From source to sink in central Gondwana: Exhumation of the Precambrian basement rocks of Tanzania and sediment accumulation in the adjacent Congo basin

Apatite fission track (AFT) and (U-Th)/He (AHe) thermochronometry data are reported and used to unravel the exhumation history of crystalline basement rocks from the elevated (>1000 m above sea level) but low-relief Tanzanian Craton. Coeval episodes of sedimentation documented within adjacent Paleozoic to Mesozoic basins of southern Tanzania and the Congo basin of the Democratic Republic of Congo indicate that most of the cooling in the basement rocks in Tanzania was linked to erosion. Basement samples were from an exploration borehole located within the craton and up to 2200 m below surface. Surface samples were also analyzed. AFT dates range between 317 ± 33 Ma and 188 ± 44 Ma. Alpha (Ft)-corrected AHe dates are between 433 ± 24 Ma and 154 ± 20 Ma. Modeling of the data reveals two important periods of cooling within the craton: one during the Carboniferous-Triassic (340–220 Ma) and a later, less well constrained episode, during the late Cretaceous. The later exhumation is well detected proximal to the East African Rift (70 Ma). Thermal histories combined with the estimated geothermal gradient of 9°C/km constrained by the AFT and AHe data from the craton and a mean surface temperature of 20°C indicate removal of up to 9 ± 2 km of overburden since the end of Paleozoic. The correlation of erosion of the craton and sedimentation and subsidence within the Congo basin in the Paleozoic may indicate regional flexural geodynamics of the lithosphere due to lithosphere buckling induced by far-field compressional tectonic processes and thereafter through deep mantle upwelling and epeirogeny tectonic processes

Combined cardiological and neurological abnormalities due to filamin A gene mutation

Background: Cardiac defects can be the presenting symptom in patients with mutations in the X-linked gene FLNA. Dysfunction of this gene is associated with cardiac abnormalities, especially in the left ventricular outflow tract, but can also cause a congenital malformation of the cerebral cortex. We noticed that some patients diagnosed at the neurogenetics clinic had first presented to a cardiologist, suggesting that earlier recognition may be possible if the diagnosis is suspected. Methods and results: From the Erasmus MC cerebral malformations database 24 patients were identified with cerebral bilateral periventricular nodular heterotopia (PNH) without other cerebral cortical malformations. In six of these patients, a pathogenic mutation in FLNA was present. In five a cardiac defect was also found in the outflow tract. Four had presented to a cardiologist before the cerebral abnormalities were diagnosed. Conclusions: The cardiological phenotype typically consists of aortic or mitral regurgitation, coarctation of the aorta or other left-sided cardiac malformations. Most patients in this category will not have a FLNA mutation, but the presence of neurological complaints, hyperlaxity of the skin or joints and/or a family history with similar cardiac or neurological problems in a possibly X-linked pattern may alert the clinician to the possibility of a FLNA mutation

Temperature effects on DNA damage during hibernation

During multiday torpor, deep-hibernating mammals maintain a hypometabolic state where heart rate and ventilation are reduced to 2%–4% of euthermic rates. It is hypothesized that this ischemia-like condition may cause DNA damage through reactive oxygen species production. The reason for intermittent rewarming (arousal) during hibernation might be to repair the accumulated DNA dam-age. Because increasing ambient temperatures (Ta’s) shortens torpor bout duration, we hypothesize that hibernating at higher Ta’swill result in a faster accumulation of genomic DNA damage. To test this, we kept 39 male and female garden dormice at a Ta of either 57C or 107C and obtained tissue at 1, 4, and 8 d in torpor to assess DNA damage and recruitment of DNA repair markers in splenocytes. DNA damage in splenocytes measured by comet assay was significantly higher in almost all torpor groups than in sum-mer euthermic groups. Damage accumulates in the first days of torpor at Ta = 57C (between days 1 and 4) but not at Ta = 107C. At the higher Ta, DNA damage is high at 24 h in torpor, indicating either a faster buildup of DNA damage at higher Ta’soranin-complete repair during arousals in dormice. At 57C, recruitment of the DNA repair protein 53BP1 paralleled the increase in DNA damage over time during torpor. In contrast, after 1 d in torpor at 107C, DNA damage levels were high, but 53BP1 was not re-cruited to the nuclear DNA yet. The data suggest a potential mis-match in the DNA damage/repair dynamics during torpor at higher Ta’s.</p

A randomized controlled trial of three years growth hormone and gonadotropin-releasing hormone agonist treatment in children with idiopathic short stature and intrauterine growth retardation

We assessed the effectiveness and safety of 3 yr combined GH and GnRH agonist (GnRHa) treatment in a randomized controlled study in children with idiopathic short stature (ISS) or intrauterine growth retardation (IUGR). Gonadal suppression, GH reserve, and adrenal development were assessed by hormone measurements in both treated children and controls during the study period. Thirty-six short children, 24 girls (16 ISS/8 IUGR) and 12 boys (8 ISS/4 IUGR), with a height SD score of -2 SD or less in early puberty (girls, B2-3; boys, G2-3), were randomly assigned to treatment (n = 18) with GH (genotropin 4 IU/m(2). day) and GnRHa (triptorelin, 3.75 mg/28 days) or no treatment (n = 18). At the start of the study mean (SD) age was 11.4 (0.56) or 12.2 (1.12) yr whereas bone age was 10.7 (0.87) or 10.9 (0.63) yrs in girls and boys, respectively. During 3 yr of study height SD score for chronological age did not change in both treated children and controls, whereas a decreased rate of bone maturation after treatment was observed [mean (SD) 0.55 (0.21) 'yr'/yr vs. 1.15 (0.37) 'yr'/yr in controls, P < 0.001, girls and boys together]. Height SD score for bone age and predicted adult height increased significantly after 3 yr of treatment; compared with controls the predicted adult height gain was 8.0 cm in girls and 10.4 cm in boys. Furthermore, the ratio between sitting height/height SD score decreased significantly in treated children, whereas body mass index was not influenced by treatment. Puberty was effectively arrested in the treated children, as was confirmed by physical examination and prepubertal testosterone and estradiol levels. GH-dependent hormones including serum insulin-like growth factor I and II, carboxy terminal propeptide of type I collagen, amino terminal propeptide of type III collagen, alkaline phosphatase, and osteocalcin were not different between treated children and controls during the study period. Thus, a GH dose of 4 IU/m(2) seems adequate for stabilization of the GH reserve and growth in these GnRHa-treated children. We conclude that 3 yr treatment with GnRHa was effective in suppressing pubertal development and skeletal maturation, whereas the addition of GH preserved growth velocity during treatment. This resulted in a considerable gain in predicted adult height, without demonstrable side effects. Final height results will provide the definite answer on the effectiveness of this combined treatment

Successful Stepwise Development of Patient Research Partnership: 14 years’ experience of actions and consequences in Outcome Measures in Rheumatology (OMERACT)

There is increasing interest in making patient participation an integral component of medical research. However, practical guidance on optimizing this engagement in healthcare is scarce. Since 2002, patient involvement has been one of the key features of the Outcome Measures in Rheumatology (OMERACT) international consensus effort. Based on a review of cumulative data from qualitative studies and internal surveys among OMERACT participants, we explored the potential benefits and challenges of involving patient research partners in conferences and working group activities. We supplemented our review with personal experiences and reflections regarding patient participation in the OMERACT process. We found that between 2002 and 2016, 67 patients have attended OMERACT conferences, of whom 28 had sustained involvement; many other patients contributed to OMERACT working groups. Their participation provided face validity to the OMERACT process and expanded the research agenda. Essential facilitators have been the financial commitment to guarantee sustainable involvement of patients at these conferences, procedures for recruitment, selection and support, and dedicated time allocated in the program for patient issues. Current challenges include the representativeness of the patient panel, risk of pseudo-professionalization, and disparity in patients’ and researchers’ perception of involvement. In conclusion, OMERACT has embedded long-term patient involvement in the consensus-building process on the measurement of core health outcomes. This integrative process continues to evolve iteratively. We believe that the practical points raised here can improve participatory research implementation

Exploring discordance between Health Literacy Questionnaire scores of people with RMDs and assessment by treating health professionals

OBJECTIVES: We studied discordance between health literacy of people with rheumatic and musculoskeletal diseases (RMDs) and assessment of health literacy by their treating health professionals, and explored whether discordance is associated with the patients' socioeconomic background. METHODS: Patients with rheumatoid arthritis (RA), spondyloarthritis (SpA), or gout from three Dutch outpatient rheumatology clinics completed the nine-domain Health Literacy Questionnaire (HLQ). Treating health professionals assessed their patients on each HLQ domain. Discordance per domain was defined as a ≥ 2-point difference on a 0-10 scale (except if both scores were below three or above seven), leading to three categories: "negative discordance" (i.e. professional scored lower), "probably the same", or "positive discordance" (i.e. professional scored higher). We used multivariable multilevel multinomial regression models with patients clustered by health professionals to test associations with socioeconomic factors (age, gender, education level, migration background, employment, disability for work, living alone). RESULTS: We observed considerable discordance (21-40% of patients) across HLQ domains. Most discordance occurred for "Critically appraising information" (40.5%, domain 5). Comparatively, positive discordance occurred more frequently. Negative discordance was more frequently and strongly associated with socioeconomic factors, specifically lower education level and non-Western migration background (for five HLQ domains). Associations between socioeconomic factors and positive discordance were less consistent. CONCLUSION: Frequent discordance between patients' scores and professionals' estimations indicates there may be hidden challenges in communication and care, which differ between socioeconomic groups. Successfully addressing patients' health literacy needs cannot solely depend on health professionals' estimations but will require measurement and dialogue

Dual target strategy: a proposal to mitigate the risk of overtreatment and enhance patient satisfaction in rheumatoid arthritis

Commentary - abstract not available

Cost-effectiveness of rotavirus vaccination in the Netherlands; the results of a consensus model

Contains fulltext : 96770.pdf (publisher's version ) (Open Access)BACKGROUND: Each year rotavirus gastroenteritis results in thousands of paediatric hospitalisations and primary care visits in the Netherlands. While two vaccines against rotavirus are registered, routine immunisation of infants has not yet been implemented. Existing cost-effectiveness studies showed inconsistent results for these vaccines because of lack of consensus on the impact. We aimed to investigate which factors had a major impact on cost-effectiveness and were primarily responsible for the large differences in previously estimated cost-effectiveness ratios. METHODS: Based on updated data on health outcomes and cost estimates, we re-assessed the cost-effectiveness of routine paediatric rotavirus vaccination within the National Immunization Program for the Netherlands. Two consensus meetings were organised with national and international experts in the field to achieve consensus and resolve potential controversies. RESULTS: It was estimated that rotavirus vaccination in the Netherlands could avert 34,214 cases of rotavirus gastroenteritis in children aged less than 5 years. Notably, 2,779 hospitalisations were averted of which 315 were extensions of existing hospital stays due to nosocomial rotavirus infection. With a threshold varying from 20K euro - 50K euro per QALY and according to the base-case scenario, the full vaccination costs per child leading to cost-effectiveness was euro 57.76 -euro 77.71. Results were sensitive to the inclusion of potential vaccine induced herd protection, QALY losses and number of deaths associated with rotavirus gastroenteritis. CONCLUSIONS: Our economic analysis indicates that inclusion of rotavirus vaccination in the Dutch National Immunization Program might be cost-effective depending on the cost of the vaccine and the impact of rotavirus gastroenteritis on children's quality of life

Instrument Selection Using the OMERACT Filter 2.1: The OMERACT Methodology.

Objective: Outcome Measures in Rheumatology (OMERACT) Filter 2.1 revised the process used for core outcome measurement set selection to add rigour and transparency in decision making. This paper describes OMERACT’s methodology for instrument selection. Methods: We presented instrument selection processes, tools, and reporting templates at OMERACT 2018, introducing the concept of “3 pillars, 4 questions, 7 measurement properties, 1 answer”. Truth, Discrimination and Feasibility are the three original OMERACT pillars. Based on these, we developed four signaling questions. We introduced the Summary of Measurement Properties (SOMP) table which summarizes the seven measurement properties: Truth (domain match, construct validity), Discrimination (test-retest reliability, longitudinal construct validity (responsiveness), clinical trial discrimination, thresholds of meaning), and Feasibility. These properties address a set of standards which, when met, answer the one question: Is there enough evidence to support the use of this instrument in clinical research of the benefits and harms of treatments in the population and study setting described? The OMERACT Filter 2.1 was piloted on two instruments by the Psoriatic Arthritis Working Group Results: The methodology was reviewed in a full plenary session and facilitated breakout groups. Tools to facilitate retention of the process (i.e., “The OMERACT Way”) were provided. The two instruments were presented and the recommendation of the working group was endorsed in the first OMERACT Filter 2.1 Instrument Selection votes. Conclusion: Instrument Selection using OMERACT Filter 2.1 is feasible and is now being implemented