Histological examination of the rib is of critical value in perinatal pathology and points to the health of the child preceding death. The rib is considered ideal because it is the most rapidly growing long bone in infants and demonstrates growth arrest at onset of the insult. We aimed to identify (1) changes in the perichondrial ring (PR) in the rib of infants and children up to 16 months of age dying suddenly at our institution and (2) any association with presence of histological changes of vitamin D deficiency (VDD)/metabolic bone disease (MBD) in the growth plate. Retrospective review of the PR histology and comparison with the presence or absence of histological features of VDD in the growth plate of 167 cases. The cases were anonymised and divided in six age/gender categories. Periphyseal abnormalities were only seen in 38% of the cases; of whom 33% had established and 67% had mild changes. Only 14.5% of cases with established histological appearance of VDD at the growth plate had significant PR abnormality; of whom majority (83%) were ≤3 months of age and none ≥9 months old, reflecting a temporal relation with birth and beyond the perinatal period. The histological changes in the PR are significantly associated with histological changes of VDD/MBD at the rib growth plate with an OR of 3.04.The histological changes in the PR are significantly associated with histological changes of VDD/MBD at the rib growth plate with an OR of 3.04. Both glucose and triglyceride production are increased in type 2 diabetes and nonalcoholic fatty liver disease (NAFLD). For decades, the leading hypothesis to explain these paradoxical observations has been selective hepatic insulin resistance wherein insulin drives de novo lipogenesis (DNL) while failing to suppress glucose production. Here, we aimed to test this hypothesis in humans. We recruited obese subjects who met criteria for bariatric surgery with ( = 16) or without ( = 15) NAFLD and assessed ) insulin-mediated regulation of hepatic and peripheral glucose metabolism using hyperinsulinemic-euglycemic clamps with [6,6- H ]glucose, ) fasting and carbohydrate-driven hepatic DNL using deuterated water ( H O), and ) hepatocellular insulin signaling in liver biopsy samples collected during bariatric surgery. Compared with subjects without NAFLD, those with NAFLD demonstrated impaired insulin-mediated suppression of glucose production and attenuated-not increased-glucose-stimulated/high-insulin lipogenesis. Fructose-stimulated/low-insulin lipogenesis was intact. Hepatocellular insulin signaling, assessed for the first time in humans, exhibited a proximal block in insulin-resistant subjects Signaling was attenuated from the level of the insulin receptor through both glucose and lipogenesis pathways. The carbohydrate-regulated lipogenic transcription factor was increased in subjects with NAFLD. Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key.Acute increases in lipogenesis in humans with NAFLD are not explained by altered molecular regulation of lipogenesis through a paradoxical increase in lipogenic insulin action; rather, increases in lipogenic substrate availability may be the key. Leucine-rich α-2 glycoprotein 1 (LRG1) is a circulating protein potentially involved in several pathways related to pathogenesis of heart failure (HF). We aimed to study whether plasma LRG1 is associated with risks of incident HF and hospitalization attributable to HF (HHF) in individuals with type 2 diabetes. A total of 1,978 individuals with type 2 diabetes were followed for a median of 7.1 years (interquartile range 6.1-7.6). Association of LRG1 with HF was studied using cause-specific Cox regression models. In follow-up, 191 incident HF and 119 HHF events were identified. As compared with quartile 1, participants with LRG1 in quartiles 3 and 4 had 3.60-fold (95% CI 1.63-7.99) and 5.99-fold (95% CI 2.21-16.20) increased risk of incident HF and 5.88-fold (95% CI 1.83-18.85) and 10.44-fold (95% CI 2.37-45.98) increased risk of HHF, respectively, after adjustment for multiple known cardiorenal risk factors. As a continuous variable, 1 SD increment in natural log-transformed LRG1 was associated with 1.78-fold (95% CI 1.33-2.38) adjusted risk of incident HF and 1.92-fold (95% CI 1.27-2.92) adjusted risk of HHF. Adding LRG1 to the clinical variable-based model improved risk discrimination for incident HF (area under the curve [AUC] 0.79-0.81; = 0.02) and HHF (AUC 0.81-0.84; = 0.02). Plasma LRG1 is associated with risks of incident HF and HHF, suggesting that it may potentially be involved in pathogenesis of HF in individuals with type 2 diabetes. Additional studies are warranted to determine whether LRG1 is a novel biomarker for HF risk stratification.Plasma LRG1 is associated with risks of incident HF and HHF, suggesting that it may potentially be involved in pathogenesis of HF in individuals with type 2 diabetes. Additional studies are warranted to determine whether LRG1 is a novel biomarker for HF risk stratification.Immunocytokines hold great potential as anticancer agents, as they use a specific antitumor antibody to deliver an immune-activating cytokine directly to the immunosuppressive tumor microenvironment (TME). selleck kinase inhibitor We have developed a novel immunocytokine (KD033) composed of a fully human, high-affinity antiprogrammed death-ligand 1 (PD-L1) linked to the sushi-domain of the human IL-15/IL-15 receptor alpha (IL-15/IL-15Rα) complex. A murine PD-L1 cross-reactive KD033 surrogate (srKD033) and a nontargeting antibody (ntKD033) were also developed to investigate mechanism of action in murine tumor models. Efficacy analyses showed a robust antitumor effect of single-dose srKD033 in several diverse syngeneic murine tumor models. In a CT26 murine colon tumor model, single-dose srKD033 produced durable antitumor immunity as evidenced by resistance to subsequent tumor rechallenges. Mice responding to srKD033 treatment showed increased retention of PD-L1/IL-15 in the TME which likely facilitated prolonged IL-15-induced expansion of cytotoxic cells.