
16.  SwissPalm: Protein Palmitoylation database 
F1000Research  2015;4:261.
Protein S-palmitoylation is a reversible post-translational modification that regulates many key biological processes, although the full extent and functions of protein S-palmitoylation remain largely unexplored. Recent developments of new chemical methods have allowed the establishment of palmitoyl-proteomes of a variety of cell lines and tissues from different species.  As the amount of information generated by these high-throughput studies is increasing, the field requires centralization and comparison of this information. Here we present SwissPalm (, our open, comprehensive, manually curated resource to study protein S-palmitoylation. It currently encompasses more than 5000 S-palmitoylated protein hits from seven species, and contains more than 500 specific sites of S-palmitoylation. SwissPalm also provides curated information and filters that increase the confidence in true positive hits, and integrates predictions of S-palmitoylated cysteine scores, orthologs and isoform multiple alignments. Systems analysis of the palmitoyl-proteome screens indicate that 10% or more of the human proteome is susceptible to S-palmitoylation. Moreover, ontology and pathway analyses of the human palmitoyl-proteome reveal that key biological functions involve this reversible lipid modification. Comparative analysis finally shows a strong crosstalk between S-palmitoylation and other post-translational modifications. Through the compilation of data and continuous updates, SwissPalm will provide a powerful tool to unravel the global importance of protein S-palmitoylation.
PMCID: PMC4544385  PMID: 26339475
S-palmitoylation; palmitoyl-proteomes; database; proteomics; Acyl-biotin exchange; Acyl-RAC
17.  Humanized Chronic Graft-versus-Host Disease in NOD-SCID il2rγ-/- (NSG) Mice with G-CSF-Mobilized Peripheral Blood Mononuclear Cells following Cyclophosphamide and Total Body Irradiation 
PLoS ONE  2015;10(7):e0133216.
Chronic graft-versus-host disease (cGvHD) is the major source of late phase morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Humanized acute GvHD (aGvHD) in vivo models using NOD-SCID il2rγ-/- (NSG) mice are well described and are important tools for investigating pathogenicity of human cells in vivo. However, there have been only few reported humanized cGvHD mouse models. We evaluated if prolonged inflammation driven by low dose G-CSF-mobilized human PBMCs (G-hPBMCs) would lead to cGvHD following cyclophosphamide (CTX) administration and total body irradiation (TBI) in NSG mice. Engraftment was assessed in peripheral blood (PB) and in specific target organs by either flow cytometry or immunohistochemistry (IHC). Tissue samples were harvested 56 days post transplantation and were evaluated by a pathologist. Some mice were kept for up to 84 days to evaluate the degree of fibrosis. Mice that received CTX at 20mg/kg did not show aGvHD with stable expansion of human CD45+ CD3+ T-cells in PB (mean; 5.8 to 23.2%). The pathology and fibrosis scores in the lung and the liver were significantly increased with aggregation of T-cells and hCD68+ macrophages. There was a correlation between liver pathology score and the percentage of hCD68+ cells, suggesting the role of macrophage in fibrogenesis in NSG mice. In order to study long-term survival, 6/9 mice who survived more than 56 days showed increased fibrosis in the lung and liver at the endpoint, which suggests the infiltrating hCD68+ macrophages may be pathogenic. It was shown that the combination of CTX and TBI with a low number of G-hPBMCs (1x106) leads to chronic lung and liver inflammation driven by a high infiltration of human macrophage and mature human T cells from the graft, resulting in fibrosis of lung and liver in NSG mice. In conclusion this model may serve as an important pre-clinical model to further current understanding of the roles of human macrophages in cGvHD.
PMCID: PMC4503770  PMID: 26176698
18.  Chasing the Effects of Pre-Analytical Confounders – A Multicenter Study on CSF-AD Biomarkers 
Core cerebrospinal fluid (CSF) biomarkers – Aβ42, Tau, and phosphorylated Tau (pTau) – have been recently incorporated in the revised criteria for Alzheimer’s disease (AD). However, their widespread clinical application lacks standardization. Pre-analytical sample handling and storage play an important role in the reliable measurement of these biomarkers across laboratories.
In this study, we aim to surpass the efforts from previous studies, by employing a multicenter approach to assess the impact of less studied CSF pre-analytical confounders in AD-biomarkers quantification.
Four different centers participated in this study and followed the same established protocol. CSF samples were analyzed for three biomarkers (Aβ42, Tau, and pTau) and tested for different spinning conditions [temperature: room temperature (RT) vs. 4°C; speed: 500 vs. 2000 vs. 3000 g], storage volume variations (25, 50, and 75% of tube total volume), as well as freezing-thaw cycles (up to five cycles). The influence of sample routine parameters, inter-center variability, and relative value of each biomarker (reported as normal/abnormal) was analyzed.
Centrifugation conditions did not influence biomarkers levels, except for samples with a high CSF total protein content, where either non-centrifugation or centrifugation at RT, compared to 4°C, led to higher Aβ42 levels. Reducing CSF storage volume from 75 to 50% of total tube capacity decreased Aβ42 concentration (within analytical CV of the assay), whereas no change in Tau or pTau was observed. Moreover, the concentration of Tau and pTau appears to be stable up to five freeze–thaw cycles, whereas Aβ42 levels decrease if CSF is freeze-thawed more than three times.
This systematic study reinforces the need for CSF centrifugation at 4°C prior to storage and highlights the influence of storage conditions in Aβ42 levels. This study contributes to the establishment of harmonized standard operating procedures that will help reducing inter-lab variability of CSF-AD biomarkers evaluation.
PMCID: PMC4495343  PMID: 26217300
Alzheimer’s disease; cerebrospinal fluid; biomarkers; BIOMARKAPD; standardized operating procedures; β-amyloid; tau protein; phosphorylated tau protein
19.  STRATEGIC-1: A multiple-lines, randomized, open-label GERCOR phase III study in patients with unresectable wild-type RAS metastatic colorectal cancer 
BMC Cancer  2015;15:496.
The management of unresectable metastatic colorectal cancer (mCRC) is a comprehensive treatment strategy involving several lines of therapy, maintenance, salvage surgery, and treatment-free intervals. Besides chemotherapy (fluoropyrimidine, oxaliplatin, irinotecan), molecular-targeted agents such as anti-angiogenic agents (bevacizumab, aflibercept, regorafenib) and anti-epidermal growth factor receptor agents (cetuximab, panitumumab) have become available. Ultimately, given the increasing cost of new active compounds, new strategy trials are needed to define the optimal use and the best sequencing of these agents. Such new clinical trials require alternative endpoints that can capture the effect of several treatment lines and be measured earlier than overall survival to help shorten the duration and reduce the size and cost of trials.
STRATEGIC-1 is an international, open-label, randomized, multicenter phase III trial designed to determine an optimally personalized treatment sequence of the available treatment modalities in patients with unresectable RAS wild-type mCRC. Two standard treatment strategies are compared: first-line FOLFIRI-cetuximab, followed by oxaliplatin-based second-line chemotherapy with bevacizumab (Arm A) vs. first-line OPTIMOX-bevacizumab, followed by irinotecan-based second-line chemotherapy with bevacizumab, and by an anti-epidermal growth factor receptor monoclonal antibody with or without irinotecan as third-line treatment (Arm B). The primary endpoint is duration of disease control. A total of 500 patients will be randomized in a 1:1 ratio to one of the two treatment strategies.
The STRATEGIC-1 trial is designed to give global information on the therapeutic sequences in patients with unresectable RAS wild-type mCRC that in turn is likely to have a significant impact on the management of this patient population. The trial is open for inclusion since August 2013.
Trial registration
STRATEGIC-1 is registered at NCT01910610, 23 July, 2013. STRATEGIC-1 is registered at EudraCT-No.: 2013-001928-19, 25 April, 2013.
Electronic supplementary material
The online version of this article (doi:10.1186/s12885-015-1503-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4490616  PMID: 26141683
Colorectal cancer; Therapeutics; Strategy; RAS; KRAS; NRAS; Clinical trial
20.  Computer-assisted, Le Fort-based, face–jaw–teeth transplantation: a pilot study on system feasiblity and translational assessment 
Le Fort-based face–jaw–teeth transplantation (FJTT) attempts to marry bone and teeth geometry of size-mismatched face–jaw–teeth segments to restore function and form due to severe mid-facial trauma. Recent development of a computer-assisted planning and execution (CAPE) system for Le Fort-based FJTT in a pre-clinical swine model offers preoperative planning, and intraoperative navigation. This paper addresses the translation of the CAPE system to human anatomy and presents accuracy results.
Single-jaw, Le Fort-based FJTTs were performed on plastic models, one swine and one human, and on a human cadaver. Preoperative planning defined the goal placement of the donor’s Le Fort-based FJTT segment on the recipient. Patient-specific navigated cutting guides helped achieve planned osteotomies. Intraoperative cutting guide and donor fragment placement were compared with postoperative computed tomography (CT) data and the preoperative plan.
Intraoperative measurement error with respect to postoperative CT was less than 1.25 mm for both mock transplants and 3.59 mm for the human cadaver scenario. Donor fragment placement (as compared to the planned position) was less accurate for the human model test case (2.91 mm) compared with the swine test (2.25 mm) and human cadaver (2.26 mm).
The results indicate the viability of the CAPE system for assisting with Le Fort-based FJTT and demonstrate the potential in human surgery. This system offers a new path forward to achieving improved outcomes in Le Fort-based FJTT and can be modified to assist with a variety of other surgeries involving the head, neck, face, jaws and teeth.
PMCID: PMC4480220  PMID: 25230895
Face–jaw–teeth transplantation; Face transplant; Le Fort-based transplant; Surgical cutting guide; Navigation; Preoperative planning
21.  Outcomes of hematopoietic cell transplantation for diffuse large B cell lymphoma transformed from follicular lymphoma 
There are limited data on the outcomes of autologous or allogeneic hematopoietic cell transplantation in diffuse large B-cell lymphoma transformed from follicular lymphoma. We analyzed transplant outcomes in 141 subjects with biopsy-proven diffuse large B-cell lymphoma transformed from follicular lymphoma reported to the Center for International Blood and Marrow Transplant Research from 1990–2009. Two groups were identified: autotransplant (N=108) and allotransplant (N=33). Fewer autotransplants were done for transformed follicular lymphoma in 2003–2009, with a shift favoring allotransplants. Autotransplant had 1 year non-relapse mortality of 8% (95% confidence intervals [CI] 4–14), 5 year progression free survival of 35% (95% CI 26–45), and 5 year overall survival of 50% (95% CI 40–59). Allotransplant had 1 year non-relapse mortality of 41% (95% CI 23–58), 5 year progression free survival of 18% (95% CI 6–35), and 5 year overall survival of 22% (95% CI 8–41). Autotransplant for transformed follicular lymphoma achieves sustained remission in a high proportion of subjects. The high non-relapse mortality of allotransplant obscured any benefit that might be associated with this transplant modality.
PMCID: PMC4060436  PMID: 24641828
transformed follicular lymphoma; transplant
22.  Control of the Coupled Motion of a 6 DoF Robotic Arm and a Continuum Manipulator for the Treatment of Pelvis Osteolysis 
The paper addresses the coupled motion of a 6 degree of freedom robot and a snake-like dexterous manipulator (SDM) designed for the treatment of bone defects behind the implant during total hip arthroplasty revision surgery. We have formulated the problem as a weighted, multi-objective constraint, linear optimization. A remote center of motion (RCM) acts as a virtual constraint for the robot. The coupled robot kinematics does not assume piecewise-constant curvature for the SDM. We have evaluated our method by simulating the coupled system inside a potential lesion area.
PMCID: PMC4479257  PMID: 25571490
23.  Robustness and Accuracy of Feature-Based Single Image 2-D–3-D Registration Without Correspondences for Image-Guided Intervention 
2-D-to-3-D registration is critical and fundamental in image-guided interventions. It could be achieved from single image using paired point correspondences between the object and the image. The common assumption that such correspondences can readily be established does not necessarily hold for image guided interventions. Intraoperative image clutter and an imperfect feature extraction method may introduce false detection and, due to the physics of X-ray imaging, the 2-D image point features may be indistinguishable from each other and/or obscured by anatomy causing false detection of the point features. These create difficulties in establishing correspondences between image features and 3-D data points. In this paper, we propose an accurate, robust, and fast method to accomplish 2-D–3-D registration using a single image without the need for establishing paired correspondences in the presence of false detection. We formulate 2-D–3-D registration as a maximum likelihood estimation problem, which is then solved by coupling expectation maximization with particle swarm optimization. The proposed method was evaluated in a phantom and a cadaver study. In the phantom study, it achieved subdegree rotation errors and submillimeter in-plane (X –Y plane) translation errors. In both studies, it outperformed the state-of-the-art methods that do not use paired correspondences and achieved the same accuracy as a state-of-the-art global optimal method that uses correct paired correspondences.
PMCID: PMC4479265  PMID: 23955696
2-D–3-D registration; feature-based registration; image-guided interventions (IGIs); particle swarm optimization (PSO)
24.  Patient-specific finite element modeling for femoral bone augmentation 
Medical engineering & physics  2013;35(6):860-865.
The aim of this study was to provide a fast and accurate finite element (FE) modeling scheme for predicting bone stiffness and strength suitable for use within the framework of a computer-assisted osteoporotic femoral bone augmentation surgery system. The key parts of the system, i.e. preoperative planning and intraoperative assessment of the augmentation, demand the finite element model to be solved and analyzed rapidly. Available CT scans and mechanical testing results from nine pairs of osteoporotic femur bones, with one specimen from each pair augmented by polymethylmethacrylate (PMMA) bone cement, were used to create FE models and compare the results with experiments. Correlation values of R2 = 0.72–0.95 were observed between the experiments and FEA results which, combined with the fast model convergence (~3 min for ~250,000 degrees of freedom), makes the presented modeling approach a promising candidate for the intended application of preoperative planning and intraoperative assessment of bone augmentation surgery.
PMCID: PMC4476497  PMID: 23375663
Femoroplasty; Finite element analysis; Biomechanics; Bone cement
25.  Development of a biomechanical guidance system for periacetabular osteotomy 
This paper presents and validates a computer-navigated system for performing periacetabular osteotomy (PAO) to treat developmental dysplasia of the hip. The main motivation of the biomechanical guidance system (BGS) is to plan and track the osteotomy fragment in real time during PAO while simplifying the procedure for less-experienced surgeons. The BGS aims at developing a platform for comparing biomechanical states of the joint with the current gold standard geometric assessment of anatomical angles. The purpose of this study was to (1) determine the accuracy with which the BGS tracks the hip joint through repositioning and (2) identify improvements to the workflow.
Nineteen cadaveric validation studies quantified system accuracy, verified system application, and helped to refine surgical protocol. In two surgeries, navigation and registration accuracy were computed by affixing fiducials to two cadavers prior to surgery. All scenarios compared anatomical angle measurements and joint positioning as measured intraoperatively to postoperatively.
In the two cases with fiducials, computed fragment transformations deviated from measured fiducial transformations by 1.4 and 1.8 mm in translation and 1.0° and 2.2° in rotation, respectively. The additional seventeen surgeries showed strong agreement between intraoperative and postoperative anatomical angles, helped to refine the surgical protocol, and demonstrated system robustness.
Estimated accuracy with BGS appeared acceptable for future surgical applications. Several major system requirements were identified and addressed, improving the BGS and making it feasible for clinical studies.
PMCID: PMC4476510  PMID: 25234421
Periacetabular osteotomy; Developmental dysplasia; Computer-assisted surgery; Orthopedics

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