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Background: The nucleus accumbens (NAc) mediates reward learning and motivation. Despite an abundance of neuropeptides, peptidergic neurotransmission from the NAc has not been integrated into current models of reward learning. The existence of a sparse population of neurons containing corticotropin-releasing factor (CRF) has been previously documented. Here, we provide a comprehensive analysis of their identity and functional role in shaping reward learning., Methods: Our multidisciplinary approach included fluorescent in situ hybridization (n = ≥3 mice), tract tracing (n = 5 mice), ex vivo electrophysiology (n = ≥30 cells), in vivo calcium imaging with fiber photometry (n = ≥4 mice), and use of viral strategies in transgenic lines to selectively delete CRF peptide from NAc neurons (n = ≥4 mice). Behaviors used were instrumental learning, sucrose preference, and spontaneous exploration in an open field., Results: We showed that the vast majority of NAc CRF-containing neurons are spiny projection neurons (SPNs) comprising dopamine D 1 -, D 2 -, or D 1 /D 2 -containing SPNs that primarily project and connect to the ventral pallidum and to a lesser extent the ventral midbrain. As a population, they display mature and immature SPN firing properties. We demonstrated that NAc CRF-containing neurons track reward outcomes during operant reward learning and that CRF release from these neurons acts to constrain initial acquisition of action-outcome learning and at the same time facilitates flexibility in the face of changing contingencies., Conclusions: CRF release from this sparse population of SPNs is critical for reward learning under normal conditions., (Copyright © 2024 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Rationale and Objectives: There is universal interest in increasing sustainability in health care, including in imaging. We studied and characterized energy consumption in a representative imaging department in Denmark to identify and quantify the effect of specific optimizations., Methods: Protocols and energy parameters for the three main scanner modalities along with supportive systems and workflows were monitored and scrutinized. Potential savings were measured and/or calculated., Results: Only few optimizations were identified at the protocol level. However, examination of usage patterns and cooling systems revealed numerous potential optimizations which fell into three categories. 1) Optimizations requiring minimal changes in installations or workflows, for example, reduction of bed-position time, 2) optimizations requiring altered work flows such as strict adherence to timed shut-down procedures and 3) optimizations requiring retro-fitting equipment, typically at considerable monetary expense, for example fitting variable flow control on pumps. The single biggest identified optimization was raising the temperature of the circulating cooling water., Conclusion: This study highlights the complexity of increasing sustainability in health care, specifically in imaging. We identified multiple potential optimizations but also technical, monetary and organizational barriers preventing immediate implementation., Competing Interests: Declaration of competing interest None of the authors have any conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: We aimed to investigate the quality of evidence and the expected added clinical value of treatments recommended by the Danish Medicines Council (DMC)., Study Design: This was an observational study., Methods: The DMC prepares reports on drugs considered for possible new standard treatments in Danish hospitals. These reports evaluate the available evidence on efficacy and safety. The quality of evidence is systematically rated by the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) criteria, and estimates of added clinical value are presented. The recommendations take into account expected economic implications of new treatments. The publicly available reports up until December 29, 2021, were downloaded from the DMC Web page. Reports on drugs marked "recommended" were included. Data on quality of evidence, expected clinical value, and economic implications were imputed in a Microsoft Excel spreadsheet., Results: Seventy-nine reports were included in the analysis. In 79% of these, the quality of evidence was rated low (24%) or very low (55%), whereas no recommendations were based on evidence rated as high quality. Three (5%) of recommended treatments were expected to add large clinical value., Conclusions: Most recommendations by the DMC are based on evidence formally rated as low or very low quality by GRADE, and no recommendations were based on evidence rated as high quality. The added clinical value of the treatments was often not documented and rarely large. Continued attention to improve the clinical evidence behind national recommendations is necessary., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Aging alters biological processes resulting in body fat redistribution, loss of lean muscle mass, and reduced muscle strength, termed sarcopenia. Nutrition is an important modifiable risk factor in the development of sarcopenia. Food insecurity refers to limited or uncertain access to enough food for an active, healthy life, and is prevalent among older adults. The objective of this study was to examine the relationship between food insecurity and probable sarcopenia in older adults., Methods: We examined 3632 adults ≥60 years old from the 2011-2014 National Health and Nutrition Examination Surveys (NHANES). For our analysis food insecurity was identified using the Food Security Survey Module (FSSM). The primary outcome was based on the Sarcopenia Definitions and Outcomes consortium (SDOC) definition. Secondary outcomes were based on three other different grip strength cut-offs as there is debate within the field as to the optimal definition of sarcopenia. Consistent with the revised European consensus on the definition and diagnosis of Sarcopenia (EWGSOP2) recommendations, we used the term probable sarcopenia throughout this text as definitions were based on muscle strength alone and did not include an evaluation of muscle quality. Sensitivity analyses were performed using the standard four category definition of food security. We used logistic regression to examine the association between food insecurity and sarcopenia., Results: Using the Sarcopenia Definitions and Outcomes Consortium definition, 24.7% were classified as having probable sarcopenia (low grip strength); 5.5% had food insecurity and food insecurity was associated with probable sarcopenia (OR 1.51, 95%CI 1.03-2.22). Using three other definitions of probable sarcopenia, food insecurity was significantly associated with probable sarcopenia using the Foundation for the National Institute of Health definition using grip strength alone (OR 1.71, 95%CI 1.08-2.71), but food insecurity was not associated with food insecurity using definitions related to grip strength/BMI (OR 1.16, 95%CI 0.76-1.78) or grip strength/weight (OR 1.14, 95%CI 0.85-1.54)., Conclusions: In this nationally representative cohort study, individuals classified as having food insecurity were more likely to have probable sarcopenia (low grip strength) compared to those with full food security. Future studies should examine whether food insecurity interventions may reduce probable sarcopenia and associated adverse outcomes., Competing Interests: Conflict of interest None., (Copyright © 2022 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Type 2 diabetes mellitus represents a multi-dimensional challenge for European and global societies alike. Building on an iterative six-step disease management process that leverages feedback loops and utilizes commodity digital tools, the PDM-ProValue study program demonstrated that integrated personalized diabetes management, or iPDM, can improve the standard of care for persons living with diabetes in a sustainable way. The novel "iPDM Goes Europe" consortium strives to advance iPDM adoption by (1) implementing the concept in a value-based healthcare setting for the treatment of persons living with type 2 diabetes, (2) providing tools to assess the patient's physical and mental health status, and (3) exploring new avenues to take advantage of emerging big data resources., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Self-reported weight change may lead to adverse outcomes. We evaluated weight change with cutpoints of low lean mass (LLM) in older adults., Methods: Of 4984 subjects ≥60 years from NHANES 1999-2004, we applied LLM cutoffs of appendicular lean mass (ALM):body mass index (BMI) males<0.789, females<0.512. Self-reported weight was assessed at time of survey, and questions asked participants their weight one and 10 years earlier, and at age 25. Weight changes were categorized as greater/less/none than 5%. Logistic regression assessed weight change (gain, loss, no change) on LLM, after adjustment., Results: Of 4984 participants (56.5% female), mean age and BMI were 71.1 years and 28.2 kg/m 2 . Mean ALM was 19.7 kg. In those with LLM, 13.5% and 16.3% gained/lost weight in the past year, while 48.9% and 19.4% gained/lost weight in the past decade. Compared to weight at age 25, 85.2 and 6.1% of LLM participants gained and lost ≥5% of their weight, respectively. Weight gain over the past year was associated with a higher risk of LLM (OR 1.35 [0.99,1.87]) compared to weight loss ≥5% over the past year (0.89 [0.70,1.12]). Weight gain (≥5%) over 10-years was associated with a higher risk of LLM (OR 2.03 [1.66, 2.49]) while weight loss (≥5%) was associated with a lower risk (OR 0.98 [0.76,1.28]). Results were robust compared to weight at 25 years (gain OR 2.37 [1.76,3.20]; loss OR 0.95 [0.65,1.39])., Conclusion: Self-reported weight gain suggests an increased risk of LLM. Future studies need to verify the relationship with physical function., Competing Interests: Conflicts of interest There are no conflicts of interest pertaining to this manuscript., (Copyright © 2019 Elsevier Ltd and European Society for Clinical Nutrition and Metabolism. All rights reserved.)

Sequestration in the bone marrow niche may allow leukemic stem cells to evade exposure to drugs. Because the CXCR4/SDF-1 axis is an important mechanism of leukemic stem cell interaction with marrow stroma, we tested whether plerixafor, an antagonist of CXCR4, may dislodge chronic myeloid leukemia (CML) cells from the niche, sensitizing them to tyrosine kinase inhibitors. We initially treated mice with retrovirally induced CML-like disease with imatinib plus plerixafor. Plerixafor mobilized CXCR4(+) cells, but no difference was observed in leukemia burden, possibly reflecting insufficient disease control by imatinib. In a second series of experiments, we tested the combination of plerixafor with dasatinib in the same as well as an attenuated CML model. Despite much improved leukemia control, plerixafor failed to reduce leukemia burden over dasatinib alone. In addition, mice receiving plerixafor had an increased incidence of neurologic symptoms in association with CNS infiltration by BCR-ABL-expressing cells. We conclude that plerixafor is ineffective in reducing leukemia burden in this model but promotes CNS infiltration. Beneficial effects of combining tyrosine kinase inhibitors with plerixafor may be observed in a situation of minimal residual disease, but caution is warranted when disease control is incomplete.

Bone marrow failure is a nearly universal complication of Fanconi anemia. The proteins encoded by FANC genes are involved in DNA damage responses through the formation of a multisubunit nuclear complex that facilitates the E3 ubiquitin ligase activity of FANCL. However, it is not known whether loss of E3 ubiquitin ligase activity accounts for the hematopoietic stem cell defects characteristic of Fanconi anemia. Here we provide evidence that FANCL increases the activity and expression of β-catenin, a key pluripotency factor in hematopoietic stem cells. We show that FANCL ubiquitinates β-catenin with atypical ubiquitin chain extension known to have nonproteolytic functions. Specifically, β-catenin modified with lysine-11 ubiquitin chain extension efficiently activates a lymphocyte enhancer-binding factor-T cell factor reporter. We also show that FANCL-deficient cells display diminished capacity to activate β-catenin leading to reduced transcription of Wnt-responsive targets c-Myc and Cyclin D1. Suppression of FANCL expression in normal human CD34(+) stem and progenitor cells results in fewer β-catenin active cells and inhibits expansion of multilineage progenitors. Together, these results suggest that diminished Wnt/β-catenin signaling may be an underlying molecular defect in FANCL-deficient hematopoietic stem cells leading to their accelerated loss.

Proinflammatory cytokines such as TNFα are elevated in patients with myeloproliferative neoplasms (MPN), but their contribution to disease pathogenesis is unknown. Here we reveal a central role for TNFα in promoting clonal dominance of JAK2(V617F) expressing cells in MPN. We show that JAK2(V617F) kinase regulates TNFα expression in cell lines and primary MPN cells and TNFα expression is correlated with JAK2(V617F) allele burden. In clonogenic assays, normal controls show reduced colony formation in the presence of TNFα while colony formation by JAK2(V617F)-positive progenitor cells is resistant or stimulated by exposure to TNFα. Ectopic JAK2(V617F) expression confers TNFα resistance to normal murine progenitor cells and overcomes inherent TNFα hypersensitivity of Fanconi anemia complementation group C deficient progenitors. Lastly, absence of TNFα limits clonal expansion and attenuates disease in a murine model of JAK2(V617F)-positive MPN. Altogether our data are consistent with a model where JAK2(V617F) promotes clonal selection by conferring TNFα resistance to a preneoplastic TNFα sensitive cell, while simultaneously generating a TNFα-rich environment. Mutations that confer resistance to environmental stem cell stressors are a recognized mechanism of clonal selection and leukemogenesis in bone marrow failure syndromes and our data suggest that this mechanism is also critical to clonal selection in MPN.

Background: It is now well accepted that neuroendocrine activation is of pathophysiological and prognostic importance in patients with chronic heart failure (CHF). We hypothesized that the different neuroendocrine factors reflect different aspects of the cardiac dysfunction in CHF patients and that neuroendocrine profiling could be of value. In order to study this, we investigated the relationship between hormones and cardiac dimensions and function of both the right and left ventricle., Methods: Twenty-three patients with newly diagnosed, untreated CHF were included. Right (RVEF) and left ventricular ejection fractions (LVEF) and volumes were measured by means of first-pass and equilibrium radionuclide ventriculography., Results: LVEF was 0.29 (range: 0.11-0.55). Two-thirds of the patients had dilated left ventricles with volumes above upper reference limit. Right ventricular ejection fraction was normal in all subjects as well as right ventricular volumes. Likewise, on average, the lung transit time (LTT) was normal. Brain natriuretic peptide (BNP) significantly correlated with LVEF, left ventricular end-diastolic volume index (LVEDVI) and left ventricular end-systolic volume index (LVESVI). Adrenaline correlated significantly with both right ventricular end-diastolic volume index and right ventricular end-systolic volume index. Lung transit time correlated with atrial natriuretic peptide (ANP) and BNP (only ANP in multivariate analysis)., Conclusions: (1) BNP reflects the LVEF as well as diastolic and systolic dimensions; (2) adrenaline reflects the right ventricular systolic and diastolic dimensions; and (3) ANP reflects the lung transit time. We conclude that "neuroendocrine profiling" may potentially be of diagnostic and therapeutic use.

Aim: The aim of this investigation was (1) to study the effect of untreated chronic heart failure (CHF) on alveolar membrane diffusion capacity (transfer coefficient, K(CO)) in elderly patients and (2) to study the impact of the standard regime of medical treatment with diuretics and ACE-inhibitor/angiotensin-II receptor antagonists on K(CO) in these patients., Methods: Non-medicated patients (except for diuretics) with symptoms of heart failure (NYHA II-III) and echocardiographically estimated left ventricular ejection fraction (LVEF) <0.40 were recruited. All were characterized according to the results of multiple ECG-gated radionuclide ventriculography (MUGA). LVEF<0.50 when measured by MUGA was considered as heart failure (HF). A total of 20 patients fulfilled the criteria. All patients had a lung function test including measurement of K(CO) and a MUGA for LVEF measurement performed prior to medical treatment (baseline) and after 1 year of treatment with diuretics and ACE-inhibitors/angiotensin-II receptor antagonists. Age- and gender-matched healthy volunteers were included as control group., Results: (mean+/-S.E.M.): K(CO) at baseline was 0.95+/-0.06 and 1.25+/-0.04 mmol/min x kPa/l in HF patients and controls, respectively (p<0.05). After 1 year of treatment, K(CO) was normalized in the HF group (1.23+/-0.13 mmol/s x kPa, p<0.05). LVEF increased in the HF group from 0.28+/-0.03 at baseline to 0.34+/-0.03 after 1 year of treatment (p<0.05)., Conclusion: Elderly patients with symptomatic HF (NYHA II-III) and reduced systolic function have respiratory dysfunction in the form of reduced K(CO). One year of medical treatment had a significant beneficial effect on K(CO) and LVEF.