ANTIFON-CLIC®, a new clinical decision support system for the treatment of invasive aspergillosis: is it clinically relevant?

BACKGROUND: Invasive aspergillosis (IA) is increasing especially in new groups of patients. Despite advances in management, morbidity and mortality related to IA remain high. Thus, Clinical Decision Support System (CDSS) dedicated to IA are needed to promote the optimal antifungal for each group of patients. PATIENTS AND METHODS: This was a retrospective multicenter cohort study involving intensive care units and medical units. Adult patients who received caspofungin, isavuconazole, itraconazole, liposomal amphotericin B, posaconazole, or voriconazole, for the treatment of IA were eligible for enrollment. The primary objective was the concordance between the clinician's prescription and the prescription recommended by the CDSS. The secondary objective was the concordance according to different hospitals, departments, and indications. RESULTS: Eighty-eight patients (n=88) from three medical hospitals were included. The overall concordance was 97% (85/88) including 100% (41/41) for center A, 92% (23/25) for center B, and 95% (21/22) for center C. There was no significant difference in concordance among the hospitals (P=0.973), the departments (P=1.000), and the indications (P=0.799). The concordance was 70% (7/10) for isavuconazole due to its use as an empirical treatment and 100% (78/78) for the other antifungals. DISCUSSION: The concordance rate was high whatever the hospital, the department, and the indication. The only discrepancy was attributed to the use of isavuconazole as an empirical treatment which is a therapeutic option not included in the CDSS. CONCLUSIONS: This new CDSS dedicated to IA is meeting the clinical practice. Its implementation in routine will help to support antifungal stewardship.

[The BSE2 scale : A new clinical tool for the diagnostic of ASD within NDDs]. / L'échelle ECA2 : un nouvel outil clinique pour le diagnostic du TSA au sein des TND.

OBJECTIVES: The behavioral summarized evaluation scales, the BSE and its revised version the BSE-R, were developed and validated in the 1980-1990s. The BSE-R is still used daily by clinical teams in France and foreign countries, and it is recommended by the French Health Authority (2018). Having taken into account knowledge improvement in neurodevelopment and autism spectrum disorder (ASD) and the importance of observation by relatives in ecological context, the second version of the BSE was developed. This paper presents the construction and the validation study of the second version of the behavioral summarized evaluation scale, the BSE2 and the BSE2-P rated by parents. METHODS: Construct validity of the BSE2 scale has been studied in a population of 244 children and adolescents with ASD according to DSM-5 criteria, aged from 30 months to 18 years. Discriminant validity has been analyzed using a population of 86 patients of the same age, with neurodevelopmental disorder (NDD) without comorbidity of ASD. RESULTS: BSE2 comprises 30 items and is a two-dimensional scale as was BSE-R. Both dimensions, labelled "Interaction" (11 items) and "Modulation" (11 items), accounted for 41.7 % of the total variance. They describe autism severity and are in accordance with the two DSM-5 dimensions. Internal consistency (0.927 and 0.850 respectively) and inter-rater reliability (0.932 and 0.897 respectively) are good or excellent for both dimensions. Sensibility and specificity (0.758 and 0.767 respectively) range BSE2 among the tools with good psychometric properties. The parent version, BSE2-P, dedicated to ecological context is easily rated by parents. CONCLUSIONS: BSE2 scale for children and adolescents is a clinical tool with good psychometric properties. Its two-dimensional structure is in accordance with DSM-5 criteria. This scale covers all spectrum of ASD clinical forms in both children and adolescents. It can be used to identify ASD in complex neurodevelopmental disorders with several comorbidities and can help to distinguish autism symptomatology from other neurodevelopmental diagnoses. Furthermore, this scale allows to expand the rating context, involving parents to define and adjust the individualized therapeutic project. Thus the BSE2 is a valuable clinical tool for practitioners for both diagnosis and follow-up.

Renal transplantation outcomes in obese patients: a French cohort-based study.

BACKGROUND: Whilst there are a number of publications comparing the relationship between body mass index (BMI) of kidney transplant recipients and graft/patient survival, no study has assessed this for a French patient cohort. METHODS: In this study, cause-specific Cox models were used to study patient and graft survival and several other time-to-event measures. Logistic regressions were performed to study surgical complications at 30 days post-transplantation as well as delayed graft function. RESULTS: Among the 4691 included patients, 747 patients were considered obese with a BMI level greater than 30 kg/m2. We observed a higher mortality for obese recipients (HR = 1.37, p = 0.0086) and higher risks of serious bacterial infections (HR = 1.24, p = 0.0006) and cardiac complications (HR = 1.45, p < 0.0001). We observed a trend towards death censored graft survival (HR = 1.22, p = 0.0666) and no significant increased risk of early surgical complications. CONCLUSIONS: We showed that obesity increased the risk of death and serious bacterial infections and cardiac complications in obese French kidney transplant recipients. Further epidemiologic studies aiming to compare obese recipients versus obese candidates remaining on dialysis are needed to improve the guidelines for obese patient transplant allocation.

Management of long ureteral stenosis: Alternatives to indwelling ureteral stents.

OBJECTIF: Evaluate kidney autotransplantation (KAT) and ileal ureter substitution (IUS) practice and outcome as alternatives to indwelling ureteral stents for the management of long ureteral stenosis (US). MATERIAL: We included all patients treated for US with KAT or IUS in 5 French university urology centers between 2010 and 2018. We excluded US due to urothelial carcinoma. Primary endpoint was the preservation of ipsilateral kidney and renal function without any urinary diversion. RESULTS: 22 patients were treated with KAT (n=8, 36.4%) and IUS (n=14, 63.6%). Mean US length was 4.6cm and 6cm (P=0.52) in KAT and IUS groups respectively. US etiologies were lithiasis, iatrogenic, retroperitoneal fibrosis or extrinsic compression. US level was varied. The surgery was described as difficult because of peritoneal adhesions or major peri-ureteral fibrosis. Mean operating time and hospital stay were 336 and 346minutes (P=0.87) and 8 and 15 days respectively (P=0.001). Postoperative complications were mostly Clavien ≤2 (n=17, 77.3%). Revision surgery was required in the KAT group in 3 cases (37.5%), for textiles, renal vein thrombosis and anastomotic leak, none in the IUS group. The mean follow-up was 15.7 months. All but one (in the KAT group) ipsilateral kidneys were preserved, without renal function impairment (Δcreat +2.1 vs. +2.4µmol/l respectively, P=0.67), nor urinary diversion. CONCLUSION: KAT and IUS are safe alternatives whose indication depends on surgeons expertise. Our study pointed out the scarcity of this practice suggesting the need to refer patients to expert centers. LEVEL OF EVIDENCE: 3.

[Sensory-psychomotor evaluation in Autism: A new tool for functional diagnosis]. / L'évaluation sensori-psychomotrice dans l'autisme : un nouvel outil d'aide au diagnostic fonctionnel.

INTRODUCTION: Psychomotor impairments in Autism Spectrum Disorders (ASD) have frequently been described in scientific literature. Such deficits impact upon the development of social motor function and interfere with the ability to adjust to everyday life. The inclusion of sensory-motor signs in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) confirms their importance in the diagnosis of ASD. Previous literature has shown the presence precocity of these signs, sometimes before the alteration of the social communication. To our knowledge, there are no existing clinical tools to measure sensory-psychomotor deficit, specifically in ASD. The current paper presents the construction and validation of a new scale, designed to evaluate sensory-psychomotor signs in Autism: 'the Sensory-psychomotor Particularities Scale in Autism' (SPSA). METHOD: The scale is composed of 160 items describing common sensory-psychomotor signs in autism. These items are grouped into 20 variables: touch, nociception, vestibular sensitivity, proprioceptive sensitivity, vision, auditory, multimodality, tone, posture, balance, global coordination, manual dexterity, body schema, bodily self-consciousness, relational adjustment, emotional expression, use of objects, space, time and tonico-emotional regulation. For each item, the psychomotor therapist evaluated sensori-psychomotor signs according to a five-level Likert scale (0="the sign is never expressed by the person", 1="weakly expressed", 2="moderately expressed", 3="severely expressed" and 4="the sign is very characteristic of the person and very severely expressed"). This is completed by a family interview in order to assess the impact of these signs on everyday situations. The study included 111 children with autism. The presence of neurological and genetic diseases was exclusion criteria. For each child, a global developmental evaluation was carried out by an expert clinical team specializing in ASD. Standardized clinical tools were used: Autism Diagnostic Observation Schedule (ADOS), Childhood Autism Rating Scale (CARS), Behavior Summarized Evaluation scale (BSE-R), Repeated and Restricted Behavior scale (RRB), Movement Assessment Battery for Children (M-ABC), Motor Development Rating scale (MDR), Sensory Profile (SP). Developmental quotients (DQ) were evaluated using various tests depending on age and ability. RESULTS: Factor analysis produced three clinically relevant factors: F1: "sensory-emotional synchronization", F2: "multisensory integration" and F3: "motor skills": each containing a similar quantity of items. They account for roughly equal percentages of variance (18.9%, 18.0%, 16.8%, respectively). The factorial structure does not change if the 26 children with comorbid developmental coordination disorder are removed. The three factors show good internal consistency and excellent inter-rater reliability. F1 is comprised of 6 items: touch, nociception, proprioceptive sensitivity, vision, emotional expression and tonico-emotional regulation. This factor is significantly associated with items of the Sensory Profile (touch processing, poor registration, sensory seeking). F2 is comprised of 5 items: multimodality, bodily self-consciousness, relational adjustment, use of objects and space. This factor is associated with ADOS, BSE-R and RRB scores, and the item "touch processing" of the Sensory Profile. F3 is comprised of 4 items: tone, posture, global coordination, manual dexterity. This factor is associated with the M-ABC, the MDR and the item "low endurance" of the Sensory Profile. CONCLUSION: The SPSA is a relevant clinical tool to assess the severity of sensory-psychomotor clinical signs in order to describe the individual profiles of children with ASD. It represents a critical step in advancing knowledge of the complex and heterogeneous pattern of psychomotor development in autism. It could make a valuable contribution to the field, both in research and clinical practice.

Facial emotion recognition in children with or without Attention Deficit/Hyperactivity Disorder: Impact of comorbidity.

OBJECTIVES: This study sought to assess facial emotion recognition deficit in children with Attention Deficit/Hyperactivity Disorder (ADHD) and to test the hypothesis that it is increased by comorbid features. METHOD: Forty children diagnosed with ADHD were compared with 40 typically developing children, all aged from 7 to 11years old, on a computerized facial emotion recognition task (based on the Pictures of Facial Affect). Data from parents' ratings of ADHD and comorbid symptoms (on the Conners' Revised Parent Rating Scale) were also collected. RESULTS: Children with ADHD had significantly fewer correct answer scores than typically developing controls on the emotional task while they performed similarly on the control task. Recognition of sadness was especially impaired in children with ADHD. While ADHD symptoms were slightly related to facial emotion recognition deficit, oppositional symptoms were related to a decrease in the number of correct answers on sadness and surprise recognition. CONCLUSION: Facial emotion recognition deficit in children with ADHD might be related to an impaired emotional process during childhood. Moreover, Oppositional Defiant Disorder seems to be a risk factor for difficulties in emotion recognition especially in children with ADHD.

[Therapeutic education: A lever to change perceptions of bipolar disorder in family caregivers]. / L'éducation thérapeutique : un levier pour modifier les perceptions du trouble bipolaire chez les aidants familiaux.

OBJECTIVES: The patient with bipolar disorder and his family are caught in a reciprocal interaction: on one hand, the pathology leads to family sufferings and on the other hand, family behavior affects the disease of the patient and its development. Therefore, it seems of core importance that the psychologist should work with the family on their perception of bipolar disorder, that is to say, on their knowledge and psychological representations of the pathology. The aim of our study is to assess whether the initial perception of bipolar disorder evolves after a therapeutic education program. METHOD: Our research was conducted at the Bipolar Expertise Centre in Bordeaux/Centre Expert Bipolaire in Bordeaux on a sample of 145 participants (78patients and 67 family caregivers). They were all interviewed before and after the therapeutic education program (12 sessions in 6months). The Brief Illness Perception Questionnaire Revised (Moss-Morris, 2002) measures the perception of bipolar disorder and the BP Quizz (Fondation Fondamental) assesses the degree of knowledge of the disorder. RESULTS: Results show that therapeutic education helps families to level up their knowledge about bipolar disorder. Furthermore, representations on bipolar disorder have globally changed so that on average, bipolar disorder is viewed as less threatening by families after 12 sessions of therapeutic education. More precisely, after the program, families have a better understanding and a better insight of the disorder, which is then perceived as being less severe. On the emotional level, anxiety and stress have decreased. So there are an increase of knowledge and a change in perception. CONCLUSION: Our study shows that the therapeutic education program enables families to change their perception of the disease, that is to say, their knowledge but also their representations of the disease, which is a fundamental element according to the models of therapeutic education. Our results point out one of the active processes of therapeutic education at work in the sessions: in the perception of the disease, which is composed of both knowledge and representations of the disease, just a change in representations constitutes a lever for therapeutic education. Therefore, working on representations should be a therapeutic target. As a conclusion, we can say that therapeutic education of families cannot be reduced to an educational dimension which would only consist of gaining knowledge. Then, the right posture of the psychologist is to hold each participant's own development and changing process of representations.

Using a sequential explanatory mixed method to evaluate the therapeutic window of opportunity for initiating osteoporosis treatment following fragility fractures.

Interventions targeting patients with recent fragility fracture and their physician were most successful at initiating osteoporosis treatment during the first 12 months. This window of opportunity had already closed after 1 year. The reasons for declining or accepting the intensive intervention were explored in patients still untreated at 12 months. INTRODUCTION: A fragility fracture (FF) event identifies patients most likely to benefit from osteoporosis treatment. Nonetheless, most FF patients go untreated. Our objective was to determine how long an incident FF remains a strong incentive to initiate osteoporosis treatment. METHODS: A total of 1086 men and women over age 50 with a recent FF event were assigned to either standard care (SC), to minimal (MIN), or intensive (INT) interventions targeting patients and their family physician to initiate osteoporosis treatment. Inpatients with FF (mainly hip) evaluated by rheumatologists were also included in a specialized group (SPE; n = 324). At 1 year, untreated patients in both the SC and the MIN groups were offered an INT intervention. The cohort was followed through 48 months. A qualitative analysis of patient-centered decision-making associated with initiation of treatment was conducted. RESULTS: In MIN and INT groups, osteoporosis treatment was initiated in 41.0 and 54.3% of untreated patients by 12 months, respectively, compared to 68.4% in SPE and 18.9% in SC groups; initiation rates drastically dropped thereafter. Over 4863 patient-years of follow-up, the rates of new FF were 3.4 per 100 patient-years, without significant differences between patients with initial major or minor FF, nor between control or intervention groups. Failure by patients and physicians to recognize FF as a sign of underlying bone disease contributed the most to lack of treatment. CONCLUSION: While incident FFs are an ideal opportunity for starting osteoporosis treatment, 1 year later, the therapeutic window of opportunity has already closed.

Cracks in Tension-Field Elastic Sheets.

We consider the deformation of a thin elastic sheet which is stiff in traction but very soft in compression, as happens in the presence of wrinkling. We use the tension-field material model and explore numerically the response of a thin sheet containing multiple cracks of different geometries, when subjected to applied tension. With a single crack, the stress concentrates along a St. Andrew's cross-shaped pattern, whose branches extend from the crack tips to the corners of the domain; at a (small) distance r from the crack tip, the stress displays the usual r^{-1/2} stress singularity but with an unusual and nonuniversal angular dependence. A strong interaction between multiple cracks is reported and discussed: in particular, for certain configurations of the cracks, the tensile stiffness of a cracked sheet can be zero even though the sheet is made up of a single component.

Risk of Subsequent Fragility Fractures Observed After Low-Trauma Ankle Fractures.

While fragility fractures (FFs) are one of the strongest predictors of subsequent osteoporotic fractures, it remains unclear whether low-trauma ankle fractures have this ability. The aim of the study was to identify the characteristics of patients with low-trauma ankle FFs who develop subsequent FFs. The OPTIMUS initiative is a strategy to improve osteoporosis treatment post-FF in orthopedic clinics. FRAX scores without BMD (FRAX-BMI) were calculated at time of inclusion. Recurrent FFs were recorded over a 48-month follow-up. All FFs were X-ray-confirmed. A total of 265 patients with initial ankle FF were included (190 women; mean age 62.8 ± 9.6 years), of whom 15 developed new FFs. Patients with ankle FFs had longer time until recurrence and lower 2-year incidence of recurrent FFs (3.2%) compared with those having wrist FFs (9.0%) or other initial FFs (9.6%), and 4-year incidence rates of 6.2, 13.4, and 15.3%, respectively (log-rank test, p = 0.001). With an ankle FF at inclusion, recurrent FFs were more frequent in patients with previous FF (6.2 per 100 patient-years; p < 0.01) or high-risk FRAX-BMI scores pre- or post-FF (2.4 or 2.0 per 100 patient-years, respectively; ns), compared to patients without any of these conditions (0.7 per 100 patient-years). Ankle FFs represent a clinical opportunity for identifying at-risk patients who should be targeted for treatment (previous FFs and/or high-risk FRAX). Because of mechanical factors and other contributors involved, ankle FFs themselves do not predict subsequent FFs overall, and their inclusion in FRAX-BMI risk calculation may thus not be warranted.

Interface bonding in silicon oxide nanocontacts: interaction potentials and force measurements.

The interface bonding between two silicon-oxide nanoscale surfaces has been studied as a function of atomic nature and size of contacting asperities. The binding forces obtained using various interaction potentials are compared with experimental force curves measured in vacuum with an atomic force microscope. In the limit of small nanocontacts (typically <103 nm2) measured with sensitive probes the bonding is found to be influenced by thermal-induced fluctuations. Using interface interactions described by Morse, embedded atom model, or Lennard-Jones potential within reaction rate theory, we investigate three bonding types of covalent and van der Waals nature. The comparison of numerical and experimental results reveals that a Lennard-Jones-like potential originating from van der Waals interactions captures the binding characteristics of dry silicon oxide nanocontacts, and likely of other nanoscale materials adsorbed on silicon oxide surfaces. The analyses reveal the importance of the dispersive surface energy and of the effective contact area which is altered by stretching speeds. The mean unbinding force is found to decrease as the contact spends time in the attractive regime. This contact weakening is featured by a negative aging coefficient which broadens and shifts the thermal-induced force distribution at low stretching speeds.

[Validation in Arabic of the Revised Autistic Behavior Summarized Evaluation Scale (BSE-R)]. / Validation en arabe de l'Échelle d'Évaluation des Comportements Autistiques, version Révisée (ECA-R).

The Behavioral Summarized Evaluation is a rating scale specifically related to the assessment of autistic behaviors in children and young teenagers with Autism Spectrum Disorder, such as communication, social interaction and interests. It also facilitates progressive recording of the evolution of children with ASD involved in short-term therapeutical studies. In the absence of standardized tools to assess autistic behaviors and effects of therapeutics in Lebanon, the BSE-R validation is an urgent need. The purpose of this study is to validate the BSE-R to the Lebanese population. METHOD: Specialized translators and clinicians ensured forward and backward translation of the scale into Arabic. The participants consisted of 100 children with ASD, diagnosed upon DSMIV-TR criterion (age range: 35 to 153 months, DS: 28.0). Fifty-eight had intellectual disability (ID). Scores of autism severity as measured by CARS1 (Schopler et al., 1980) varied from 20-58.5. Trained raters on recorded individual and group situations performed BSE-R ratings. RESULTS: BSE-R for Lebanese was found to have excellent inter-rater reliability. The internal validity highlighted a main factor which describes the severity of core autistic behaviors related to social interactions and communication, and behavioral specificities and particular interests with an internal consistency of 0.91 in a one-to-one setting and 0.92 in group settings. External validity of the scale as measured by correlations with CARS and the age of the children showed that this main factor is essentially determined by ASD severity, not by the severity of ID. It was named "relational deficiency" according to the initial paper of Barthélémy et al. (1997). CONCLUSION: BSE-R in Arabic is a practical tool, useful to all team members working with ASD children in Lebanon and the Arab countries. It will also allow future research based on reliable tools at an international level.

Impact of the addition of a nitrifying activated sludge on ammonia oxidation during composting of residual household wastes.

AIMS: To investigate the nitrogen-microbial community dynamics during composting of a mixture of nitrifying waste activated sludge (WAS) and fine organic fraction of residual household waste (RHW). To examine whether the addition of nitrifying sludge could promote ammonia oxidation and reduce ammonia emissions. METHODS AND RESULTS: The fine organic fraction of RHW was mixed with the WAS and homogenized. The mixture and each waste alone were loaded in aerobic cells under controlled conditions, respectively. Both nitrogen and microbial community dynamics were monitored during 50 days of composting. The ammonia oxidizers were quantified and identified in the sludge and compost. The changes in ammonia-oxidizing bacteria (AOB) concentrations corresponded to the ammonia oxidation rates calculated from nitrogen balance. The addition of WAS did not efficiently reduce ammonia emissions because the Nitrosomonas oligotropha-like AOB introduced declined during the active stage of composting. Ammonia oxidation was probably limited by the intense heterotrophic activities at the active stage. Nitrosomonas europaea/eutropha and Nitrosomonas nitrosa-like AOB were established only during the maturation stage. They were the main contributors to ammonia oxidation during composting. CONCLUSIONS: The mixing of nitrifying WAS with the RHW during the early stages of composting does not promote ammonia oxidation nor reduce ammonia emissions because of limiting biologic factors during the active stage of composting. SIGNIFICANCE AND IMPACT OF THE STUDY: The mixing of activated sludge with RHW before composting is a common practice on composting plants. This study proved the limitation of this practice to reduce ammonia emissions during composting via bioaugmentation of ammonia-oxidizing organisms. It correlated successfully the ammonia oxidation rate with different groups of ammonia oxidizers and explains the fail of promoting ammonia oxidation during the early stages of composting. It suggests Nit. europaea/eutropha and Nit. nitrosa-like AOB were the main contributors to ammonia oxidation during composting.

Unravelling caramelization and Maillard reactions in glucose and glucose + leucine model cakes: Formation and degradation kinetics of volatile markers extracted during baking.

A large number of volatile compounds are formed during the baking of foods by reactions such as caramelization and Maillard reactions. Elucidating the reaction mechanisms may be useful to predict and control food quality. Ten reaction volatile markers were extracted during baking of solid model cakes implemented with known amounts of precursors (glucose with or without leucine) and then quantified by Thermal desorption-Gas chromatography-Mass spectrometry. The kinetic data showed that the level of air convection in the oven had no significant influence on the reaction rates. In contrast, increasing baking temperatures had a nonlinear accelerating impact on the generation of newly formed volatile compounds with a bell-shaped kinetic curve found for most of the markers at 200 °C. The presence of leucine triggered the activation of the Maillard and Strecker routes with a specific and very rapid formation of 3-Methylbutanal and pyrazines. A dynamic model was developed, combining evaporation flow rate and kinetic formation and consumption of reaction markers. It can be used to describe, for two furanic compounds of different volatilities, the vapor concentrations in the oven from the concentrations measured in the model cakes.

The natural history of clinical operational tolerance after kidney transplantation through twenty-seven cases.

We report here on a European cohort of 27 kidney transplant recipients displaying operational tolerance, compared to two cohorts of matched kidney transplant recipients under immunosuppression and patients who stopped immunosuppressive drugs and presented with rejection. We report that a lower proportion of operationally tolerant patients received induction therapy (52% without induction therapy vs. 78.3%[p = 0.0455] and 96.7%[p = 0.0001], respectively), a difference likely due to the higher proportion (18.5%) of HLA matched recipients in the tolerant cohort. These patients were also significantly older at the time of transplantation (p = 0.0211) and immunosuppression withdrawal (p = 0.0002) than recipients who rejected their graft after weaning. Finally, these patients were at lower risk of infectious disease. Among the 27 patients defined as operationally tolerant at the time of inclusion, 19 still display stable graft function (mean 9 ± 4 years after transplantation) whereas 30% presented slow deterioration of graft function. Six of these patients tested positive for pre-graft anti-HLA antibodies. Biopsy histology studies revealed an active immunologically driven mechanism for half of them, associated with DSA in the absence of C4d. This study suggests that operational tolerance can persist as a robust phenomenon, although eventual graft loss does occur in some patients, particularly in the setting of donor-specific alloantibody.

Immunohistochemistry to identify EGFR mutations or ALK rearrangements in patients with lung adenocarcinoma.

BACKGROUND: Immunohistochemistry has been proposed as a specific and sensitive method to identify EGFR mutations or ALK rearrangements in lung tumours. PATIENTS AND METHODS: We assessed EGFR and KRAS by direct sequencing in 154 patients with lung adenocarcinoma. ALK rearrangements were assayed by FISH and RT-PCR. Immunohistochemistry was carried out and evaluated closely following published methods using recommended monoclonal rabbit or mouse antibodies. RESULTS: Thirteen of 36 exon 19 EGFR-mutated tumours (36%)-including 12 of 22 with p.Glu746_Ala750del (55%)-were positive with the 6B6 antibody that was raised against p.Glu746_Ala750del. One hundred eleven of 114 EGFR exon 19 wild-type tumours (97%) were negative with 6B6. Four of 21 exon 21 EGFR-mutated tumours (19%)-including 4 of 17 with p.Leu858Arg (24%)-were positive with the 43B2 antibody that was raised against p.Leu858Arg. One hundred twenty-two of 124 (98%) EGFR exon 21 wild-type tumours were negative with 43B2. Two of four ALK rearrangements-including two of three with ELM4-ALK fusion transcripts-were identified with the 5A4 antibody. Eleven of 13 tumours without ALK rearrangement (85%) were negative with 5A4. CONCLUSIONS: Immunohistochemistry is a specific means for identification of EGFR mutations and ALK rearrangements. It suffers, however, from poor sensitivity.

Tackiness and cohesive failure of granular pastes: mechanistic aspects.

Granular pastes are dense dispersions of non-colloidal grains in a simple or a complex fluid. Typical examples are the coating, gluing or sealing mortars used in building applications. We study the rupture of a thick layer of mortar paste in a simple pulling test where the paste is confined between two flat surfaces. It is shown that, depending on the rheological properties of the paste and the plate separation velocity, two main failure modes are obtained. The first mode is the inwards shear flow of the paste with viscous fingering instabilities, similarly to what has been observed with Newtonian fluids and with non-Newtonian colloidal suspensions or polymer solutions. The second failure mode is stemming from the expansion of bubbles, similarly to what has been observed in soft adhesive polymer layers and, more recently, in highly viscous fluids. It is shown that the crossover between the two failure modes is determined by the conditions required to generate a pressure drop able to trigger the growth of pre-existing micro-bubbles smaller than the inter-granular distance.

Multilevel modeling in food science: A case study on heat-induced ascorbic acid degradation kinetics.

Characterization of variation of experimental results is achieved by repeating experiments. Frequently, results are averaged before data are analysed but that may not be the best practice because valuable information is then lost. Three other ways to analyze repetitions are: (1) each experiment is analyzed on its own (no pooling of data), (2) all experiments are analyzed together in one go (complete pooling), (3) data are analyzed together while allowing for similarities as well as differences in the result (partial pooling). Multilevel modeling uses partial pooling by partitioning variance over more than one level. Level 1 consists of the measurements themselves; higher levels consist of groups or clusters of measurements (repetitions, experiments at various temperatures, at various pH values, etc.) and parameters are analyzed both at the population and at the group/cluster level. The approach is applied to a case study in which heat-induced isothermal degradation of ascorbic acid was studied with 15 repetitions in an aqueous solution, making it a two-level study. The data were analyzed using averaging and complete pooling, complete pooling without averaging, no-pooling at all, and partial pooling. The kinetic model was established by letting the data decide about the order of the reaction, while this was compared to a model where the order was fixed at 1 (first-order model). Results show that both averaging with complete pooling, as well as complete pooling without averaging, strongly underestimate variation. The no-pooling technique overestimates variation, while partial pooling partitions variation over the levels and thus gives a better impression of the variation involved. The kinetics of ascorbic acid appear to be subject to strong variation when each experiment is considered separately because it is a compound that is very sensitive to all kinds of experimental conditions. With multilevel modeling it appeared to be possible to characterize the uncertainties involved much better than with single level modeling. A Bayesian analysis was performed, in which parameters are allowed to be variable, which is useful because multilevel modeling leads to characterization of variation of parameters. The Bayesian method allows to visualize the posterior distribution of parameters, thereby giving more insight in their behaviour. Also, a Bayesian analysis focuses more strongly on predictive accuracy of models, including multilevel models. The predictive accuracy of 4 models describing the same ascorbic acid data was compared and the multilevel model with reaction order estimated from the data performed by far the best in this regard. The pros and cons of multilevel modeling are discussed and it is concluded that multilevel modeling is to be preferred whenever the data allow to perform such an analysis.