Setting up pharmacovigilance based on available endTB Project data for bedaquiline.

SETTING: Active pharmacovigilance (PV) is recommended for TB programmes, notably for multidrug-resistant TB (MDR-TB) patients treated with new drugs. Launched with the support of UNITAID in April 2015, endTB (Expand New Drug markets for TB) facilitated treatment with bedaquiline (BDQ) and/or delamanid of >2600 patients in 17 countries, and contributed to the creation of a central PV unit (PVU).OBJECTIVE: To explain the endTB PVU process by describing the serious adverse events (SAEs) experienced by patients who received BDQ-containing regimens.DESIGN: The overall PV strategy was in line with the 'advanced´ WHO active TB drug safety monitoring and management (aDSM) system. All adverse events (AEs) of clinical significance were followed up; the PVU focused on signal detection from SAEs.RESULTS and CONCLUSION: Between 1 April 2015 and 31 March 2019, the PVU received and assessed 626 SAEs experienced by 417 BDQ patients. A board of MDR-TB/PV experts reviewed unexpected and possibly drug-related SAEs to detect safety signals. The experts communicated on clusters of risks factors, notably polypharmacy and off-label drug use, encouraging a patient-centred approach of care. Organising advanced PV in routine care is possible but demanding. It is reasonable to expect local/national programmes to focus on clinical management, and to limit reporting to aDSM systems to key data, such as the SAEs.

Tumour response 3 months after neoadjuvant single-fraction radiotherapy for low-risk breast cancer.

Introduction: Standard treatment for early-stage invasive breast cancer (bca) consists of breast-conserving surgery and several weeks of adjuvant radiotherapy (rt). Neoadjuvant single-fraction rt is a novel approach for early-stage bca. We sought to investigate the effect of delaying surgery after neoadjuvant rt with respect to the rate of pathologic response (pr). Methods: Women 65 years of age or older with a new diagnosis of stage i luminal A bca were eligible for inclusion. A single 20 Gy dose to the primary breast tumour was given, followed by breast-conserving surgery 3 months later. The primary endpoint was the pr rate assessed by microscopic evaluation using the Miller-Payne system. Results: To date, 10 patients have been successfully treated. Median age of the patients was 72 years (range: 65-84 years). In 8 patients, neoadjuvant rt resulted in a tumour pr with median residual cellularity of 3%. No immediate rt complications other than mild dermatitis were noted. Conclusions: This study demonstrates a method for delivering single-fraction rt that can lead to a high level of pr in most patients. Continued accrual to this study and subsequent trials are needed to determine the feasibility, safety, and role of this novel technique in the management of early-stage bca.

Nitrous oxide, methane and carbon dioxide patterns and dynamics from an experimental pig mass grave.

The objective of the three-year study was to examine spatial and temporal patterns of fluxes and soil pore air concentrations of methane (CH4), carbon dioxide (CO2) and nitrous oxide (N2O) from an experimental mass grave located in a temperate environment. The mass grave (5×10m) contained twenty pig carcasses at a depth of approximately 1m was compared to a plot of the same dimensions containing only disturbed soil, as well as an undisturbed plot. Soil pore air CH4 concentrations were sub-ambient (<1.8ppm) except at 75 and 100cm depths at the mass grave in years 1 and 2 but decreased in year 3. The consumption of CH4 within the aerobic soil resulted in small negative fluxes at the soil surface. Soil pore air CO2 concentration showed an increase with depth in all three plots, with the largest increase (>100,000ppm at 1m) in the mass grave, though there was a marked decrease from years 1 to 3. Surface fluxes of CO2 showed strong seasonal variations, peaking in summer. Soil pore air N2O concentration showed major increases in the mass grave, compared to the other two plots with the pattern maintained over the three years, resulting in larger surface fluxes of N2O. To establish the role of the carcasses in N2O dynamics, we incubated a soil sample containing carcass material which resulted in fast rates of N2O production and consumption. The maintenance of elevated pore air concentration and surface flux of N2O throughout the 3 years suggests that this is a long-term pattern and likely the best of the three gases to use to detect graves. Thus, we suggest that measurement of soil pore air concentrations, especially of N2O, could be a simple and effective approach to help determine the location of clandestine graves.

[Characteristics, diseases and mortality of people admitted to nursing homes for dependent seniors during the first quarter of 2013 in France]. / Caractéristiques, pathologies et mortalité des résidents en établissements d'hébergement pour personnes âgées dépendantes (Ehpad) admis au cours du premier trimestre 2013 en France.

BACKGROUND: To describe the state of health, through healthcare consumption and mortality, of people admitted to nursing homes (Ehpad) in France. METHODS: People over the age of 65 years admitted to an Ehpad institution during the first quarter of 2013, beneficiaries of the national health insurance general scheme (69% of the population of this age), were identified from the Resid-Ehpad database and their reimbursed health care was extracted from the SNIIRAM database, identifying 56 disease groups by means of algorithms (long-term disease diagnoses and hospitalisations, medicinal products, specific procedures). Disease prevalences were compared to those of other beneficiaries by age- and sex-standardized morbidity/mortality ratios (SMR). RESULTS: A total of 25,534 people were admitted (mean age: 86 years, 71% women). Before admission, these people presented a marker for cardiovascular or neurovascular disease (48% of cases), dementia (34%), cancer (18%), and psychiatric disorders (14%). Compared to non-residents, new residents more frequently presented dementia (SMR=3-40 according to age and sex), psychiatric disorders (SMR=2.5-12, including psychotic disorders SMR=18-21 in the 65-74 year age-group), neurological disorders (SMR=2-12, including epilepsy SMR=14 in the 65-74 year age-group), and cardiovascular and neurovascular disease (SMR=1.2-3). Overall mortality in 2013 was 22%, with a maximum excess between the ages of 65-74 years (males, SMR=8.8, females, SMR=15.9). CONCLUSION: Medical and administrative data derived from linking the Resid-Ehpad/Sniiram databases reveal a severely impaired state of health, considering healthcare use of institutionalized dependent elderly people, and a high prevalence of diseases responsible for severe dependence and excess mortality, especially among the younger residents.

Nitrous oxide, methane and carbon dioxide dynamics from experimental pig graves.

Twelve pig carcasses were buried in single, shallow and deep (30 and 90 cm, respectively) graves at an experimental site near Ottawa, Ontario, Canada, with three shallow and three deep wrapped in black plastic garbage bags. An additional six carcasses were left at the surface to decompose, three of which were bagged. Six reference pits without remains were also dug. The objective of this three-year study was to examine the biogeochemistry and utility of nitrous oxide (N2O), methane (CH4) and carbon dioxide (CO2) in grave detection and whether grave depth or cadaver condition (bagged versus bare) affected soil pore air concentrations and emission of the three gases. Graves showed significantly higher (α=0.05) concentrations and surface fluxes of N2O and CO2 than reference pits, but there was no difference in CH4 between graves and reference pits. While CH4 decreased with depth in the soil profiles, N2O and CO2 showed a large increase compared to reference pits. Shallow graves showed significantly higher emissions and pore air concentrations of N2O and CO2 than deep graves, as did bare versus bagged carcasses.

Detection of single graves by airborne hyperspectral imaging.

Airborne hyperspectral imaging (HSI) was assessed as a potential tool to locate single grave sites. While airborne HSI has shown to be useful to locate mass graves, it is expected the location of single graves would be an order of magnitude more difficult due to the smaller size and reduced mass of the targets. Two clearings were evaluated (through a blind test) as potential sites for containing at least one set of buried remains. At no time prior to submitting the locations of the potential burial sites from the HSI were the actual locations of the sites released or shared with anyone from the analysis team. The two HSI sensors onboard the aircraft span the range of 408-2524nm. A range of indicators that exploit the narrow spectral and spatial resolutions of the two complimentary HSI sensors onboard the aircraft were calculated. Based on the co-occurrence of anomalous pixels within the expected range of the indicators three potential areas conforming to our underlying assumptions of the expected spectral responses (and spatial area) were determined. After submission of the predicted burial locations it was revealed that two of the targets were located within GPS error (10m) of the true burial locations. Furthermore, due to the history of the TPOF site for burial work, investigation of the third target is being considered in the near future. The results clearly demonstrate promise for hyperspectral imaging to aid in the detection of buried remains, however further work is required before these results can justifiably be used in routine scenarios.

Prolonged Therapy with Imatinib Mesylate before Surgery for Advanced Gastrointestinal Stromal Tumor Results of a Phase II Trial.

Purpose. Proven efficacy of imatinib mesylate in gastrointestinal stromal tumour (GIST) has led to its use in advanced disease and, more recently, in adjuvant and neoadjuvant settings. The purpose of this study was to evaluate the optimal neoadjuvant imatinib duration to reduce the morbidity of surgery and increase the possibility of resection completeness in advanced tumours. Patients and Method. Patients with advanced GIST were enrolled into a registered open-label multicenter trial and received imatinib daily for a maximum of 12 months, followed by en bloc resection. Data were prospectively collected regarding tumour assessment, response rate, surgical characteristics, recurrence, and survival. Results. Fourteen patients with advanced GIST were enrolled. According to RECIST criteria, 6 patients had partial response and 8 had stable disease. The overall tumour size reduction was 25% (0-62.5%), and there was no tumour progression. Eleven patients underwent tumour resection, and all had R0 resection. After a median followup of 48 months, 4-year OS and DFS were 100% and 64%, respectively. Conclusion. This prospective trial showed that one year of neoadjuvant imatinib in advanced GIST is safe and associated with high rate of complete microscopic resection. It is not associated with increased resistance, progression, or complication rates.

G117C MelB, a mutant melibiose permease with a changed conformational equilibrium.

Replacement of the glycine at position 117 by a cysteine in the melibiose permease creates an interesting phenotype: while the mutant transporter shows still transport activity comparable to the wild type its pre steady-state kinetic properties are drastically altered. The transient charge displacements after substrate concentration jumps are strongly reduced and the fluorescence changes disappear. Together with its maintained transport activity this indicates that substrate translocation in G117C melibiose permease is not impaired but that the initial conformation of the mutant transporter differs from that of the wild type permease. A kinetic model for the G117C melibiose permease based on a rapid dynamic equilibrium of the substrate free transporter is proposed. Implications of the kinetic model for the transport mechanism of the wild type permease are discussed.

When cats' ways of life interact with their viruses: a study in 15 natural populations of owned and unowned cats (Felis silvestris catus).

In natural populations, virus circulation is influenced by host behavior and physiological characteristics. Cat populations exhibit a great variability in social and spatial structure, the existence of different ways of life within a same population may also result in different epidemiological patterns. To test this hypothesis, we used a logistic regression to analyze the risk factors of Feline immunodeficiency virus (FIV), feline herpes virus (FHV), feline calicivirus (FCV), and feline parvovirus (FPV) infection in owned (fed and sheltered) and unowned (neither fed nor sheltered, unsocialized) cats living in a rural environment in the North Eastern part of France. A serological survey was carried out in 492 non-vaccinated and non-sterilized individuals from 15 populations living in the same area. The prevalence of feline leukemia virus (FeLV) was also studied, but too few were infected to analyze the risk factors of this virus. For each virus, the epidemiological pattern was different in owned and unowned cats. Unowned cats were more frequently infected by directly transmitted viruses like FIV, FHV and FCV (21.22%, 67.66%, 86.52% in unowned cats vs 9.55%, 53.88%, 77.18% in owned cats, respectively), a difference that may be explained by a more solitary and more aggressive behavior in unowned adults, and/or possibly by a higher sensitivity related to a more stressful life. On the contrary, owned cats were more frequently infected with FPV (36.41% in owned cats vs 15.61% in unowned cats), possibly as a result of their concentration around human settlements. The present study showed that owned and unowned cats living in a same area have behavioral and physiological characteristics sufficiently different to influence virus circulation. Pooling different types of cats in a single sample without taking it into account could give a wrong picture of the epidemiology of their viruses. The conclusion of this work can be extended to any epidemiological studies led in wildlife species with flexible behavior as any variations in social or spatial structure, between or within populations, could result in different virus circulation.

Validation study of the s classification for melanoma patients with positive sentinel nodes: the Montreal experience.

BACKGROUND: Standard of care is to perform a complete lymph node dissection (CLND) in melanoma patients with positive sentinel lymph nodes (SLNs). However, less than 20% will have metastases in non-SLNs. The S classification was described to predict the non-SLN status, hoping to identify a subset of patients who can be spared the CLND. We tried to validate the feasibility and usefulness of this classification. MATERIALS AND METHODS: We performed a retrospective chart review. All melanoma cases between 1996 and 2006 were included, and 359 patients with SLN biopsies were identified. All pathology slides were reviewed with an emphasis on the S classification. RESULTS: There were 365 SLN biopsies performed. A total of 82 patients (22.8%) had positive SLNs, while 277 patients (77.2%) had negative SLNs. There were 22 patients classified as SI, 18 as SII, 37 as SIII, and 5 were unclassified. On CLND, only 10 patients (12.2%) had positive non-SLNs. None of these were classified as SI while 2 patients (11%) were classified as SII and 8 (22%) as SIII. The S category was found to be a predictor of non-SLN status, and this reached statistical significance (P = 0.044). On univariate analysis, only an increasing Breslow depth and ulceration were predictive of a non-SI status. CONCLUSION: Our results suggest that the S classification is easily feasible and predicts the status of non-SLNs. No patient with SI status was found to have additional non-SLN positive nodes. A larger-scale, prospective trial should be done to confirm these results and possibly spare patients the morbidity of CLND with a positive SLN.

Predictive modeling of a mixture of thyroid hormone disrupting chemicals that affect production and clearance of thyroxine.

Thyroid hormone (TH) disrupting compounds interfere with both thyroidal and extrathyroidal mechanisms to decrease circulating thyroxine (T(4)). This research tested the hypothesis that serum T(4) concentrations of rodents exposed to a mixture of both TH synthesis inhibitors (pesticides) and stimulators of T(4) clearance in the liver (polyhalogenated aromatic hydrocarbons, PHAHs) could be best predicted by an integrated addition model. Female Long-Evans rats, 23 days of age, were dosed with dilutions of a mixture of 18 PHAHs (2 dioxins, 4 dibenzofurans, and 12 PCBs, including dioxin-like and non-dioxin like PCBs) and a mixture of 3 pesticides (thiram, pronamide, and mancozeb) for four consecutive days. Serum was collected 24 hours after the last exposure and T(4) concentrations were measured by radioimmunoassay. Animals exposed to the highest dose of the mixture experienced a 45% decrease in serum T(4). Three additivity model predictions (dose addition, effect addition, and integrated addition) were generated based on single chemical data, and the results were compared. Effect addition overestimated the effect produced by the combination of all 21 chemicals. The results of the dose- and integrated-addition models were similar, and both provided better predictions than the effect-addition model. These results support the use of dose- and integrated additivity models in predicting the effects of complex mixtures.

A comparative study on androgen metabolism in three invertebrate species.

A comparative approach was taken in this study to evaluate androgen (androstenedione and testosterone) metabolism in three invertebrate species: the gastropod Marisa cornuarietis, the amphipod Hyalella azteca, and the echinoderm Paracentrotus lividus. The existence of 17beta/3beta-hydroxysteroid dehydrogenase (HSD) and 5alpha-reductase catalyzed reactions was demonstrated in all three species. Androstenedione was primarily converted to 5alpha-androstanedione in M. cornuarietis, while it was primarily metabolized to testosterone in P. lividus and H. azteca. In addition, and consistent with vertebrate findings, tissue specific pathways and sexual dimorphism in androgen metabolism were observed. Namely, testosterone was metabolized to dihydrotestosterone in P. lividus gonads (via 5alpha-reductase), and metabolized to 4-androstene-3beta,17beta-diol in the digestive tube (via 3beta-hydroxysteroid dehydrogenase). Furthermore, the synthesis of 17beta-reduced metabolites of androstenedione (testosterone and dihydrotestosterone) was 3- to 4-fold higher in males of M. cornuarietis than in females. Organotin compounds, which have been shown to interfere with some aspects of androgen metabolism, had no major effect on testosterone metabolism in any of the three species. Fenarimol enhanced 5alpha-reductase-mediated catalysis in gonads of P. lividus. Overall, results demonstrate the ubiquity of some androgen biotransformation processes in invertebrates and reveals interphyla differences in androgen metabolic pathways, and different sensitivity of these pathways to some xenobiotics.

Androgen metabolism in invertebrates and its modulation by xenoandrogens: a comparative study.

Marisa cornuarietis (Mollusc), Hyalella azteca (Crustacean), and Paracentrotus lividus (Echinoderm) demonstrated the ability to metabolize androgens through different pathways catalyzed by 5alpha-reductases (5alpha-R), hydroxysteroid dehydrogenases (HSD), hydroxylases, sulfotransferases (SULT), and fatty-acid acyl-CoA acyltransferases (ATAT). Interspecies differences and tissue-specific distribution of those enzymatic activities were observed. Xenobiotics, such as triphenyltin, tributyltin, and fenarimol, interfered with some of the pathways studied, namely, testosterone sulfation, testosterone esterification, and 5alpha-R activity. The work evidenced different sensitivity of those pathways to androgenic compounds, together with interphyla differences in androgen metabolism.

Testosterone conjugating activities in invertebrates: are they targets for endocrine disruptors?

Testosterone conjugation activities, microsomal acyltransferases and cytosolic sulfotransferases, were investigated in three invertebrate species, the gastropod Marisa cornuarietis, the amphipod Hyalella azteca, and the echinoderm Paracentrotus lividus. The goals of the study were to characterize steroid conjugation pathways in different invertebrate phyla and to assess the susceptibility of those processes to disruption by environmental chemicals. All three species exhibited palmitoyl-CoA: testosterone acyltransferase activity (ATAT) in the range of 100-510 pmol/min/mg protein. Despite similarities in specific activities, kinetic studies indicated that ATAT had a higher affinity for testosterone but a lower V(max) in M. cornuarietis than in P. lividus, and intermediate values were found for H. azteca. In contrast, the activity of testosterone sulfotransferase (SULT) was rather low (0.05-0.18 pmol/min/mg protein) in M. cornuarietis and H. azteca. The low activity precluded kinetic analyses and inhibition studies with these species. P. lividus digestive tube displayed high SULT activity (50-170 pmol/min/mg protein) at moderate testosterone concentrations, but was inhibited at high testosterone concentrations. The interference of model pollutants (triphenyltin (TPT), tributyltin (TBT), and fenarimol) with these conjugation pathways was investigated in vitro. Both TPT and TBT (100 microM) inhibited ATAT in P. lividus (68 and 42% inhibition, respectively), and appeared to act as non-competitive inhibitors. ATAT activity in M. cornuarietis was less affected by organotins, and a significant inhibition (20% inhibition) was detected only with TBT. Fenarimol (100 microM) did not affect ATAT in any of the species tested. Sulfation of testosterone was suppressed by the organotins as well as fenarimol when using cytosolic preparations from P. lividus. These results demonstrated the existence of interphyla differences in testosterone conjugation, and revealed that these processes can serve as targets for endocrine disrupting chemicals.

[Transradial approach for diagnostic angiography]. / Artériographie diagnostique par voie transradiale.

Seventy five arteriographies were performed via the transradial route using 5F 130cm - long catheter. Prior to puncture the radial artery was evaluated with Allen test. Satisfying quality examinations were obtained for the thoracic aorta, selective carotid arteries examinations, infra renal aorta, pelvic and legs arteries. The major advantages obtained for the technique were the very low rate complication and technical failure. Transradial route for arteriography is a reasonable alternative approach to transfemoral or brachial arteriography for out patient management (peripheral angiography) in case in which transfemoral route is not feasible but also with patients with important haemorragic-risks.

[Aneurysm of the persistent sciatic artery]. / Anévrisme de l'artère sciatique persistante.

The authors report a case of persistent sciatic artery presenting with limb ischemia and pulsatile mass in the buttock treated only by femoro tibio peroneal by pass graft since follow up helical CTA at six months showed spontaneous aneurysmal exclusion by thrombosis of the persistent sciatic artery above the aneurysm. Review of the literature confirms the rarity of this anomaly, which is frequently associated with aneurysmal transformation and its specific inherent complications. It is treated by femoro popliteal shunt with endovascular embolization.

[Endovascular embolization of a splenic aneurysm and of a false aneurysm of the splenic artery]. / Traitement d'un anévrisme et d'un faux anévrisme spléniques par embolisation artérielle percutanée.

Splenic artery aneurysms, once considered rare entities are now being reported with increasing frequency. Rupture may be the presenting and only symptom and can be fatal. The authors present two cases of splenic aneurysms treated by endovascular embolization. The initial imaging work-up included sonography, angiography and helical computed tomography with multiplanar and 3D reformations. This enabled comprehensive evaluation of the aneurysms, including their configuration, essential for coil selection. Embolization was uneventful. Post-embolization angiograms confirmed exclusion of the aneurysms. Follow-up CT at 9 months showed complete thrombosis of the aneurysms and no evidence of pancreatic or splenic complication. Endovascular management for definitive treatment of splenic aneurysms is technically possible and should be considered.

Alterations in sexually dimorphic biotransformation of testosterone in juvenile American alligators (alligator mississippiensis) from contaminated lakes.

The goal of this study was to determine whether hepatic biotransformation of testosterone is normally sexually dimorphic in juvenile alligators and whether living in a contaminated environment affects hepatic dimorphism. Lake Woodruff served as our reference site. Moonshine Bay, located on the west side of Lake Okeechobee, served as an intermediate site. Lake Apopka, the Belle Glade area located at the south end of Lake Okeechobee, and Water Conservation Area 3A, in the northern Everglades, served as our contaminated sites (all lakes are in Florida). Normal testosterone hydroxylase activity exhibited sexually dimorphic patterns of expression, with reference animals from Lake Woodruff exhibiting a female:male ratio of 1.44. This pattern was perturbed in all of the intermediate and contaminated sites investigated. Normal testosterone oxido-reductase activity exhibited sexually dimorphic expression (Lake Woodruff female:male ratio of 1.45). This pattern was altered in all contaminated sites investigated. UDP-Glucuronosyltransferase activity exhibited no sexually dimorphic pattern in animals collected from our reference site, with Lake Woodruff animals exhibiting a female:male ratio of 1.06. This pattern was perturbed in animals from Water Conservation Area 3A, which exhibited a female:male ratio of 0.65. Sulfotransferase activity demonstrated no sexual dimorphism at any of the sites investigated, although elevated activity was observed in males from the Lake Okeechobee watershed compared to those from Lake Woodruff. These data demonstrate different patterns of hepatic androgen biotransformation in animals living in contaminated environments.