Advantages of non-cryopreserved autologous hematopoietic stem cell transplantation against a cryopreserved strategy.

Autologous stem cell transplantation (auto-HSCT) is an effective treatment strategy for hematological malignancies. The standard mode of handling hematopoietic progenitors for the autologous procedure (CRYO) consists on its collection and freezing with dimethyl sulfoxide (DMSO) and its subsequent thawing and re-infusion. This process is toxic and expensive. Non-cryopreserved (non-CRYO) is a less expensive mode of auto-HSCT. We designed a comparative study between both strategies performed in two different centers to analyze the short-term complications. In total 111 auto-HSCT were performed from January/2015 to October/2016 (42 non-CRYO and 74 CRYO). There were 74 males and 69 (62%) patients had the underlying diagnosis of multiple myeloma. No differences were seen on the characteristics of the apheresis products and their viability. Engraftment was significantly faster in the non-CRYO group (p = 0.001). Febrile neutropenia and severe mucositis were lower in the non-CRYO group (40% vs 92% p = 0.0001 and 11% vs 64%, p = 0.001, respectively). In addition, length of hospitalization was 5 days shorter in the non-CRYO group (p = 0.0001). Overall responses and transplantation outcomes were similar. Our data demonstrate a clear advantage of the non-CRYO over CRYO auto-HSCT with faster engraftment, lower incidence of febrile neutropenia and shorter hospital stay after the transplantation procedure. These data are especially relevant for centers with high transplant activity or with limited resources.

A glimpse of gluons through deeply virtual compton scattering on the proton.

The internal structure of nucleons (protons and neutrons) remains one of the greatest outstanding problems in modern nuclear physics. By scattering high-energy electrons off a proton we are able to resolve its fundamental constituents and probe their momenta and positions. Here we investigate the dynamics of quarks and gluons inside nucleons using deeply virtual Compton scattering (DVCS)-a highly virtual photon scatters off the proton, which subsequently radiates a photon. DVCS interferes with the Bethe-Heitler (BH) process, where the photon is emitted by the electron rather than the proton. We report herein the full determination of the BH-DVCS interference by exploiting the distinct energy dependences of the DVCS and BH amplitudes. In the regime where the scattering is expected to occur off a single quark, measurements show an intriguing sensitivity to gluons, the carriers of the strong interaction.

Rosenbluth Separation of the π

We report the first longitudinal-transverse separation of the deeply virtual exclusive π^{0} electroproduction cross section off the neutron and coherent deuteron. The corresponding four structure functions dσ_{L}/dt, dσ_{T}/dt, dσ_{LT}/dt, and dσ_{TT}/dt are extracted as a function of the momentum transfer to the recoil system at Q^{2}=1.75 GeV^{2} and x_{B}=0.36. The ed→edπ^{0} cross sections are found compatible with the small values expected from theoretical models. The en→enπ^{0} cross sections show a dominance from the response to transversely polarized photons, and are in good agreement with calculations based on the transversity generalized parton distributions of the nucleon. By combining these results with previous measurements of π^{0} electroproduction off the proton, we present a flavor decomposition of the u and d quark contributions to the cross section.

Relationship between achieved personalized glycaemic targets and monitoring of clinical events in elderly diabetic patients.

AIM: Recent guidelines for the management of type 2 diabetes (T2DM) in the elderly recommend adjusting the therapeutic target (HbA1c) according to the patient's health. Our study aimed to explore the association between achieving the recommended personalized HbA1c target and the occurrence of major clinical events under real-life conditions. METHODS: The T2DM S.AGES cohort was a prospective multicentre study into which 213 general practitioners recruited 983 non-institutionalized T2DM patients aged>65 years. The recommended personalized HbA1c targets were<7%, <8% and <9% for healthy, ill and very ill patients, respectively. Major clinical events (death from any cause, major vascular events and/or hospitalization) were recorded during the 3-year follow-up. Mixed-effects logistic regression models were used for the analyses. RESULTS: Of the 747 patients analyzed at baseline, 551 (76.8%) were at their recommended personalized HbA1c target. During follow-up, 391 patients (52.3%) experienced a major clinical event. Of the patients who did not achieve their personalized HbA1c target (compared with those who did), the risk (OR) of a major clinical event was 0.95 (95% CI: 0.69-1.31; P=0.76). The risk of death, major vascular event and hospitalization were 0.88 (95% CI: 0.40-1.94; P=0.75), 1.14 (95% CI: 0.7-1.83; P=0.59) and 0.84 (95% CI: 0.60-1.18; P=0.32), respectively. CONCLUSION: Over a 3-year follow-up period, our results showed no difference in risk of a major clinical event among patients, regardless of whether or not they achieved their personalized recommended HbA1c target. These results need to be confirmed before implementing a more permissive strategy for treating T2DM in elderly patients.

Association mapping for phenology and plant architecture in maize shows higher power for developmental traits compared with growth influenced traits.

Plant architecture, phenology and yield components of cultivated plants have repeatedly been shaped by selection to meet human needs and adaptation to different environments. Here we assessed the genetic architecture of 24 correlated maize traits that interact during plant cycle. Overall, 336 lines were phenotyped in a network of 9 trials and genotyped with 50K single-nucleotide polymorphisms. Phenology was the main factor of differentiation between genetic groups. Then yield components distinguished dents from lower yielding genetic groups. However, most of trait variation occurred within group and we observed similar overall and within group correlations, suggesting a major effect of pleiotropy and/or linkage. We found 34 quantitative trait loci (QTLs) for individual traits and six for trait combinations corresponding to PCA coordinates. Among them, only five were pleiotropic. We found a cluster of QTLs in a 5 Mb region around Tb1 associated with tiller number, ear row number and the first PCA axis, the latter being positively correlated to flowering time and negatively correlated to yield. Kn1 and ZmNIP1 were candidate genes for tillering, ZCN8 for leaf number and Rubisco Activase 1 for kernel weight. Experimental repeatabilities, numbers of QTLs and proportion of explained variation were higher for traits related to plant development such as tillering, leaf number and flowering time, than for traits affected by growth such as yield components. This suggests a simpler genetic determinism with larger individual QTL effects for the first category.

Spatial Distribution of Eukaryotic Communities Using High-Throughput Sequencing Along a Pollution Gradient in the Arsenic-Rich Creek Sediments of Carnoulès Mine, France.

Microscopic eukaryotes play a key role in ecosystem functioning, but their diversity remains largely unexplored in most environments. To advance our knowledge of eukaryotic microorganisms and the factors that structure their communities, high-throughput sequencing was used to characterize their diversity and spatial distribution along the pollution gradient of the acid mine drainage at Carnoulès (France). A total of 16,510 reads were retrieved leading to the identification of 323 OTUs after normalization. Phylogenetic analysis revealed a quite diverse eukaryotic community characterized by a total of eight high-level lineages including 37 classes. The majority of sequences were clustered in four main groups: Fungi, Stramenopiles, Alveolata and Viridiplantae. The Reigous sediments formed a succession of distinct ecosystems hosting contrasted eukaryotic communities whose structure appeared to be at least partially correlated with sediment mineralogy. The concentration of arsenic in the sediment was shown to be a significant factor driving the eukaryotic community structure along this continuum.

Rosenbluth Separation of the π

We present deeply virtual π^{0} electroproduction cross-section measurements at x_{B}=0.36 and three different Q^{2} values ranging from 1.5 to 2 GeV^{2}, obtained from Jefferson Lab Hall A experiment E07-007. The Rosenbluth technique is used to separate the longitudinal and transverse responses. Results demonstrate that the cross section is dominated by its transverse component and, thus, is far from the asymptotic limit predicted by perturbative quantum chromodynamics. Nonetheless, an indication of a nonzero longitudinal contribution is provided by the measured interference term σ_{LT}. Results are compared with several models based on the leading-twist approach of generalized parton distributions (GPDs). In particular, a fair agreement is obtained with models in which the scattering amplitude includes convolution terms of chiral-odd (transversity) GPDs of the nucleon with the twist-3 pion distribution amplitude. This experiment, together with previous extensive unseparated measurements, provides strong support to the exciting idea that transversity GPDs can be accessed via neutral pion electroproduction in the high-Q^{2} regime.

Characterization of Pseudomonas chlororaphis from Theobroma cacao L. rhizosphere with antagonistic activity against Phytophthora palmivora (Butler).

AIM: To isolate and characterize rhizobacteria from Theobroma cacao with antagonistic activity against Phytophthora palmivora, the causal agent of the black pod rot, which is one of the most important diseases of T. cacao. METHODS AND RESULTS: Among 127 rhizobacteria isolated from cacao rhizosphere, three isolates (CP07, CP24 and CP30) identified as Pseudomonas chlororaphis, showed in vitro antagonistic activity against P. palmivora. Direct antagonism tested in cacao detached leaves revealed that the isolated rhizobacteria were able to reduce symptom severity upon infection with P. palmivora Mab1, with Ps. chlororaphis CP07 standing out as a potential biocontrol agent. Besides, reduced symptom severity on leaves was also observed in planta where cacao root system was pretreated with the isolated rhizobacteria followed by leaf infection with P. palmivora Mab1. The production of lytic enzymes, siderophores, biosurfactants and HCN, as well as the detection of genes encoding antibiotics, the formation of biofilm, and bacterial motility were also assessed for all three rhizobacterial strains. By using a mutant impaired in viscosin production, derived from CP07, it was found that this particular biosurfactant turned out to be crucial for both motility and biofilm formation, but not for the in vitro antagonism against Phytophthora, although it may contribute to the bioprotection of T. cacao. CONCLUSIONS: In the rhizosphere of T. cacao, there are rhizobacteria, such as Ps. chlororaphis, able to protect plants against P. palmivora. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides a theoretical basis for the potential use of Ps. chlororaphis CP07 as a biocontrol agent for the protection of cacao plants from P. palmivora infection.

Therapeutic management in ambulatory elderly patients with atrial fibrillation: the S.AGES cohort.

UNLABELLED: Few epidemiologic studies have specifically focused on very old community dwelling population with atrial fibrillation (AF). The objectives of the AF-S.AGES cohort were to describe real-life therapeutic management of non-institutionalized elderly patients with AF according to age groups, i.e., 65-79 and ≥ 80 and to determine the main factors associated with anticoagulant treatment in both groups. METHODS: Observational study (N=1072) aged ≥ 65 years old, recruited by general practitioners. Characteristics of the sample were first evaluated in the overall sample and according to age (< 80 or ≥ 80 years) and to use of anticoagulant treatment at inclusion. Logistic models were used to analyze the determinants of anticoagulant prescription among age groups. RESULTS: Mean age was 78.0 (SD=6.5) years and 42% were ≥ 80 years. Nineteen percent had paroxysmal AF, 15% persistent, 56% permanent and 10% unknown type, 77% were treated with vitamin K antagonists (VKA), 17% with antiplatelet therapy with no differences between age groups. Rate-control drugs were more frequently used than rhythm-control drugs (55% vs. 37%, p < 0.001). VKA use was associated with permanent AF, younger age and cancer in patients ≥ 80 years old and with permanent AF and preserved functional autonomy in patients < 80 years old. Hemorrhagic scores were independently associated with non-use of VKA whereas thromboembolic scores were not associated with VKA use. CONCLUSIONS: In this elderly AF outpatient population, use of anticoagulant therapy was higher even after 80 years than in previous studies suggesting that recent international guidelines are better implemented in the elderly population.

Two dosing regimens of certolizumab pegol in patients with active rheumatoid arthritis.

OBJECTIVE: To investigate clinical efficacy and safety of 2 certolizumab pegol (CZP) maintenance dosing regimens plus methotrexate (MTX) in active rheumatoid arthritis (RA) patients achieving the American College of Rheumatology 20% improvement criteria (ACR20) after the CZP 200 mg every 2 weeks open-label run-in period. METHODS: DOSEFLEX (dosing flexibility) was a double-blind, placebo-controlled randomized study with an open-label run-in phase. During the run-in phase, all patients received CZP 400 mg (weeks 0, 2, and 4) and 200 mg every 2 weeks to week 16. Week 16 ACR20 responders were randomized 1:1:1 at week 18 to CZP 200 mg every 2 weeks, 400 mg every 4 weeks, or placebo. RESULTS: A total of 209 (of 333) patients were randomized at week 18 (CZP: 200 mg, n = 70; 400 mg, n = 70; placebo, n = 69). Groups had similar baseline characteristics (week 0). Week 34 ACR20 response rates were comparable between the CZP 200 mg every 2 weeks and the 400 mg every 4 weeks groups (67.1% versus 65.2%), which was significantly higher than placebo (44.9%; P = 0.009 and P = 0.017). ACR50/70 and remission criteria were met more frequently in CZP groups than placebo at week 34, with similar responses between anti-tumor necrosis factor-experienced and naive patients. Improvements from baseline Disease Activity Score in 28 joints using the erythrocyte sedimentation rate and Health Assessment Questionnaire disability index scores were maintained in CZP groups from week 16 to 34 while worsening on placebo. Adverse event (AE) rates in the double-blind phase were 62.9% versus 60.9% versus 62.3%; serious AE rates were 7.1% versus 2.9% versus 0.0% (CZP 200 mg, 400 mg, and placebo groups). CONCLUSION: In active RA patients with an incomplete MTX response, CZP 200 mg every 2 weeks and 400 mg every 4 weeks were comparable and better than placebo for maintaining clinical response to week 4 following a 16-week, open-label run-in phase.

Les sinusites chroniques de la face dans le service d'ORL du CHU Yalgado Ouedraogo de Ouagadougou; a propos de 365 cas

But: Analyser les aspects epidemiologiques; diagnostiques et therapeutiques des sinusites chroniques de la face. Methode: Il s'est agit d'une etude retrospective de 05 ans; portant sur 365 cas de sinusites chroniques. Resultats: L'incidence annuelle etait de 73 cas/an et l'age moyen de 33 ans. Les principaux motifs de consultation etaient les cephalees (80;80); l'obstruction nasale (34;79) et la rhinorrhee (19;72). Les sinus maxillaires (96;44) et ethmoidaux (60;39) etaient les plus touches et les facteurs etiologiques etaient domines par les allergies naso-sinusiennes (73;15); les infections aero-digestives (19;18) et les blocages ostiaux mecaniques (7;67). Le traitement; medical (79;45) et medico-chirurgical (20;55) a permis d'obtenir une evolution favorable (90;96). Les complications ont ete observees dans 5;75 avec un taux de letalite de 1;92

Rapid impact of phenanthrene and arsenic on bacterial community structure and activities in sand batches.

The impact of both organic and inorganic pollution on the structure of soil microbial communities is poorly documented. A short-time batch experiment (6 days) was conducted to study the impact of both types of pollutants on the taxonomic, metabolic and functional diversity of soil bacteria. For this purpose sand spiked with phenanthrene (500 mg kg(-1) sand) or arsenic (arsenite 0.66 mM and arsenate 12.5 mM) was supplemented with artificial root exudates and was inoculated with bacteria originated from an aged PAH and heavy-metal-polluted soil. The bacterial community was characterised using bacterial strain isolation, TTGE fingerprinting and proteomics. Without pollutant, or with phenanthrene or arsenic, there were no significant differences in the abundance of bacteria and the communities were dominated by Pseudomonas and Paenibacillus genera. However, at the concentrations used, both phenanthrene or arsenic were toxic as shown by the decrease in mineralisation activities. Using community-level physiological profiles (Biolog Ecoplates™) or differential proteomics, we observed that the pollutants had an impact on the community physiology, in particular phenanthrene induced a general cellular stress response with changes in the central metabolism and membrane protein synthesis. Real-time PCR quantification of functional genes and transcripts revealed that arsenic induced the transcription of functional arsenic resistance and speciation genes (arsB, ACR3 and aioA), while no transcription of PAH-degradation genes (PAH-dioxygenase and catechol-dioxygenase) was detected with phenanthrene. Altogether, in our tested conditions, pollutants do not have a major effect on community abundance or taxonomic composition but rather have an impact on metabolic and functional bacterial properties.

Umbilical cord blood transplantation in hematologic diseases in patients over 15 years old: long-term experience at the Pontificia Universidad Católica de Chile.

Most patients who require a sibling stem cell transplantation do not have a matched donor. In our experience, only 1/3 patients have a matched unrelated donor (MUD); therefore, the majority of the patients will require umbilical cord blood (UCB). Patients treated for hematologic diseases with UCB transplants were included. UCB selection and conditioning regimens were performed according to the Minnesota group. Graft-versus-host disease (GVHD) prophylaxis, infection prevention, and patient care were performed according to institutional guidelines. We analyzed patients and graft demography, neutrophil and platelet recovery, chimerism kinetics, GVHD incidence, overall (OS), progression-free survival (PFS) and transplant-related mortality (TRM). We included 29 patients with a median age of 34.8 years (range 15-55). Eighteen were male and the median weight was 72.6 kg (range 54-100). Nineteen patients had acute leukemia. Myeloablative (MA) conditioning was used in 27 patients. Seventeen received double UCB (DUCB) grafts. Median total nucleated cell (10(7)/kg) was 4.2 (range 3.9-4.9) and 4.4 (range 2.8-6.3) for single UCB (SUCB) and DUCB transplants, respectively. Median time for neutrophil engraftment was 24.7 (range 14-43) and 25.8 days (range 14-52) after SUCB and DUCB transplants, respectively. Median time for platelet engraftment was 147 (range 30-516) and 81 days (range 37-200) after SUCB and DUCB transplants, respectively. All the patients receiving MA conditioning had >95% chimerism shortly after transplant. Cumulative incidence of grades II-IV and III-IV acute GVHD was 41% and 20%, respectively. Localized chronic GVHD was seen in 14% of the patients. Median follow-up was 16.7 months (range 1-63). Five-year OS and PFS were 38% and 39%, respectively. One-year TRM was 42%. UCB transplantation is associated with potential cure of hematologic malignancies and our results are similar to other series. Studies are needed to decrease mortality and improve immune reconstitution.

The therapeutic management of chronic pain in ambulatory care patients aged 65 and over in France: the S.AGES Cohort. Baseline data.

OBJECTIVE: The main objective of the S.AGES (Elderly Subjects) cohort study is to describe the current therapeutic strategy for chronic pain in non-institutionalised elderly patients in France. METHODS: In this prospective cohort study, non-institutionalised patients aged 65 years and over with chronic pain were recruited by general practitioners (GP) across France. All medicinal and non- medicinal prescriptions were recorded at inclusion and will be followed up over 3 years via an eCRF. Data recorded at baseline are presented in this paper. RESULTS: Two hundred and sixty GPs enrolled 1379 evaluable patients between June 3rd, 2009 and June 3rd, 2011. Pain was mainly of a mechanical nature, due to osteoarthritis or common back pain. 80% of the patients had moderate or severe pain. More than a third of patients were treated with a step 1 analgesic (mainly paracetamol), and approximately 30% received a step 2 analgesic (23% dextropropoxyphene and 40.3% tramadol/paracetamol combination). Only 3% received step 3 analgesics; this rate remained low even in patients with severe pain. The proportion of patients treated with an antiepileptic was higher in case of neuropathic pain. More than 25% of patients did not receive any analgesic medication. CONCLUSION: The baseline S.AGES study results exhibit a well-balanced therapeutic management of chronic pain by GPs for ambulatory elderly patients. Clinicaltrials.org NCT01065909.

Archaeal diversity: temporal variation in the arsenic-rich creek sediments of Carnoulès Mine, France.

The Carnoulès mine is an extreme environment located in the South of France. It is an unusual ecosystem due to its acidic pH (2-3), high concentration of heavy metals, iron, and sulfate, but mainly due to its very high concentration of arsenic (up to 10 g L⁻¹ in the tailing stock pore water, and 100-350 mg L⁻¹ in Reigous Creek, which collects the acid mine drainage). Here, we present a survey of the archaeal community in the sediment and its temporal variation using a culture-independent approach by cloning of 16S rRNA encoding genes. The taxonomic affiliation of Archaea showed a low degree of biodiversity with two different phyla: Euryarchaeota and Thaumarchaeota. The archaeal community varied in composition and richness throughout the sampling campaigns. Many sequences were phylogenetically related to the order Thermoplasmatales represented by aerobic or facultatively anaerobic, thermoacidophilic autotrophic or heterotrophic organisms like the organotrophic genus Thermogymnomonas. Some members of Thermoplasmatales can also derive energy from sulfur/iron oxidation or reduction. We also found microorganisms affiliated with methanogenic Archaea (Methanomassiliicoccus luminyensis), which are involved in the carbon cycle. Some sequences affiliated with ammonia oxidizers, involved in the first and rate-limiting step in nitrification, a key process in the nitrogen cycle were also observed, including Candidatus Nitrososphaera viennensis and Candidatus nitrosopumilus sp. These results suggest that Archaea may be important players in the Reigous sediments through their participation in the biochemical cycles of elements, including those of carbon and nitrogen.

Effect of arsenite on swimming motility delays surface colonization in Herminiimonas arsenicoxydans.

Herminiimonas arsenicoxydans is a Gram-negative bacterium able to detoxify arsenic-contaminated environments by oxidizing arsenite [As(III)] to arsenate [As(V)] and by scavenging arsenic ions in an extracellular matrix. Its motility and colonization behaviour have been previously suggested to be influenced by arsenite. Using time-course confocal laser scanning microscopy, we investigated its biofilm development in the absence and presence of arsenite. Arsenite was shown to delay biofilm initiation in the wild-type strain; this was partly explained by its toxicity, which caused an increased growth lag time. However, this delayed adhesion step in the presence of arsenite was not observed in either a swimming motility defective fliL mutant or an arsenite oxidase defective aoxB mutant; both strains displayed the wild-type surface properties and growth capacities. We propose that during the biofilm formation process arsenite acts on swimming motility as a result of the arsenite oxidase activity, preventing the switch between planktonic and sessile lifestyles. Our study therefore highlights the existence, under arsenite exposure, of a competition between swimming motility, resulting from arsenite oxidation, and biofilm initiation.

High-resolution spectroscopy of Lambda16N by electroproduction.

An experimental study of the (16)O(e,e'K(+))(Lambda)(16)N reaction has been performed at Jefferson Lab. A thin film of falling water was used as a target. This permitted a simultaneous measurement of the p(e,e'K(+))Lambda, Sigma(0) exclusive reactions and a precise calibration of the energy scale. A ground-state binding energy of 13.76+/-0.16 MeV was obtained for (Lambda)(16)N with better precision than previous measurements on the mirror hypernucleus (Lambda)(16)O. Precise energies have been determined for peaks arising from a Lambda in s and p orbits coupled to the p(1/2) and p(3/2) hole states of the (15)N core nucleus.

Active or passive pain coping strategies in hip and knee osteoarthritis? Results of a national survey of 4,719 patients in a primary care setting.

OBJECTIVE: To study pain coping strategies in patients with hip and knee osteoarthritis (OA), and to assess the psychometric qualities of the French version of the Pain Coping Inventory (PCI). METHODS: We conducted a national, cross-sectional survey in a primary care setting in France. A total of 1,811 general practitioners included 5,324 patients with hip and knee OA who completed several questionnaires, including the PCI, which assesses ability to cope with pain. RESULTS: The records of 4,719 (86.4%) patients were analyzed (knee 2,781; hip 1,553; hip and knee 385). Supporting the structure of the original questionnaire, we found that the 33 PCI questionnaire items could be grouped into 3 domains defining active coping strategies and 3 defining passive coping strategies. Acceptable convergent validity was found for the PCI (Cronbach's alpha coefficient for each domain >0.68). Coping strategy scores were significantly higher in patients with both knee and hip involvement (mean +/- SD 2.3 +/- 0.4) than for patients with OA at 1 site (mean +/- SD 2.1 +/- 0.4), and in women compared with men (P < 0.001). The use of passive pain coping strategies increased with OA duration, and was greater in older and overweight patients, in patients with no current physical activity or major impairment, in retired and nonworking patients, and in patients who were not married, and to a lesser extent in patients with higher pain intensity. Compared with previous data, patients with OA demonstrated lower active and higher passive strategies than patients with rheumatoid arthritis and other chronic painful conditions. CONCLUSION: The PCI has good structural validity and is highly suitable for analyzing active and passive pain coping strategies in OA. In OA, active and passive coping strategies differ significantly as a function of age, body mass index, OA involvement, professional and marital status, sport activities, and OA duration, with pain intensity having a weaker effect.

3He spin-dependent cross sections and sum rules.

We present a measurement of the spin-dependent cross sections for the 3He over -->(e over -->,e')X reaction in the quasielastic and resonance regions at a four-momentum transfer 0.1< or =Q2< or =0.9 GeV2. The spin-structure functions have been extracted and used to evaluate the nuclear Burkhardt-Cottingham and extended Gerasimov-Drell-Hearn sum rules for the first time. The data are also compared to an impulse approximation calculation and an exact three-body Faddeev calculation in the quasielastic region.