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Adrenal insufficiency (AI) is a severe endocrine disorder characterized by insufficient glucocorticoid (GC) and/or mineralocorticoid (MC) secretion by the adrenal glands, due to impaired adrenal function (primary adrenal insufficiency, PAI) or to insufficient adrenal stimulation by pituitary ACTH (secondary adrenal insufficiency, SAI) or tertiary adrenal insufficiency due to hypothalamic dysfunction. In this review, we describe rare genetic causes of PAI with isolated GC or combined GC and MC deficiencies and we also describe rare syndromes of isolated MC deficiency. In children, the most frequent cause of PAI is congenital adrenal hyperplasia (CAH), a group of adrenal disorders related to steroidogenic enzyme deficiencies, which will not be included in this review. Less frequently, several rare diseases can cause PAI, either affecting exclusively the adrenal glands or with systemic involvement. The diagnosis of these diseases is often challenging, due to the heterogeneity of their clinical presentation and to their rarity. Therefore, the current review aims to provide an overview on these rare genetic forms of paediatric PAI, offering a review of genetic and clinical features and a summary of diagnostic and therapeutic approaches, promoting awareness among practitioners, and favoring early diagnosis and optimal clinical management in suspect cases.

Abstract The airway epithelium represents the main barrier between inhaled air and the tissues of the respiratory tract and is therefore an important point of contact with xenobiotic substances into the human body. Several studies have recently shown that in vitro models of the airway grown at an air–liquid interface (ALI) can be particularly useful to obtain mechanistic information about the toxicity of chemical compounds. However, such methods are not very amenable to high throughput since the primary cells cannot be expanded indefinitely in culture to obtain a sustainable number of cells. Induced pluripotent stem cells (iPSCs) have become a popular option in the recent years for modelling the airways of the lung, but despite progress in the field, such models have so far not been assessed for their ability to metabolise xenobiotic compounds and how they compare to the primary bronchial airway model (pBAE). Here, we report a comparative analysis by TempoSeq (oligo-directed sequencing) of an iPSC-derived airway model (iBAE) with a primary bronchial airway model (pBAE). The iBAE and pBAE were differentiated at an ALI and then evaluated in a 5-compound screen with exposure to a sub-lethal concentration of each compound for 24 h. We found that despite lower expression of xenobiotic metabolism genes, the iBAE similarly predicted the toxic pathways when compared to the pBAE model. Our results show that iPSC airway models at ALI show promise for inhalation toxicity assessments with further development. Graphical abstract

Homograft heart valves may have significant advantages and are preferred for the repair of congenital valve malformations, especially in young women of childbearing age, athletes and in patients with active endocarditis. A growing problem, however, is the mismatch between tissue donation and the increasing demand. The aim of this paper is to describe the initiation process of a homograft procurement program to attenuate the shortage of organs. A comprehensive description of the infrastructure and procedural steps required to initiate a cardiac and vascular tissue donation program combined with a prospective follow-up of all homografts explanted at our institution. Between January 2020 and May 2022, 28 hearts and 12 pulmonary bifurcations were harvested at our institution and delivered to the European homograft bank. Twenty-seven valves (19 pulmonary valves, 8 aortic valves) were processed and allocated for implantation. The reasons for discarding a graft were either contamination (n = 14), or morphology (n = 13) or leaflet damage (n = 2). Five homografts (3 PV, 2 AV) have been cryopreserved and stored while awaiting allocation. One pulmonary homograft with a leaflet cut was retrieved by bicuspidization technique and awaits allocation, as a highly requested small diameter graft. The implementation of a tissue donation program in cooperation with a homograft bank can be achieved with reasonable additional efforts at a transplant center with an in-house cardiac surgery department. Challenging situations with a potential risk of tissue injury during procurement include re-operation, harvesting by a non-specialist surgeon and prior central cannulation for mechanical circulatory support.

Aims As the first long-term RCT on insoluble cereal fibre, the optimal fibre trial demonstrated glycometabolic benefits, confirming cohort studies. The combined study intervention of lifestyle recommendations and supplementation with insoluble oat hulls fibre allows to clarify, which amount of fibre is required for a beneficial effect. Methods One hundred and eighty participants with impaired glucose tolerance underwent the one-year PREDIAS lifestyle programme and received a blinded, randomized fibre or placebo supplement for two years. We conducted a regression analyses and cut-off-based tertile comparisons in subjects with full data on dietary compliance (food records and accounted supplement; n = 120) after one year, investigating effects on fasting blood parameters, oral glucose tolerance test and anthropometry. Results We found a nonlinear inverse relation between fibre intake and change in postprandial 2-h glucose levels, showing a metabolic benefit beyond 14 g and a plateau beyond 25 g of total insoluble fibre per day. 2-h glucose levels improved significantly stronger in both upper tertiles (−0.9 [−1.6;−0.2] mmol/l, p = 0.047, and −0.6 [−1.6;0.3] mmol/l, p = 0.010) compared to the lowest tertile (0.1 [−1.2;1.1] mmol/l), also when adjusted for changes in bodyweight. Subjects with the highest fibre intake showed superior effects on fasting and postprandial insulin resistance, hepatic insulin clearance, leucocyte count and fatty liver index. Conclusions Extending the knowledge on the benefits of insoluble oat hulls fibre, our post hoc analysis demonstrates a dose effect for glycaemia and associated metabolic markers. Further research is needed in order to replicate our findings in larger trials.

Hutchinson-Gilford progeria syndrome (HGPS) is a rare premature ageing disorder caused by a point mutation in the LMNA gene (LMNA c.1824 C > T), resulting in the production of a detrimental protein called progerin. Adenine base editors recently emerged with a promising potential for HGPS gene therapy. However adeno-associated viral vector systems currently used in gene editing raise concerns, and the long-term effects of heterogeneous mutation correction in highly proliferative tissues like the skin are unknown. Here we use a non-integrative transient lentiviral vector system, expressing an adenine base editor to correct the HGPS mutation in the skin of HGPS mice. Transient adenine base editor expression corrected the mutation in 20.8-24.1% of the skin cells. Four weeks post delivery, the HGPS skin phenotype was improved and clusters of progerin-negative keratinocytes were detected, indicating that the mutation was corrected in both progenitor and differentiated skin cells. These results demonstrate that transient non-integrative viral vector mediated adenine base editor expression is a plausible approach for future gene-editing therapies.

The continuum of growth hormone (GH)-IGF-I axis defects extends from severe to mild GH deficiency, through short stature disorders of undefined aetiology, to GH insensitivity disorders which can also be mild or severe. This group of defects comprises a spectrum of endocrine, biochemical, phenotypic and genetic abnormalities. The extreme cases are generally easily diagnosed because they conform to well-studied phenotypes with recognised biochemical features. The milder cases of both GH deficiency and GH insensitivity are less well defined and also overlap with the group of short stature conditions, labelled as idiopathic short stature (ISS). In this review the continuum model, which plots GH sensitivity against GH secretion, will be discussed. Defects causing GH deficiency and GH insensitivity will be described, together with the use of a diagnostic algorithm, designed to aid investigation and categorisation of these defects. The continuum will also be discussed in the context of growth-promoting endocrine therapy.

During reactive transport modeling, the computing cost associated with chemical equilibrium calculations can be 10 to 10,000 times higher than that of fluid flow, heat transfer, and species transport computations. These calculations are performed at least once per mesh cell and once per time step, amounting to billions of them throughout the simulation employing high-resolution meshes. To radically reduce the computing cost of chemical equilibrium calculations (each requiring an iterative solution of a system of nonlinear equations), we consider an on-demand machine learning algorithm that enables quick and accurate prediction of new chemical equilibrium states using the results of previously solved chemical equilibrium problems within the same reactive transport simulation. The training operations occur on-demand, rather than before the start of the simulation when it is not clear how many training points are needed to accurately and reliably predict all possible chemical conditions that may occur during the simulation. Each on-demand training operation consists of fully solving the equilibrium problem and storing some key information about the just computed chemical equilibrium state (which is used subsequently to rapidly predict similar states whenever possible). We study the performance of the on-demand learning algorithm, which is mass conservative by construction, by applying it to a reactive transport modeling example and achieve a speed-up of one or two orders of magnitude (depending on the activity model used). The implementation and numerical tests are carried out in Reaktoro (reaktoro.org), a unified open-source framework for modeling chemically reactive systems.

Thermal spallation drilling is a contact-less means of borehole excavation that works by exposing a rock surface to a high-temperature jet flame. In this study, we investigate crucial factors for the success of such thermal drilling operations using numerical simulations of the thermomechanical processes leading to rock failure at the borehole surface. To that end, we integrate a model developed for spalling failure with our thermomechanical simulations. In particular, we consider the role of material heterogeneities, maximum jet-flame temperature and maximum jet-flame temperature rise time on the onset of inelastic deformation and subsequent damage. We further investigate differences in energy consumption for the studied system configurations. The simulations highlight the importance of material composition, as thermal spallation is favored in fine-grained material with strong material heterogeneity. The model is used to test the relationship between the jet-flame temperature and the onset of thermal spallation.

Three new 2-pyrral amino acid Schiff base palladium (II) complexes were synthesized, characterized and their activity against six bacterial species was investigated. The ligands: Potassium 2-pyrrolidine-L-methioninate (L1), Potassium 2-pyrrolidine-L-histidinate (L2) and Potassium 2-pyrrolidine-L-tryptophanate (L3) were synthesized and reacted with dichloro(1,5-cyclooctadiene)palladium(II) to form new palladium (II) complexes C1, C2 and C3, respectively. 1H NMR, FTIR, UV–Vis, elemental analysis and conductivity measurements were used to characterize the products. The antibacterial activities of the compounds were evaluated against Gram-positive Staphylococcus aureus (S. aureus, ATCC 25923), methicillin-resistant Staphylococcus aureus (MRSA, ATCC 33591), Staphylococcus epidermidis (S. epidermidis, ATCC 12228) and Streptococcus pyogenes (S. pyogenes, ATCC 19615) and, gram-negative Pseudomonas aeruginosa (P. aeruginosa, ATCC 27853) and Klebsiella pneumoniae (K. pneumoniae, ATCC 13883) using the agar well diffusion assay and microtitre plate serial dilution method. The palladium complexes were active against the selected bacteria with the imidazole ring containing complex C2 and indole heterocyclic ring containing complex C3 showing the highest activity.

Mineral precipitation can drastically alter a reservoir’s ability to transmit mass and energy during various engineering/natural subsurface processes, such as geothermal energy extraction and geological carbon dioxide sequestration. However, it is still challenging to explain the relationships among permeability, porosity, and precipitation patterns in reservoirs, particularly in fracture-dominated reservoirs. Here, we investigate the pore-scale behavior of single-species mineral precipitation reactions in a fractured porous medium, using a phase field lattice-Boltzmann method. Parallel to the main flow direction, the medium is divided into two halves, one with a low-permeability matrix and one with a high-permeability matrix. Each matrix contains one flow-through and one dead-end fracture. A wide range of species diffusivity and reaction rates is explored to cover regimes from advection- to diffusion-dominated, and from transport- to reaction-limited. By employing the ratio of the Damkohler (Da) and the Peclet (Pe) number, four distinct precipitation patterns can be identified, namely (1) no precipitation (Da/Pe 100), (3) fracture isolation (1 1), and (4) diffusive precipitation (1 < Da/Pe

An assisted method to segment Visceral Adipose Tissue (VAT) and Subcutaneous Adipose Tissue (SAT) from Magnetic Resonance Imaging (MRI) slices is presented. The segmentation process, called shape-based segmentation, consists in three main steps: 1) to draw a series of closed curves at different slices that separates the abdominal structures of interest, 2) to generate a 3D model from the closed curves for each abdominal structure by using shape-based interpolation and 3) to apply a segmentation algorithm to define the adipose tissue. The 3D models considerably simplify the problem since the abdominal structures are separated, and in turn, this reduces the possibility of large segmentation errors. In addition, a fully automatic segmentation procedure was also implemented. Twenty slices of MRI at the abdominal region for each of twelve subjects were analysed. The results of the shape-based and automatic segmentation were compared with the expert segmentation carried out in the slice located at the umbilicus level. Correlation Coefficient (CC) and volume error (VE) were used as performance measures. The comparison between the expert and shape-based segmentation for SAT yielded results of CC= 0.974 and VE=-0.01 ± 5.8 cm3, while for VAT the performance indexes were CC= 0.993 and VE= 0.9 ± 1.8 cm3. The results suggest that the shape-based segmentation provides an accurate and simple assessment of the abdominal adiposity with minimal human intervention and it could be used as a simple tool in clinics.

Background Diffusion weighted imaging (DWI) with intravoxel incoherent motion (IVIM) modelling can inform on tissue perfusion without exogenous contrast administration. Dynamic-contrast-enhanced (DCE) MRI can also characterise tissue perfusion, but requires a bolus injection of a Gadolinium-based contrast agent. This study compares the use of DCE-MRI and IVIM-DWI methods in assessing response to anti-angiogenic treatment in patients with colorectal liver metastases in a cohort with confirmed treatment response. Methods This prospective imaging study enrolled 25 participants with colorectal liver metastases to receive Regorafenib treatment. A target metastasis > 2 cm in each patient was imaged before and at 15 days after treatment on a 1.5T MR scanner using slice-matched IVIM-DWI and DCE-MRI protocols. MRI data were motion-corrected and tumour volumes of interest drawn on b=900 s/mm2 diffusion-weighted images were transferred to DCE-MRI data for further analysis. The median value of four IVIM-DWI parameters [diffusion coefficient D (10−3 mm2/s), perfusion fraction f (ml/ml), pseudodiffusion coefficient D* (10−3 mm2/s), and their product fD* (mm2/s)] and three DCE-MRI parameters [volume transfer constant Ktrans (min−1), enhancement fraction EF (%), and their product KEF (min−1)] were recorded at each visit, before and after treatment. Changes in pre- and post-treatment measurements of all MR parameters were assessed using Wilcoxon signed-rank tests (P Functional MR parameters were also compared against Response Evaluation Criteria In Solid Tumours v.1.1 (RECIST) evaluations. Results Significant treatment-induced reductions of DCE-MRI parameters across the cohort were observed for EF (91.2 to 50.8%, P−1, Ptrans (0.109 to 0.078 min−1, P=0.002). For IVIM-DWI, only D (a non-perfusion parameter) increased significantly post treatment (0.83 to 0.97 × 10−3 mm2/s, Ptrans and D* (r=0.60; P=0.002) and fD* (r=0.67; P Conclusion IVIM-DWI perfusion-related parameters showed limited sensitivity to the anti-angiogenic effects of Regorafenib treatment in colorectal liver metastases and showed low correlation with DCE-MRI parameters, despite profound and significant post-treatment reductions in DCE-MRI measurements. Trial registration NCT03010722 clinicaltrials.gov; registration date 6th January 2015.

Parkinson’s disease is a neurodegenerative pathology difficult to diagnose. Researches have confirmed the presences of death cells in the brain produced by the modification of a protein called alpha-synuclein synuclein in people with Parkinson disease. Currently, a great amount of research is conducted to identify its biomarkers for early diagnostics. Recently, a studio found differences between the alpha- synuclein of the skin from Parkinson’s disease and normal patients. In this paper, we use Raman spectroscopy through a numerical model to simulate the vibrational modes of well-defined finite clusters of alpha-synuclein in normal and pathological state, using the Gaussian09 software. The results of the model in the range of x − y cm−1 are in good agreement with the experimental Raman spectra acquired from human skin with alpha-synuclein in the normal and pathological state.

Computerized Perimetry (CP) is one of the clinical tests commonly used to evaluate peripheral vision and monitor the progress of eye diseases such as glaucoma. The aim of CP is to determine retinal sensitivity using luminous stimuli of variable intensity at different positions of the visual field. In modern campimetry devices, patients must respond to each perceived stimulus by pressing a button; however, this characteristic makes the test more susceptible to spurious and erroneous interpretations due to tiredness, lack of concentration, or device design flaws. This work presents an alternative paradigm for automatically assessing stimulus perception through a low-cost eye tracker and a computer monitor. We tested the preliminary version of the paradigm among eight subjects and obtained favorable results. In conclusion, our eye-tracking paradigm tool could help design more reliable visual field tests using low-cost portable equipment.

RATIONALE AND OBJECTIVES: Rimcazole, a σ-receptor antagonist with affinity for the dopamine transporter (DAT), decreases rates of cocaine self-administration at doses lower than those that affect food-reinforced responding. As response rates are multiply determined, behavioral-economic analyses were used to provide measures of the reinforcing effectiveness of cocaine and food after rimcazole treatment. Further, effects of combinations of the DAT inhibitor, methylphenidate, and σ-receptor antagonists (BD1008, BD1063) were compared to those of rimcazole to assess mechanism of rimcazole effects. METHODS: Male Sprague-Dawley rats were trained to lever press with food reinforcement (one or three 20-mg sucrose pellets) or cocaine injection (0.1 or 0.32 mg/kg) under fixed-ratio (FR) 5-response schedules. Drugs or vehicle were administered (i.p.) 5-min before sessions in which FR value was increased from 5 to 80. Economic demand functions were generated from effects of FR value (price) on intake (consumption), with the parameters of demand, consumption at no cost (Q(0)) and sensitivity to price (essential value, EV), derived. RESULTS: Rimcazole dose-dependently decreased Q(0) and EV at both cocaine doses/injection. In contrast, rimcazole had no effect on these parameters at either food amount. Combinations of methylphenidate and the σ-receptor antagonists decreased Q(0) at the lower cocaine dose/injection, but had no effect on EV; these treatments were ineffective on both economic parameters at the higher cocaine dose/injection and at either food amount. CONCLUSIONS: Though the drug combinations only replicated rimcazole’s effects incompletely, the present results suggest a specific decrease in the reinforcing effects of cocaine due to dual DAT σ-receptor blockade.

To study the evolution and optimal management of metastatic bone disease (mBD) in patients with neuroendocrine neoplasms (NENs). Seventy-four patients were recruited from four NEN centers in this observational multicenter study. Pancreas and small bowel were the most common primaries (30 and 27%, respectively). Almost all gastrointestinal (GI)-NENs were grades 1 and 2, whereas bronchopulmonary-thymic were atypical carcinoids. Thirty-two (43%) patients had synchronous metastatic bone disease (mBD) and three patients reported bone-specific symptoms; metachronous mBD developed at a median of 35 (range: 4–395) months. Thirty-six (86%) of patients with metachronous mBD had stage IV disease at diagnosis. Somatostatin receptor functional imaging and computed tomography were the modalities mostly used for mBD identification. Fifty-two patients received assessable bone-related therapy (bisphosphonates, denosumab, local radiotherapy, and radionuclide treatment). Improvement in mBD was seen in 5, stable disease in 22, and deterioration in 25 patients. The presence of synchronous mBD and the negative outcome of bone-related therapy negatively affected overall survival (OS). In the multivariate analysis, the stronger predictor of OS was the outcome of bone-related therapy (HR: 4.753; 95% CI: 1.589–14.213). Bisphosphonates therapy was the mostly used bone-specific treatment but its monthly administration did not affect OS. At last follow-up, 39 patients were alive with OS 50 (14–463) months. Early investigation for mBD offers a prognostic marker of patients with NENs, since synchronous mBD has a negative impact on survival. The outcome of bone-related therapy affects OS but the monthly administration of bisphosphonates did not show a benefit over less intense schemes.

Lehrkrafte gelten als wichtige Akteure im Bildungsbereich mit substantiellem Einfluss auf das Lernen und die psychosoziale Entwicklung ihrer Schuler/-innen. Das gesellschaftliche Ansehen des Lehrerberufs durfte bedeutsam sein fur die Studienwahl von Abiturient/-innen und die berufliche Zufriedenheit der Lehrkrafte. 1995 betitelte ein niedersachsischer Ministerprasident Lehrkrafte noch als „faule Sacke“. Durch die Analyse von Printmedien soll gepruft werden, wie sich das gesellschaftliche Ansehen von Lehrkraften mittlerweile darstellt. In dieser Studie wurde eine Zufallsstichprobe von N = 570 Artikeln der Printmedien FOCUS, DER SPIEGEL und DIE ZEIT analysiert, die zwischen 2004 und 2014 veroffentlicht und in denen der Lehrerberuf thematisiert wurde. Insgesamt N = 1653 Textstellen wurden qualitativen und quantitativen Inhaltsanalysen unterzogen, um die Fragen zu beantworten, wie Lehrkrafte und der Lehrerberuf in Printmedien dargestellt werden, d. h. uber welche Themen mit welcher Valenz berichtet wird. Es zeigt sich, dass uber alle mit dem Lehrerberuf im Zusammenhang stehenden Themen wie den Unterricht, die Aus- und Weiterbildung, die Arbeitsbedingungen, den Lehrkraftearbeitsmarkt und das Schulsystem negativ, uber die Lehrkrafte selbst hingegen weniger negativ berichtet wird. Neutral bis positiv wird die Motivation von Lehrkraften in allen drei Printmedien dargestellt, d. h. die „faule Sacke“-These trifft nicht zu. Zwischen den Printmedien zeigen sich Unterschiede in der Valenz: Der FOCUS stellt Lehrkrafte bezogen auf ihr Wissen und Konnen, ihre Personlichkeit und ihren gesellschaftlichen Einfluss leicht positiv dar, die anderen Medien berichten positiv ausschlieslich uber die Motivation (SPIEGEL) oder den gesellschaftlichen Einfluss (ZEIT).

As planetary boundaries loom, there is an urgent need to develop sustainable equilibriums between societies and the resources they consume, thereby avoiding regime shifts to undesired states. Transient system trajectories to a stable state may differ substantially, posing significant challenges to distinguishing sustainable from unsustainable trajectories. We use stylized models to show how feedbacks between anthropogenic harvest regimes and resource availability drive transient dynamics. We show how substantial time lags may occur between interventions and social-ecological outcomes, and that sudden system collapses need not be linked to recent environmental changes. Historical reconstructions of island state populations show a variety of transient dynamics that closely corresponds to model expectations based on island differences in productivity and harvesting regime. We conclude that vulnerable social-ecological systems may persist when the population:resource ratio remains within a viable range of intermediate (rather than small) values, which implies that averting environmental crises may require counter-intuitive measures. Transient states influence the sustainable or unsustainable trajectories of social-ecological systems and lead to time lags between rapid regime shifts and the change or intervention which caused them, according to theoretical models of island states.