First direct evidence of lion hunting and the early use of a lion pelt by Neanderthals.

During the Upper Paleolithic, lions become an important theme in Paleolithic art and are more frequent in anthropogenic faunal assemblages. However, the relationship between hominins and lions in earlier periods is poorly known and primarily interpreted as interspecies competition. Here we present new evidence for Neanderthal-cave lion interactions during the Middle Paleolithic. We report new evidence of hunting lesions on the 48,000 old cave lion skeleton found at Siegsdorf (Germany) that attest to the earliest direct instance of a large predator kill in human history. A comparative analysis of a partial puncture to a rib suggests that the fatal stab was delivered with a wooden thrusting spear. We also present the discovery of distal lion phalanges at least 190,000 old from Einhornhöhle (Germany), representing the earliest example of the use of cave lion skin by Neanderthals in Central Europe. Our study provides novel evidence on a new dimension of Neanderthal behavioral complexity.

Mind-body and art therapies impact on emotional regulation in patients with chronic diseases: a pragmatic mixed-methods randomized controlled trial.

BACKGROUND: Effective emotional regulation is recognized as essential to a good mental health of people with chronic diseases, and Mind-body and Art Therapies (MBATs) could have a positive effect on emotional regulation skills in this population. Thus, we aimed to evaluate the effect of MBATs on emotional regulation as measured by the Difficulties in Emotion Regulation Scale (DERS) questionnaire. METHODS: A convergent mixed approach nested in a pragmatic superiority two arms parallel randomized controlled trial was conducted. French speaking adults with one or more chronic somatic illnesses and not suffering from a chronic psychiatric disorder unrelated to one of their chronic somatic illness were included. At inclusion, non-directive interviews were conducted, followed by an initial DERS assessment. The same combination of evaluation was implemented after 6 months of activity (T1). After inclusion, each participant was randomized within either the intervention group (G1) or the control group (G2) following a controlled wait-list design by use of a pregenerated randomization list. Staff and patient were blinded to this list until the initial evaluation was completed, after which the trial was conducted in an open-label fashion. Participants chose 2 mediations: one creativity-focused (art-therapy, writing workshop, theatre of life, vocal workshop) and one mind-body-focused (mindfulness meditation, Pilates, shiatsu, ayurvedic massages). G1 started their mediations immediately after inclusion, while G2 started 6 months later. Primary outcome was the change in means at 6 months in the overall DERS score compared between each group. Non-directive interviews were carried out at the inclusion and after 6 months of MBATs. A continuous inductive analysis was carried out on gathered material in G1 to explore the participants' experiences regarding their disease and their perceived changes associated to the intervention. RESULTS: A total of 150 patients was randomized (75 per groups) at the end of the study. At T1, 133 patients filled out the final questionnaire (67 in G1 vs 66 in G2) and 112 interviews were analysed (54 in G1 vs 58 in G2). All 150 patients were analysed (intention to treat) using a multiple imputation approach. The mean DERS score at T0 was equal to 82.8 ± 21.1 and 85.0 ± 20.2 in G1 and G2 respectively. On average, at T1, the score decreased in the G1 (Δ = -4.8, SD = 21.3) and in G2 (Δ = -0.11, SD = 17.8). The difference in decrease, however, was not statistically significant (p = 0.13). Qualitative analysis underlined some MBATs benefits on emotional regulation, especially on regulation strategies. No harms related to the intervention has been observed. CONCLUSIONS: This study only partially supports benefits on MBAT on emotional regulation skills enhancement in patients with chronic disease receiving MBATs, as measured by the DERS scale. TRIAL REGISTRATION: The protocol was registered on Clinical Trials (NCT02911207).

[MEN for multiple endocrin neoplasms: When evokate MEN? Update 2022]. / Mise au point sur les néoplasies endocriniennes multiples.

Multiple endocrine neoplasia (MEN) are genetic predisposition syndromes to endocrine tumors including MEN1, MEN2 and exceptionally MEN4. MEN are transmitted in an autosomal dominant fashion with a high penetrance. Classically, there is no genotype/phenotype correlation for NEM1 whereas this is the case for NEM2. Patients with NEM1, linked to an inactivating mutation of the menin gene, may present with: primary hyperparathyroidism, pituitary adenoma, duodeno-pancreatic neuroendocrine tumors (NETs), bronchial tumors with an increased risk of thymoma, adrenal cortical tumors, an increased risk of breast cancer and characteristic skin involvement such as collagenomas, lentiginomas and an increased risk of skin cancer. These patients require at least annual follow-up. Screening of children is proposed from the age of 5 years. Patients with NEM2, linked to an activating mutation of the RET proto-oncogene, all present with medullary thyroid carcinoma (MTC) at a variable age depending on the genotype. Some patients present a pheochromocytoma (50 %) and hyperparathyroidism (20 %). Pediatric forms with aggressive CMT, ganglioneuromatosis and marfanoid syndrome exist (rare NEM2B). Some mutations are associated with a risk of aggressive CMT, justifying prophylactic thyroidectomy before 6 months of age. The age of genetic testing depends on the mutation subtype in the NEM2 parent. NEM4, related to a mutation in the CDKN1B gene, are rare, with a less well-known pathogenesis and their follow-up is not well codified.

[Medical reconciliation for hospitalized patients in orthopedic surgery department: Return of experience over 2 years of practice]. / Conciliation médicamenteuse à l'entrée des patients dans une unité de chirurgie orthopédique : retour d'expérience sur plus de 2 ans de pratique.

OBJECTIVES: Some medication errors can be prevented by pharmacist action such as medication reconciliation. The main objective of this study was to evaluate the medication reconciliation activity after two years of practice. The secondary objective was to assess the medical staff's satisfaction following the setting up of the activity. METHODS: This retrospective study was realized over a period of two years in our hospital. Patients meeting the following criteria were included: 65 years and over, hospitalized in orthopedic surgery department, preferentially after a discharge of the emergency room. After the best possible medication history was established, it is compared to medicines ordered. The discrepancies were defined as intended or unintended. Study data were collected and analyzed using Excel and SPSS statistics®. RESULTS: A total of 899 patients met the inclusion criteria during the study period, mean age was 78 years (27; 104). A total of 84 % of our cohort was admitted after a discharge of the emergency room. Seventy five percent of the population had at least an unintended discrepancie, a mean of 2,3 unintended discrepancies per patient was identified. Seventy five percent of the unintended discrepancy were discussed and resolved. The medical staff was mostly satisfied of the activity. CONCLUSION: The medication reconciliation secured the drug management of hospitalized patients.

First evidence of an extensive Acheulean large cutting tool accumulation in Europe from Porto Maior (Galicia, Spain).

We describe a European Acheulean site characterised by an extensive accumulation of large cutting tools (LCT). This type of Lower Paleolithic assemblage, with dense LCT accumulations, has only been found on the African continent and in the Near East until now. The identification of a site with large accumulations of LCTs favours the hypothesis of an African origin for the Acheulean of Southwest Europe. The lithic tool-bearing deposits date back to 293-205 thousand years ago. Our chronological findings confirm temporal overlap between sites with clear "African" Acheulean affinities and Early Middle Paleolithic sites found elsewhere in the region. These complex technological patterns could be consistent with the potential coexistence of different human species in south-western Europe during the Middle Pleistocene.

Association of CTH variant with sinusoidal obstruction syndrome in children receiving intravenous busulfan and cyclophosphamide before hematopoietic stem cell transplantation.

Sinusoidal obstruction syndrome (SOS) is a severe complication of hematopoietic stem cell transplantation (HSCT) that can be fatal, often attributed to the conditioning regimen prior to HSCT. We evaluated the association of SOS risk with gene variants in cystathionase (CTH), an enzyme involved in glutathione synthesis, in 76 children receiving intravenous busulfan (Bu) before HSCT. Our results indicated an association with CTHc.1364 G>T (ORTT=10.6, 95% confidence interval (CI)=2.16, 51.54) and SOS risk, which was sex dependent (female patients, ORTT=21.82, 95% CI=3.590-132.649). The interaction between CTHc.1364 G>T and another risk variant (GSTA1*B) was explored. A recessive model with the use of GSTA1*B*B and CTH c.1364 TT genotypes proved to be useful at predicting SOS occurrence, indicating the possibility of using these gene variants as markers of SOS occurrence and to further individualize preemptive treatment aimed at reducing SOS incidence.

[Real life visual and anatomic outcomes of aflibercept treatment for treatment-naive patients with exudative age-related macular degeneration]. / Réponse visuelle et anatomique en condition de « vraie vie ¼ du traitement par aflibercept chez les patients naïfs atteints de dégénérescence maculaire liée à l'âge exsudative.

Anti-VEGF therapies have revolutionized the treatment of neovascular age-related macular degeneration (AMD). PURPOSE: The goal of this study was to evaluate the "real life" visual and anatomical outcomes of aflibercept treatment for treatment-naive patients with exudative AMD. METHODS: This was a retrospective study of patients treated with aflibercept in the department of Ophthalmology at the University Hospital of Bordeaux between November 2013 and July 2015. The follow-up period varied from 3months to 2years. All patients received an induction phase with 3monthly intravitreal injections (IVT) followed by personalized monitoring. ETDRS best-corrected visual acuity (BCVA), fundus examination and OCT were performed at each visit. Data were collected at day 0, 3 months, 6, 9, 12months, 18 and 24months. RESULTS: Forty-three eyes of forty patients, mean age 77.7years, were included, with a minimum of 3months follow-up. Twenty-five eyes were followed for 1year; 5 eyes for two years. At baseline, the mean BCVA was 55.7 letters. Patients received 7.5 injections on average the first year and 2.6 the 2nd year. The mean gain of visual acuity was +7.3 letters at 3 months, +6.2 letters at 12 months, and +6.8 letters at 2years. Anatomically, the OCT data showed a decline of all parameters. The central macular thickness decreased by 118.3µm at 3months, 136.4µm at 12months and 65.5µm at 2years. CONCLUSION: Aflibercept can achieve effective visual and anatomical outcomes with results, which approach the pivotal studies, despite the use of personalized protocols and longer monitoring intervals.

Genetic Diversification and Dispersal of Taro (Colocasia esculenta (L.) Schott).

Taro (Colocasia esculenta (L.) Schott) is widely distributed in tropical and sub-tropical areas. However, its origin, diversification and dispersal remain unclear. While taro genetic diversity has been documented at the country and regional levels in Asia and the Pacific, few reports are available from Americas and Africa where it has been introduced through human migrations. We used eleven microsatellite markers to investigate the diversity and diversification of taro accessions from nineteen countries in Asia, the Pacific, Africa and America. The highest genetic diversity and number of private alleles were observed in Asian accessions, mainly from India. While taro has been diversified in Asia and the Pacific mostly via sexual reproduction, clonal reproduction with mutation appeared predominant in African and American countries investigated. Bayesian clustering revealed a first genetic group of diploids from the Asia-Pacific region and to a second diploid-triploid group mainly from India. Admixed cultivars between the two genetic pools were also found. In West Africa, most cultivars were found to have originated from India. Only one multi-locus lineage was assigned to the Asian pool, while cultivars in Madagascar originated from India and Indonesia. The South African cultivars shared lineages with Japan. The Caribbean Islands cultivars were found to have originated from the Pacific, while in Costa Rica they were from India or admixed between Indian and Asian groups. Taro dispersal in the different areas of Africa and America is thus discussed in the light of available records of voyages and settlements.

Influence of glutathione S-transferase gene polymorphisms on busulfan pharmacokinetics and outcome of hematopoietic stem-cell transplantation in thalassemia pediatric patients.

Hematopoietic stem-cell transplantation (HSCT) is currently the only curative therapeutic option for the treatment of thalassemia. In spite of the high cure rate, HSCT can lead to life-threatening adverse events in some patients. Busulfan (Bu) is a key component of the conditioning regimen prior to HSCT. Inter-individual differences in Bu pharmacokinetics (PK) are hypothesized to influence Bu efficacy and toxicity. Since Bu is mainly metabolized by glutathione S-transferase (GST), we investigated the relationship of GSTA1 and GSTM1 genotypes with first-dose PK and HSCT outcomes in 44 children with thalassemia intermedia and thalassemia major. All children received a myeloablative conditioning regimen with IV Bu. Association analysis revealed a relationship between GSTA169C>T (or haplotype *A/*B) and first Bu dose PK that was dependent on sex and Pesaro risk classification (PRC). Among female patients and patients with PRC I-II, homozygous individuals for the GSTA1T-69 allele defining haplotype *B, had higher Bu exposure and lower clearance (P⩽0.01). Association with HSCT outcomes showed that patients with the GSTM1 null genotypes had higher occurrence of regimen-related toxicity (P=0.01). These results suggest that GST genotypes could be useful to tailor the first Bu dose accordingly to improve HSCT outcome.

Integrated pharmacokinetic, pharmacodynamic and immunogenicity profiling of an anti-CCL21 monoclonal antibody in cynomolgus monkeys.

QBP359 is an IgG1 human monoclonal antibody that binds with high affinity to human CCL21, a chemokine hypothesized to play a role in inflammatory disease conditions through activation of resident CCR7-expressing fibroblasts/myofibroblasts. The pharmacokinetics (PK) and pharmacodynamics (PD) of QBP359 in non-human primates were characterized through an integrated approach, combining PK, PD, immunogenicity, immunohistochemistry (IHC) and tissue profiling data from single- and multiple-dose experiments in cynomolgus monkeys. When compared with regular immunoglobulin typical kinetics, faster drug clearance was observed in serum following intravenous administration of 10 mg/kg and 50 mg/kg of QBP359. We have shown by means of PK/PD modeling that clearance of mAb-ligand complex is the most likely explanation for the rapid clearance of QBP359 in cynomolgus monkey. IHC and liquid chromatography mass spectrometry data suggested a high turnover and synthesis rate of CCL21 in tissues. Although lymphoid tissue was expected to accumulate drug due to the high levels of CCL21 present, bioavailability following subcutaneous administration in monkeys was 52%. In human disease states, where CCL21 expression is believed to be expressed at 10-fold higher concentrations compared with cynomolgus monkeys, the PK/PD model of QBP359 and its binding to CCL21 suggested that very large doses requiring frequent administration of mAb would be required to maintain suppression of CCL21 in the clinical setting. This highlights the difficulty in targeting soluble proteins with high synthesis rates.

Role of operative airway evaluation in children with recurrent croup: a retrospective cohort study.

OBJECTIVE: Determine which risk factors in children with recurrent croup warrant bronchoscopic evaluation. DESIGN: Retrospective cohort study. SETTING: Tertiary paediatric hospital. PARTICIPANTS: Children with recurrent croup who underwent a rigid bronchoscopy between 2001 and 2013. MAIN OUTCOME MEASURES: Bronchoscopy findings, classified as normal, mildly abnormal or significantly abnormal. RESULTS: Two hundred and thirty-five children underwent a rigid bronchoscopy and 110 underwent a flexible oesophagoscopy. One hundred and forty-five children (61.7%) had a mildly abnormal exam, and 27 children (11.5%) had significant findings that required a surgical intervention or grade 2 or greater subglottic stenosis. The significantly abnormal group included 4 children with laryngomalacia, 2 with a subglottic cyst, 8 with grade 2 or 3 subglottic stenosis and 13 children who underwent a surgical procedure for subglottic stenosis. Sixty-seven children had a preoperative diagnosis of asthma, 62 were atopic and 78 had symptoms of gastro-oesophageal reflux. Oesophagoscopy was diagnostic of gastro-oesophageal reflux in 19 of 110 cases, and 106 children (45.1%) had bronchoscopic findings suggestive of GERD. Eight children had eosinophilic oesophagitis. After multivariate analysis, significantly abnormal bronchoscopy was significantly associated with chronic cough (P = 0.02), have a previous intubation (P = 0.002) or be younger than 3 years old (P = 0.01). CONCLUSION: Significant findings on bronchoscopy that warranted further surgical intervention were uncommon in this cohort. Nearly half of the patients had evidence of gastro-oesophageal reflux. In patients without risk factors for significant abnormalities, empiric medical management may be beneficial prior to endoscopy.

The association of cytochrome P450 genetic polymorphisms with sulfolane formation and the efficacy of a busulfan-based conditioning regimen in pediatric patients undergoing hematopoietic stem cell transplantation.

Cytochrome P450 enzymes (CYPs) and flavin-containing monooxygenases (FMOs) likely have a role in the oxidation of intermediate metabolites of busulfan (Bu). In vitro studies to investigate the involvement of these enzymes are cumbersome because of the volatile nature of the intermediate metabolite tetrahydrothiophene (THT) and the lack of sensitive quantitation methods. This study explored the association between the CYP2C9, CYP2C19, CYP2B6 and FMO3 genotypes and sulfolane (Su, a water soluble metabolite of Bu) plasma levels in children undergoing hematopoietic stem cell transplantation (HSCT). The relationship between these genotypes and the effectiveness of myeloablative conditioning was also analyzed. Sixty-six children receiving an intravenous Bu-based myeloablative conditioning regimen were genotyped for common functional variant alleles in CYP2C9 (*2 and *3), CYP2C19 (*2 and *17), FMO3 (rs2266780, rs2266782 and rs1736557) and CYP2B6 (*5 and *9). The plasma levels of Bu and its metabolite Su were measured after the ninth Bu dose in a subset of 44 patients for whom plasma samples were available. The ratio of Bu to Su was considered the metabolic ratio (MR) and was compared across the genotype groups. Higher MRs were observed in CYP2C9*2 and *3 allele carriers (mean±s.d.: 7.8±3.6 in carriers vs 4.4±2.2 in non-carriers; P=0.003). An increased incidence of graft failure was observed among patients with an MR>5 compared with those with MR values <5 (20% vs 0%; P=0.02). In contrast, a significantly higher incidence of relapse and graft failure (evaluated as event-free survival) was observed in patients with malignant disease who carried CYP2B6 alleles with reduced function on both chromosomes compared with carriers of at least one normal allele (100% vs 40%; P=0.0001). These results suggest that CYP2C9 has a role in the oxidation reactions of THT and indicate that it may be possible to predict the efficacy of Bu-based myeloablative conditioning before HSCT on the basis of CYP genotypes and Bu MRs.

ESR dosimetry of fossil enamel: some comments about measurement precision, long-term signal fading and dose-response curve fitting.

This work deals with the specific studies of three main sources of uncertainty in electron spin resonance (ESR) dosimetry/dating of fossil tooth enamel: (1) the precision of the ESR measurements, (2) the long-term signal fading the selection of the fitting function. They show a different influence on the equivalent dose (D(E)) estimates. Repeated ESR measurements were performed on 17 different samples: results show a mean coefficient of variation of the ESR intensities of 1.20 ± 0.23 %, inducing a mean relative variability of 3.05 ± 2.29 % in the D(E) values. ESR signal fading over 5 y was also observed: its magnitude seems to be quite sample dependant but is nevertheless especially important for the most irradiated aliquots. This fading has an apparent random effect on the D(E) estimates. Finally, the authors provide new insights and recommendations about the fitting of ESR dose-response curves of fossil enamel with a double saturating exponential (DSE) function. The potential of a new variation of the DSE was also explored. Results of this study also show that the choice of the fitting function is of major importance, maybe more than the other sources previously mentioned, in order to get accurate final D(E) values.

[Development of psychological and intellectual performance in transplanted sickle cell disease patients: a prospective study from pretransplant period to 5 years after HSCT]. / Développement psycho-intellectuel des enfants drépanocytaires ayant reçu une allogreffe de cellules souches hématopoïétiques.

RATIONALE: Allogeneic hematopoietic stem-cell transplantation (HSCT) is the only curative treatment for sickle cell disease (SCD). Cerebral vasculopathy was the principal indication for transplantation. These children could present impaired neuropsychological development related to different causes, hence the value of exploring their intellectual capacities before and after transplantation. MATERIAL AND METHODS: Prospective longitudinal study from 1992 to 2006 in all transplanted SCD patients. The patients were assessed using Wechsler scales with four different indices: verbal comprehension, perceptual reasoning, working memory, and processing speed (PSI), providing a full-scale intellectual quotient (IQ). RESULTS: Fifteen SCD patients (8 females and 7 males; mean age, 8.9 years) were evaluated before and 36 and 60 months after transplantation. All were from Africa and lived in France. All patients except 2 had experienced ischemic stroke before HSCT. The median full-scale IQ was 87, 94, and 94 before transplantation and 36 months and 60 months after HSCT, respectively. DISCUSSION: At pre-HSCT evaluation, full-scale IQ was considered as "low average". This relatively poor result could be related to impairment of PSI, which reflects frequent graphic and motor abnormalities related to the previous stroke experienced by almost all patients. At 3 years after HSCT, all indices including IQ had increased. Only the PSI had decreased, this observation being potentially related to previous stroke and to the depression frequently experienced by the transplant recipient patient after the acute phase, when the disease is cured. At 5 years after HSCT, the median full-scale IQ was stable and the PSI had increased. CONCLUSION: At the end of follow-up, the patients improved their physical and psychological well-being. This allowed them to build projects for the future and to manifest the desire of becoming an adult. Bone marrow transplantation in this cohort of children with SCD and severe cerebral vasculopathy is associated with improved performance as measured by the Wechsler scale.

Mobile gamma cameras in breast cancer care - a review.

BACKGROUND: Currently, due to progress in detection and to extended screening, surgeons have to deal with increasing numbers of non-palpable lesions in breast cancer. These lesions can be treated by radio-guided surgery in the lumpectomy associated with sentinel lymph node (SLN) procedures. Thanks to advances in detector technology, mini gamma cameras are now available, that can perform real-time lymphoscintigraphy during surgery, or at bedside. AIM: In this article, we review the clinical literature on these dedicated cameras used in breast cancer surgery. The goal is to show how these cameras are used in breast cancer treatment and in SLN biopsy and what kind of benefits they offer. METHODS: We conducted our search on MEDLINE and EMBASE databases. We performed a comprehensive review to identify clinical studies or cases using mobile gamma cameras in breast cancer surgery. RESULTS: We collected 14 articles published between January 2000 and March 2012. We analysed the use of the mobile cameras and the obtained results. CONCLUSION: Mobile gamma cameras seem to be useful imaging tools either used pre-operatively or during surgery. They assist surgeons with accurate localization of SLNs and/or radio-labelled tumours, and in verification that all radioactive nodes have been excised.

Field gamma dose-rate assessment in natural sedimentary contexts using LaBr3(Ce) and NaI(Tl) probes: a comparison between the "threshold" and "windows" techniques.

Results are presented for a series of replicate in situ gamma spectrometry measurements (n=20) made in natural sedimentary contexts using LaBr3(Ce) and NaI(Tl) probes. For both types of detectors, gamma dose rates were calculated using the "threshold" technique (Murray et al., 1978), and compared with results obtained previously by Arnold et al. (2012) using the "windows" technique (Aitken, 1985). Our results show that gamma dose rates obtained using these two techniques are consistent at 1σ for a given probe, and that the threshold technique yields reproducible results for the LaBr3(Ce) and NaI(Tl) probes. In comparison with the energy windows approach, the threshold approach offers an improvement in the precision with which gamma dose rates can be determined using the LaBr3(Ce) probe. The potential of an alternative threshold approach (the "energy threshold" approach of Guérin and Mercier, 2011) was also tested for both probe types, and the resultant gamma dose rates were found to be in agreement with those obtained using the standard threshold and energy windows techniques. Our results provide new insights into methods and instrumentation used for assessing in situ gamma dose rates in Electron Spin Resonance (ESR) and Luminescence dating. We conclude that LaBr3(Ce) probes can reliably be used for portable gamma dosimetry in low level activity sedimentary environments (500-1500µGy/a) when using the threshold approach, provided that their non-negligible internal background activities (equivalent to ∼758µGy/a for our probe) are accurately assessed and subtracted from gamma ray spectra measured in the field. Our results also suggest that there may be some minor merit in applying an internal background-subtraction procedure to NaI(Tl) gamma ray spectra when using the threshold technique, in spite of the lower intrinsic activities of NaI(Tl) detectors.