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In the world of human–robot coexistence, ensuring safe interactions is crucial. Traditional logic-based methods often lack the intuition required for robots, particularly in complex environments where these methods fail to account for all possible scenarios. Reinforcement learning has shown promise in robotics due to its superior adaptability over traditional logic. However, the exploratory nature of reinforcement learning can jeopardize safety. This paper addresses the challenges in planning trajectories for robotic arm manipulators in dynamic environments. In addition, this paper highlights the pitfalls of multiple reward compositions that are susceptible to reward hacking. A novel method with a simplified reward and constraint formulation is proposed. This enables the robot arm to avoid a nonstationary obstacle that never resets, enhancing operational safety. The proposed approach combines scalarized expected returns with a constrained Markov decision process through a Lagrange multiplier, resulting in better performance. The scalarization component uses the indicator cost function value, directly sampled from the replay buffer, as an additional scaling factor. This method is particularly effective in dynamic environments where conditions change continually, as opposed to approaches relying solely on the expected cost scaled by a Lagrange multiplier.

We describe severe hypokalaemia and hypertension due to a mineralocorticoid effect in a patient with myelodysplastic syndrome taking posaconazole as antifungal prophylaxis. Two distinct mechanisms due to posaconazole are identified: inhibition of 11β hydroxylase leading to the accumulation of the mineralocorticoid hormone 11-deoxycorticosterone (DOC) and secondly, inhibition of 11β hydroxysteroid dehydrogenase type 2 (11βHSD2), as demonstrated by an elevated serum cortisol-to-cortisone ratio. The effects were ameliorated by spironolactone. We also suggest that posaconazole may cause cortisol insufficiency. Patients taking posaconazole should therefore be monitored for hypokalaemia, hypertension and symptoms of hypocortisolaemia, at the onset of treatment and on a monthly basis. Treatment with mineralocorticoid antagonists (spironolactone or eplerenone), supplementation of glucocorticoids (e.g. hydrocortisone) or dose reduction or cessation of posaconazole should all be considered as management strategies.

Objective: To assess if 24h urinary cortisol metabolite (UCM) profiles are related to structural cardiac and arterial parameters in those with or at risk of Type 2 diabetes mellitus (T2DM). Design and method: 32 participants, 25-77 years, eGFR> 45 mL/min and no serious illness. Urine was collected over 24 hours. 2D echocardiography and arterial stiffness measures [aortic pulse wave velocity (aPWV) by Arteriograph and cardio-ankle vascular index (CAVI) by VaSera] were performed on the collection day. Steroids were extracted from urine and hydrolysed; derivatives were analysed by GC-MS. Results: Seven UCMs were quantified [tetrahydrocortisol (THF), allo-tetrahydrocortisol (a-THF), tetrahydrocortisone (THE), α-cortol (α-col), β-cortol (β-col), α-cortolone (α-cone), β-cortolone (β-cone)]. Left ventricular mass index (LVMI) correlated positively with 24h cortisol:cortisone metabolites (THF+aTHF+αcol+βcol/THE+αcortolone+βcortolone) and negatively with α:β metabolites (αcol+αcortol/βcol+βcortol), when indexed for body surface area (BSA) and height (r=0.37, 0.48 and r=−0.34, −0.49 respectively). Further, there was a positive relationship between LVMIBSA and THF:THE (r=0.35). aPWV but not CAVI was also related to 24h cortisol:cortisone metabolites (r=0.45). All p

The genetic programs responsible for pulmonary lymphatic maturation prior to birth are not known. To address this gap in knowledge, we developed a novel cell sorting strategy to collect fetal pulmonary lymphatic endothelial cells (PLECs) for global transcriptional profiling. We identified PLECs based on their unique cell surface immunophenotype (CD31+/Vegfr3+/Lyve1+/Pdpn+) and isolated them from murine lungs during late gestation (E16.5, E17.5, E18.5). Gene expression profiling was performed using whole-genome microarrays, and 1,281 genes were significantly differentially expressed with respect to time (FDR q < 0.05) and grouped into six clusters. Two clusters containing a total of 493 genes strongly upregulated at E18.5 were significantly enriched in genes with functional annotations corresponding to innate immune response, positive regulation of angiogenesis, complement & coagulation cascade, ECM/cell-adhesion, and lipid metabolism. Gene Set Enrichment Analysis identified several pathways coordinately upregulated during late gestation, the strongest of which was the type-I IFN-α/β signaling pathway. Upregulation of canonical interferon target genes was confirmed by qRT-PCR and in situ hybridization in E18.5 PLECs. We also identified transcriptional events consistent with a prenatal PLEC maturation program. This PLEC-specific program included individual genes (Ch25h, Itpkc, Pcdhac2 and S1pr3) as well as a set of chemokines and genes containing an NF-κB binding site in their promoter. Overall, this work reveals transcriptional insights into the genes, signaling pathways and biological processes associated with pulmonary lymphatic maturation in the fetal lung., Competing Interests: The authors have declared that no competing interests exist.

Airway smooth muscle (ASM) is a dynamic and complex tissue involved in regulation of bronchomotor tone, but the molecular events essential for the maintenance of ASM homeostasis are not well understood. Observational and genome-wide association studies in humans have linked airway function to the nutritional status of vitamin A and its bioactive metabolite retinoic acid (RA). Here, we provide evidence that ongoing RA signaling is critical for the regulation of adult ASM phenotype. By using dietary, pharmacologic, and genetic models in mice and humans, we show that (a) RA signaling is active in adult ASM in the normal lung, (b) RA-deficient ASM cells are hypertrophic, hypercontractile, profibrotic, but not hyperproliferative, (c) TGF-β signaling, known to cause ASM hypertrophy and airway fibrosis in human obstructive lung diseases, is hyperactivated in RA-deficient ASM, (d) pharmacologic and genetic inhibition of the TGF-β activity in ASM prevents the development of the aberrant phenotype induced by RA deficiency, and (e) the consequences of transient RA deficiency in ASM are long-lasting. These results indicate that RA signaling actively maintains adult ASM homeostasis, and disruption of RA signaling leads to aberrant ASM phenotypes similar to those seen in human chronic airway diseases such as asthma.

Bone morphogenetic protein 9 (BMP9) promotes the acquisition of the cholinergic phenotype in basal forebrain cholinergic neurons (BFCN) during development and protects these neurons from cholinergic dedifferentiation following axotomy when administered in vivo. A decline in BFCN function occurs in patients with Alzheimer's disease (AD) and contributes to the AD-associated memory deficits. We infused BMP9 intracerebroventricularly for 7 d in transgenic AD model mice expressing green fluorescent protein specifically in cholinergic neurons (APP.PS1/CHGFP) and in wild-type littermate controls (WT/CHGFP). We used 5-mo-old mice, an age when the AD transgenics display early amyloid deposition and few cholinergic defects, and 10-mo-old mice, by which time these mice exhibit established disease. BMP9 infusion reduced the number of Aβ42-positive amyloid plaques in the hippocampus and cerebral cortex of 5- and 10-mo-old APP.PS1/CHGFP mice and reversed the reductions in choline acetyltransferase protein levels in the hippocampus of 10-mo-old APP.PS1/CHGFP mice. The treatment increased cholinergic fiber density in the hippocampus of both WT/CHGFP and APP.PS1/CHGFP mice at both ages. BMP9 infusion also increased hippocampal levels of neurotrophin 3, insulin-like growth factor 1, and nerve growth factor and of the nerve growth factor receptors, tyrosine kinase receptor A and p75/NGFR, irrespective of the genotype of the mice. These data show that BMP9 administration is effective in reducing the Aβ42 amyloid plaque burden, reversing cholinergic neuron abnormalities, and generating a neurotrophic milieu for BFCN in a mouse model of AD and provide evidence that the BMP9-signaling pathway may constitute a therapeutic target for AD.