Age of the magma chamber and its physicochemical state under Elbrus Greater Caucasus, Russia using zircon petrochronology and modeling insights.

Mount Elbrus, Europe's tallest and largely glaciated volcano, is made of silicic lavas and is known for Holocene eruptions, but the size and state of its magma chamber remain poorly constrained. We report high spatial resolution U-Th-Pb zircon ages, co-registered with oxygen and hafnium isotopic values, span ~ 0.6 Ma in each lava, documenting magmatic initiation that forms the current edifice. The best-fit thermochemical modeling constrains magmatic fluxes at 1.2 km3/1000 year by hot (900 °C), initially zircon-undersaturated dacite into a vertically extensive magma body since ~ 0.6 Ma, whereas a volcanic episode with eruptible magma only extends over the past 0.2 Ma, matching the age of oldest lavas. Simulations explain the total magma volume of ~ 180 km3, temporally oscillating δ18O and εHf values, and a wide range of zircon age distributions in each sample. These data provide insights into the current state (~ 200 km3 of melt in a vertically extensive system) and the potential for future activity of Elbrus calling for much-needed seismic imaging. Similar zircon records worldwide require continuous intrusive activity by magmatic accretion of silicic magmas generated at depths, and that zircon ages do not reflect eruption ages but predate them by ~ 103 to 105 years reflecting protracted dissolution-crystallization histories.

Comparison of Rat Hepatocyte 2D-Monocultures and Hepatocytes Non-Parenchymal Cell Co-Cultures for Assessing Chemical Toxicity.

Liver responses are the most common endpoints used as the basis for setting exposure standards. Liver hepatocytes play a vital role in biotransformation of xenobiotics, but non-parenchymal cells (NPCs) in the liver are also involved in certain liver responses. Development of in vitro systems that more faithfully capture liver responses to reduce reliance on animals is a major focus of New Approach Methodology (NAMs). Since rodent regulatory studies are frequently the sole source safety assessment data, mode-of-action data, and used for risk assessments, in vitro rodent models that reflect in vivo responses need to be developed to reduce reliance on animal models. In the work presented in this paper, we developed a 2-D hepatocyte monoculture and 2-D liver cell co-culture system using rat liver cells. These models were assessed for conditions for short-term stability of the cultures and phenotypic and transcriptomic responses of 2 prototypic hepatotoxicants compounds - acetaminophen and phenobarbital. The optimized multi-cellular 2-D culture required use of freshly prepared hepatocytes and NPCs from a single rat, a 3:1 ratio of hepatocytes to NPCs and growth medium using 50% Complete Williams E medium (WEM) and 50% Endothelial Cell Medium (ECM). The transcriptomic responses of the 2 model systems to PB were compared to previous studies from TG-Gates on the gene expression changes in intact rats and the co-culture model responses were more representative of the in vivo responses. Transcriptomic read-outs promise to move beyond conventional phenotypic evaluations with these in vitro NAMs and provide insights about modes of action.

Humoral and cellular immune response to tick-borne-encephalitis (TBE) vaccination depends on booster doses in patients with Juvenile Idiopathic Arthritis (JIA).

Juvenile Idiopathic Arthritis (JIA) patients living in areas with high prevalence of tick-borne-encephalitis-virus-(TBEV)-infection are recommended for administration of inactivated TBE-vaccination. However, there are serious concerns regarding protective vaccine-induced immune responses against TBEV in immunocompromised patients. The present study aimed to analyze the humoral and cellular immune response to TBE-vaccination in previously TBE-vaccinated JIA patients compared to healthy controls (HC) including investigation of IgG-anti-TBEV avidity, neutralization capacity, cellular reactivity by IFNgamma-ELISPOT and cytokine secretion assays. Similar IgG-anti-TBEV antibody concentrations, neutralization titers and cellular reactivity were found between JIA and HC. The number and the early timing of booster vaccinations after primary vaccination had the most prominent effect on neutralizing antibodies in JIA and on IgG-anti-TBEV concentrations in both JIA and HC. Administration of booster vaccinations made it more likely for JIA patients to have IgG-anti-TBEV concentrations ≥165 VIEU/ml and avidities >60%. TNF-alpha inhibitors had a positive and MTX administration a negative effect on humoral immune responses. In conclusion, irrespective of having JIA or not, vaccinated children showed similar humoral and cellular immunity against TBEV several years after primary TBE-vaccination. However, in JIA, booster vaccinations mounted a significantly higher humoral immune response than in JIA without boosters. Our results highlight the need for timely administration of boosters particularly in JIA. Although immunosuppressive treatment at vaccinations in diagnosed JIA had a negative effect mainly on TBEV-specific cellular immunity, most JIA patients mounted a favorable humoral immune response which was maintained over time. Thus, successful TBE-vaccination seems highly feasible in JIA patients with immunosuppressive regimens.

Supportive care in the acute phase of Stevens-Johnson syndrome and toxic epidermal necrolysis: an international, multidisciplinary Delphi-based consensus.

BACKGROUND: Supportive care is the cornerstone of management of adult and paediatric Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). However, consensus on the modalities of supportive care is lacking. OBJECTIVES: Our aim in this international multicentric Delphi exercise was to establish a multidisciplinary expert consensus to standardize recommendations regarding supportive care in the acute phase of SJS/TEN. METHODS: Participants were sent a survey via the online tool SurveyMonkey, consisting of 103 statements organized into 11 topics: multidisciplinary team composition, suspect drug management, infection prevention, fluid resuscitation and prevention of hypothermia, nutritional support, pain and psychological distress management, management of acute respiratory failure, local skincare, ophthalmological management, management of other mucosa, and additional measures. Participants evaluated the level of appropriateness of each statement on a scale of 1 (extremely inappropriate) to 9 (extremely appropriate). The results were analysed according to the RAND/UCLA Appropriateness Method. RESULTS: Forty-five participants from 13 countries (on three continents) participated. After the first round, a consensus was obtained for 82.5% of the 103 initially proposed statements. After the second round, a final consensus was obtained for 102 statements. CONCLUSIONS: We have reached an international Delphi-based consensus on best supportive care practice for SJS/TEN. Our expert consensus should help guide physicians in treating patients with SJS/TEN and thereby improve short-term prognosis and the risk of sequelae.

Geochronology and geochemistry data for the Elbrus, Tyrnyauz, and Chegem magmatic centers, Greater Caucasus, Russia.

The dataset presented here is associated with the article "Young Silicic Magmatism of the Greater Caucasus, Russia with implication for its delamination origin based on zircon petrochronology and thermomechanical modeling" [1]. We present detailed sample descriptions and source locations for the rocks from the Chegem, Tyrnyauz, and Elbrus volcanic center localities presented in that study. The dataset presents extensive isotope and trace element geochemistry of zircon crystals from these rocks, major phenocrysts, and whole rock O and H isotopic and elemental compositions. Zircon ages, trace element compositions, and Hf and O isotopic compositions were obtained by both laser ablation ICP-MS and secondary ionization mass spectrometry in situ techniques and chemical abrasion isotope dilution-thermal ionization mass spectrometry techniques. We also present whole-rock major element compositions obtained by X-ray fluorescence and trace element compositions obtained by solution inductively-coupled plasma mass spectrometry. We also report δ18O analyses of phenocrysts and groundmass in samples, δ18O-δ13C analyses of limestones and limestone xenoliths in the Chegem ignimbrite, and coupled δ18O-δD-Δ17O analyses of glass and groundmass of rock samples from the Chegem ignimbrites that show abundant evidence of post-emplacement interaction with meteoric waters. To supplement the associated study [1], this article also includes field photographs, cathodoluminescence images of zircons, plots of trace element compositions in zircon, plots of stable isotopic variations in Chegem ignimbrites vs. stratigraphy, and selected trace elemental whole-rock diagrams.

[Impact of confinement on the follow-up of oral immunotherapies: A multicentre study in the Île-de-France region]. / Impact du confinement sur le suivi des immunothérapies orales alimentaires : étude multicentrique dans 3 centres d'Île-de-France.

PURPOSE OF THE STUDY: Several studies have confirmed the impact of confinement on the population, resulting in disruption of care, somatic and psychological effects. Our study looks at adverse effects and problems of adherence to oral immunotherapy therapy (OIT) during this period. PATIENTS AND METHODS: A total of 132 patients, mostly children (95%), with an atopic history (60%) followed for an OIT were included in 3 allergology centers in Île-de-France, during the period of confinement from 03/16 to 05/11/20. The main food allergens used for OIT were peanut (38%), cow's milk (24%), hazelnut (14%), egg (9%), cashew nut and pistachio nut (8%). RESULTS: Adverse effects were found in 13 patients or 10% of the cases. These reactions were mainly grade 1 and 2 according to the Ring and Messmer classification. Three patients had grade 3 reactions and six patients used epinephrine at home. Adherence was correct in 81% of cases with no omissions. Three patients increased their daily dose without medical advice. No significant difference was found in the subgroup analysis comparing age-matched children followed up in OIT in 2019 and 2020 over the same period in the same hospital. CONCLUSION: There was no increase in adverse events in OIT during the confinement period. Therapeutic education during OIT is paramount and helps to reduce the occurrence of adverse events.

The lithospheric-to-lower-mantle carbon cycle recorded in superdeep diamonds.

The transport of carbon into Earth's mantle is a critical pathway in Earth's carbon cycle, affecting both the climate and the redox conditions of the surface and mantle. The largest unconstrained variables in this cycle are the depths to which carbon in sediments and altered oceanic crust can be subducted and the relative contributions of these reservoirs to the sequestration of carbon in the deep mantle1. Mineral inclusions in sublithospheric, or 'superdeep', diamonds (derived from depths greater than 250 kilometres) can be used to constrain these variables. Here we present oxygen isotope measurements of mineral inclusions within diamonds from Kankan, Guinea that are derived from depths extending from the lithosphere to the lower mantle (greater than 660 kilometres). These data, combined with the carbon and nitrogen isotope contents of the diamonds, indicate that carbonated igneous oceanic crust, not sediment, is the primary carbon-bearing reservoir in slabs subducted to deep-lithospheric and transition-zone depths (less than 660 kilometres). Within this depth regime, sublithospheric inclusions are distinctly enriched in 18O relative to eclogitic lithospheric inclusions derived from crustal protoliths. The increased 18O content of these sublithospheric inclusions results from their crystallization from melts of carbonate-rich subducted oceanic crust. In contrast, lower-mantle mineral inclusions and their host diamonds (deeper than 660 kilometres) have a narrow range of isotopic values that are typical of mantle that has experienced little or no crustal interaction. Because carbon is hosted in metals, rather than in diamond, in the reduced, volatile-poor lower mantle2, carbon must be mobilized and concentrated to form lower-mantle diamonds. Our data support a model in which the hydration of the uppermost lower mantle by subducted oceanic lithosphere destabilizes carbon-bearing metals to form diamond, without disturbing the ambient-mantle stable-isotope signatures. This transition from carbonate slab melting in the transition zone to slab dehydration in the lower mantle supports a lower-mantle barrier for carbon subduction.

Healthcare utilization and management of actinic keratosis in primary and secondary care: a complementary database analysis.

BACKGROUND: The high prevalence of actinic keratosis (AK) requires the optimal use of healthcare resources. OBJECTIVES: To gain insight in to the healthcare utilization of people with AK in a population-based cohort, and the management of AK in a primary and secondary care setting. METHODS: A retrospective cohort study using three complementary data sources was conducted to describe the use of care, diagnosis, treatment and follow-up of patients with AK in the Netherlands. Data sources consisted of a population-based cohort study (Rotterdam Study), routine general practitioner (GP) records (Integrated Primary Care Information) and nationwide claims data (DRG Information System). RESULTS: In the population-based cohort (Rotterdam Study), 69% (918 of 1322) of participants diagnosed with AK during a skin-screening visit had no previous AK-related visit in their GP record. This proportion was 50% for participants with extensive AK (i.e. ≥ 10 AKs; n = 270). Cryotherapy was the most used AK treatment by both GPs (78%) and dermatologists (41-56%). Topical agents were the second most used treatment by dermatologists (13-21%) but were rarely applied in primary care (2%). During the first AK-related GP visit, 31% (171 of 554) were referred to a dermatologist, and the likelihood of being referred was comparable between low- and high-risk patients, which is inconsistent with the Dutch general practitioner guidelines for 'suspicious skin lesions' from 2017. Annually, 40 000 new claims representing 13% of all dermatology claims were labelled as cutaneous premalignancy. Extensive follow-up rates (56%) in secondary care were registered, while only 18% received a claim for a subsequent cutaneous malignancy in 5 years. CONCLUSIONS: AK management seems to diverge from guidelines in both primary and secondary care. Underutilization of field treatments, inappropriate treatments and high referral rates without proper risk stratification in primary care, combined with extensive follow-up in secondary care result in the inefficient use of healthcare resources and overburdening in secondary care. Efforts directed to better risk differentiation and guideline adherence may prove useful in increasing the efficiency in AK management. What's already known about this topic? The prevalence of actinic keratosis (AK) is high and, in particular, multiple AKs are a strong skin cancer predictor. The high prevalence of AK requires optimal use of healthcare resources. Nevertheless, (population based) AK healthcare utilization and management data are very rare. What does this study add? Although AK-related care already consumes substantial resources, about 70% of the AK population has never received care. Primary care AK management demonstrated underutilization of topical therapies and high referral rates without proper risk stratification, while in secondary care the extensive follow-up schedules were applied. This inefficient use of healthcare resources highlights the need for better harmonization and risk stratification to increase the efficiency of AK care.

Quantification of hyaluronan in human fasciae: variations with function and anatomical site.

Recently, alterations in fascial gliding-like movement have been invoked as critical in the etiology of myofascial pain. Various methods have been attempted for the relief of this major and debilitating clinical problem. Paramount have been attempts to restore correct gliding between fascial layers and the movement over bone, joint, and muscular structures. One of the key elements that underlies such fascial movement is hyaluronan. However, until now, the precise content of hyaluronan within fasciae has been unknown. This study quantifies for the first time the hyaluronan content of human fascial samples obtained from a variety of anatomic sites. Here, we demonstrate that the average amount varies according to anatomic site, and according to the different kinds of sliding properties of the particular fascia. For example, the fascia lata has 35 µg of hyaluronan per gram of tissue, similar to that of the rectus sheath (29 µg g-1 ). However, the types of fascia adherent to muscle contain far less hyaluronan: 6 µg g-1 in the fascia overlying the trapezius and deltoid muscles. In the fascia that surrounds joints, the hyaluronan increases to 90 µg g-1 , such as in the retinacula of the ankle, where greater degrees of movement occur. Surprisingly, no significant differences were detected at any site as a function of age or sex (P-value > 0.05, t-test) with the sole exception of the plantar fascia. This work can provide a better understanding of the role of hyaluronan in fascia. It will facilitate a better comprehension of the modulation of the hyaluronan-rich layer that occurs in relation to the various conditions that affect fascia, and the diverse factors that underlie the attendant pathologies.

Cumulative exposure to biological therapy and risk of cancer in patients with psoriasis: a meta-analysis of Psonet studies from Israel, Italy, Spain, the U.K. and Republic of Ireland.

BACKGROUND: Cancer risk following long-term exposure to systemic immunomodulatory therapies in patients with psoriasis is possible. OBJECTIVES: To assess a dose-response relationship between cumulative length of exposure to biological therapy and risk of cancer. METHODS: Four national studies (a healthcare database from Israel, and prospective cohorts form Italy, Spain and the U.K. and Republic of Ireland) collaborating through Psonet (European Registry of Psoriasis) participated in these nested case-control studies, including nearly 60 000 person-years of observation. 'Cases' were patients who developed an incident cancer. Patients with previous cancers and benign or in situ tumours were excluded. Four cancer-free controls were matched to each case on year of birth, sex, geographic area and registration year. Follow-up for controls was censored at the date of cancer diagnosis for the matched case. Conditional logistic regression was performed by each registry. Results were pooled using random-effects meta-analysis. RESULTS: A total of 728 cases and 2671 controls were identified. After matching, differences between cases and controls were present for the Charlson Comorbidity Index in all three registries, and in the prevalence of previous exposure to psoralen-ultraviolet A and smoking (the British Association of Dermatologists Biologic Interventions Register only). The risk of first cancers was not significantly associated with cumulative exposure to biologics (adjusted odds ratio per year of exposure 1·02, 95% confidence interval 0·92-1·13). Results were similar if squamous and basal cell carcinomas were included in the outcome. CONCLUSIONS: Cumulative length of exposure to biological therapies in patients with psoriasis in real-world clinical practice does not appear to be linked to a higher risk of cancer after several years of use.

Biologics combined with conventional systemic agents or phototherapy for the treatment of psoriasis: real-life data from PSONET registries.

BACKGROUND: Biologics have greatly improved psoriasis management. However, primary and secondary non-response to treatment requires innovative strategies to optimize outcomes. OBJECTIVE: To describe the use of combined treatment of biologics with conventional systemic agents or phototherapy in daily clinical practice. METHODS: We collected data on frequency of use, demographics, treatment characteristics and drug survival of biologics combined with conventional systemic agents or phototherapy in five PSONET registries. RESULTS: Of 9922 biologic treatment cycles, 982 (9.9%) were identified as combination treatment. 72.9% of treatment cycles concerned concomitant use of methotrexate, 25.3% concerned concomitant UVB therapy, acitretin or cyclosporin and 1.8% concerned combined treatment with PUVA, fumaric acids or a second biologic. Substantial variation was detected in type and frequency of combination treatments prescribed across registries. Patients initiated on combined treatment had generally severe disease and were affected with psoriasis for many years. The extent to which patients had been priory treated with biologic monotherapy and the proportion of patients affected with psoriatic arthritis differed between registries. Survival rates for etanercept, adalimumab, infliximab and ustekinumab with methotrexate ranged between 43 and 92%, 28 and 83%, 65 and 87% and 53 and 77%, respectively, across registries after one year with no consistent superior survival for a particular biologic. Longest survival on a biologic combined with methotrexate, acitretin or cyclosporin was 103, 78 and 34 months, respectively. CONCLUSION: Methotrexate was the most commonly used concomitant treatment for patients on a biologic. Wide geographical variations in treatment selection and persistence of combination treatment exist. Data derived from ongoing studies may help to determine whether combined treatment is superior to biologic monotherapy.

Age of first exposure to American football and long-term neuropsychiatric and cognitive outcomes.

Previous research suggests that age of first exposure (AFE) to football before age 12 may have long-term clinical implications; however, this relationship has only been examined in small samples of former professional football players. We examined the association between AFE to football and behavior, mood and cognition in a large cohort of former amateur and professional football players. The sample included 214 former football players without other contact sport history. Participants completed the Brief Test of Adult Cognition by Telephone (BTACT), and self-reported measures of executive function and behavioral regulation (Behavior Rating Inventory of Executive Function-Adult Version Metacognition Index (MI), Behavioral Regulation Index (BRI)), depression (Center for Epidemiologic Studies Depression Scale (CES-D)) and apathy (Apathy Evaluation Scale (AES)). Outcomes were continuous and dichotomized as clinically impaired. AFE was dichotomized into <12 and ⩾12, and examined continuously. Multivariate mixed-effect regressions controlling for age, education and duration of play showed AFE to football before age 12 corresponded with >2 × increased odds for clinically impaired scores on all measures but BTACT: (odds ratio (OR), 95% confidence interval (CI): BRI, 2.16,1.19-3.91; MI, 2.10,1.17-3.76; CES-D, 3.08,1.65-5.76; AES, 2.39,1.32-4.32). Younger AFE predicted increased odds for clinical impairment on the AES (OR, 95% CI: 0.86, 0.76-0.97) and CES-D (OR, 95% CI: 0.85, 0.74-0.97). There was no interaction between AFE and highest level of play. Younger AFE to football, before age 12 in particular, was associated with increased odds for impairment in self-reported neuropsychiatric and executive function in 214 former American football players. Longitudinal studies will inform youth football policy and safety decisions.

Injuries to the Chopart joint complex: a current review.

Chopart complex injuries (CCIs) are thought to be uncommon; however, recent literature states the rate of misdiagnosis to be between 20 and 41%. Chopart complex injuries are not ankle injuries, with which they are initially confused due to a similar mechanism of trauma in many cases. Injury to the Chopart complex commonly affects multiple structures. The key to optimal treatment is a high index of clinical suspicion combined with timely accurate imaging studies. Careful diagnostic workup with high-quality radiographs of the foot in neutral position should be obtained. Computed tomography (CT) and/or magnetic resonance imaging (MRI) are recommended to accurately assess bone and soft tissue injury. CCI frequently leads to prolonged swelling, pain and disability. In some cases, it may result in a posttraumatic flatfoot deformity.

Hawkins' type-II talar fracture with subtalar dislocation: A very unusual combination.

We report the unusual case of a 16-year-old young man who sustained a rare association of a Hawkins' type-II talar neck fracture with a complete medial subtalar dislocation (Hawkins type-IIB) that occurred as an isolated injury after indirect trauma during a soccer game. Following closed reduction of the subtalar dislocation, standard radiographs and computed tomography (CT) demonstrated a comminuted fracture of the talus involving the base of the talar neck. Open reduction was performed and the fracture was stabilized by ORIF. At 1-year follow-up, functional and radiographic outcomes were graded as excellent, with no radiographic evidence of talar osteonecrosis.