High-calorie diets uncouple hypothalamic oxytocin neurons from a gut-to-brain satiation pathway via κ-opioid signaling.

Oxytocin-expressing paraventricular hypothalamic neurons (PVNOT neurons) integrate afferent signals from the gut, including cholecystokinin (CCK), to adjust whole-body energy homeostasis. However, the molecular underpinnings by which PVNOT neurons orchestrate gut-to-brain feeding control remain unclear. Here, we show that mice undergoing selective ablation of PVNOT neurons fail to reduce food intake in response to CCK and develop hyperphagic obesity on a chow diet. Notably, exposing wild-type mice to a high-fat/high-sugar (HFHS) diet recapitulates this insensitivity toward CCK, which is linked to diet-induced transcriptional and electrophysiological aberrations specifically in PVNOT neurons. Restoring OT pathways in diet-induced obese (DIO) mice via chemogenetics or polypharmacology sufficiently re-establishes CCK's anorexigenic effects. Last, by single-cell profiling, we identify a specialized PVNOT neuronal subpopulation with increased κ-opioid signaling under an HFHS diet, which restrains their CCK-evoked activation. In sum, we document a (patho)mechanism by which PVNOT signaling uncouples a gut-brain satiation pathway under obesogenic conditions.

Managing total knee replacement under value-based payments.

OBJECTIVES: To evaluate opportunity gaps and set outcome goals in knee replacement (KR) between a primary care group taking financial risk for managing its patients and 6 fee-for-service (FFS) orthopedic groups that serve their patients. STUDY DESIGN: The opportunity gap analysis was a cross-sectional evaluation of the outcomes of interest on a risk-adjusted basis using orthopedic groups, the primary care group's patients, and regional comparisons. The impact evaluation was a historical cohort comparison tracking outcomes of interest over the time frame of the intervention. METHODS: Using risk-adjusted Medicare data, we defined opportunity gaps in the following outcomes: density of KR surgery, site of KR surgery, postacute care placement, and complications. RESULTS: Opportunity gap analysis demonstrated the following variation on a regional basis: a 2-fold difference in density of KR, a 3-fold difference in outpatient surgery, and a 2.5-fold difference in institutional postacute care placement. In the impact evaluation comparing 2019 with 2021, the primary care group's patients had reduced density of KR surgeries from 15.5 per 1000 to 13.0 per 1000, an increase in outpatient surgery from 31.0% to 81.6%, and a reduction in institutional postacute care utilization from 16.0% to 6.1%. Less pronounced trends were seen in the region for all Medicare FFS patients. These results were achieved with stable complication rates, which had an observed/expected ratio of 0.61 in 2019 and 0.63 in 2021. CONCLUSIONS: We achieved alignment of incentives through use of performance information with specific goals and promise of referrals to value-based partners. This approach resulted in improved value to patients with no evidence of harm and is translatable to other specialty care and markets.

The Complete Genome Sequence of Adansonia digitata (Malvaceae, Malvales), the African Baobab.

Adansonia digitata, the African Baobab, is a long-lived tree species found in sub-Saharan Africa. We present the whole genome sequence of this species. Illumina paired-end reads were assembled by a de novo method followed by a finishing step. The raw and assembled data are publicly available via GenBank: Sequence Read Archive (SRR23340274) and assembled genome (JAQSVH000000000).

Estradiol regulates leptin sensitivity to control feeding via hypothalamic Cited1.

Until menopause, women have a lower propensity to develop metabolic diseases than men, suggestive of a protective role for sex hormones. Although a functional synergy between central actions of estrogens and leptin has been demonstrated to protect against metabolic disturbances, the underlying cellular and molecular mechanisms mediating this crosstalk have remained elusive. By using a series of embryonic, adult-onset, and tissue/cell-specific loss-of-function mouse models, we document an unprecedented role of hypothalamic Cbp/P300-interacting transactivator with Glu/Asp-rich carboxy-terminal domain 1 (Cited1) in mediating estradiol (E2)-dependent leptin actions that control feeding specifically in pro-opiomelanocortin (Pomc) neurons. We reveal that within arcuate Pomc neurons, Cited1 drives leptin's anorectic effects by acting as a co-factor converging E2 and leptin signaling via direct Cited1-ERα-Stat3 interactions. Together, these results provide new insights on how melanocortin neurons integrate endocrine inputs from gonadal and adipose axes via Cited1, thereby contributing to the sexual dimorphism in diet-induced obesity.

CNS GNPDA2 Does Not Control Appetite, but Regulates Glucose Homeostasis.

GNPDA2 has been associated with human obesity and type-2 diabetes by using a GWAS approach. GNPDA2 is an enzyme involved in the hexosamine biosynthesis pathway, which is known to be important for nutrient sensing in various organism. Its counter enzyme, GFAT, has previously been shown to be important to the development of insulin resistance in diabetes. The implication of GNPDA2 and GFAT in metabolism is scarce and the effect of both enzymes over appetite and glucose homeostasis is unknown. Aim: Identify the role of GNPDA2 and GFAT in nutrient sensing circuits of the CNS that are important for the regulation of both appetite and glucose homeostasis. Methods: Using Long Evans rats, we administered either a GNPDA2 or GFAT antagonist or vehicle in i3vt. Key Findings: GNPDA2 is highly expressed in hypothalamus and adipose tissue, followed by muscle and liver. GNPDA2 is expressed in different hypothalamic nuclei (ARC, DMH, LHA, PVN). GNPDA2 is downregulated in hypothalamus under diet-induced obesity (as previously described), but GFAT expression does not change. Moreover, i3vt infusion of GNPDA2 or GFAT inhibitor resulted in increased c-Fos in areas related to appetite and glucose homeostasis control as PVN and DMH and to a lesser extent in the LHA and ARC. Central inhibition of GNPDA2 does not alter either acute food intake or body weight; however, GFAT inhibition diminished appetite and body weight due to visceral illness. In addition, central administration of the GNPDA2 antagonist, prior to an intraperitoneal glucose tolerance test, resulted in glucose intolerance in comparison to vehicle without altering insulin levels. Significance: These results suggest that central GNPDA2 does not control appetite, but regulates glucose homeostasis.

The Impact of Smoking in Workers' Compensation Patients Receiving Spinal Cord Stimulation.

The objective of this study was to determine the impact of smoking on clinical outcomes in workers' compensation (WC) patients receiving spinal cord stimulation (SCS). One hundred and ninety-six patients from the Ohio Bureau of Workers' Compensation were identified who received SCS with implantation occurring between 2007-2012. Patients were divided into smokers (n = 120) and nonsmokers (n = 76). Population characteristics before and after implantation were analyzed between the two groups. A multivariate logistic regression was run to determine predictors of return to work (RTW) status. Our regression determined smoking (p = 0.006; odds ratio [OR] = 0.260) and body mass index (p = 0.036; OR = 0.905) to be negative predictors of RTW status. After implantation, smokers were less likely to RTW after 6 months and had higher pain scores after 6 and 12 months. Both smokers and nonsmokers had significance reductions in opioid use after SCS implantation. (Journal of Surgical Orthopaedic Advances 30(3):185-189, 2021).

Inhibition of the Renin-Angiotensin System Reduces Gene Expression of Inflammatory Mediators in Adipose Tissue Independent of Energy Balance.

Obesity is a growing health problem worldwide. The renin-angiotensin system (RAS) is present in adipose tissue, and evidence suggests that it is involved in both diet-induced obesity and the inflammation associated with obesity. The present experiments determined the effect of (1) different angiotensin-converting enzyme (ACE) inhibitors (captopril, perindopril, enalapril) and angiotensin receptor blockers (ARBs: telmisartan, losartan) on adiposity of mice fed a high-fat diet for 28 days (2); acute treatment with the ACE-inhibitor captopril on gene expression of inflammatory markers in mice fed a high-fat diet (HFD); and (3) short-term (2 days) and chronic (28 days) treatment of ACE-inhibition on energy expenditure (EE) and energy balance in mice fed HFD ad libitum (AL), as well as receiving HFD limited to the amount of calories eaten by controls (pair-fed (PF) group). Body weight, food intake, adiposity and plasma leptin were lower in ACE inhibitor or ARB-treated groups over 28 days compared with HFD untreated mice. Short-term treatment with captopril led to increased EE relative to the level in the PF group. After 28 days, EE was lower in both captopril-treated and PF mice compared with AL, but the effect was greater in the captopril-treated group. Adiponectin was elevated in captopril-treated mice, but not in PF mice, after both 2 and 28 days. Additionally, acute RAS blockade in HFD-fed mice reduced mRNA expression for MCP-1, IL-6, TLR4, and leptin in adipose tissue relative to values in untreated groups. These data demonstrate that ACE inhibition and angiotensin receptor blockade reduce food intake to produce weight loss and suggest that the anti-inflammatory effects of ACE inhibition may be independent of weight loss.

Time to Surgery Affects Return to Work Rates for Workers' Compensation Patients With Single-Level Lumbar Disk Herniation.

The optimal timing of lumbar diskectomy in patients with lumbar disk herniation and radiculopathy has not been studied in the workers' compensation (WC) population. A total of 10,592 patients received lost-work compensation from the Ohio Bureau of Workers' Compensation for a lumbar disk herniation between 2005 and 2012. The primary outcome was whether subjects return to work (RTW). To determine the impact time to surgery had on RTW status, the authors performed a multivariate logistic regression analysis. They compared other secondary outcomes using chi-square and t tests. The authors identified 1287 WC patients with single-level disk herniation and radiculopathy. Average time from injury to surgery was 364 days (range, 2-2710 days). The WC patients with shorter duration of radiculopathy before diskectomy had higher RTW rates; fewer physical therapy, chiropractic, and psychotherapy sessions; and fewer postoperative diagnoses of psychological illnesses (P<.05). A multivariate logistic regression model showed that time to surgery was an independent, negative predictor of RTW (odds ratio [OR], 0.97 per month; P<.01). Legal representation (OR, 0.56; P<.01), psychological comorbidity (OR, 0.32; P=.01), and mean household income (OR, 1.01 per $1000; P<.01) also significantly affected RTW status. These results confirm that the duration of radiculopathy due to single-level lumbar disk herniation has a predictive value for the WC population undergoing diskectomy. Within 12 weeks of injury, post-diskectomy patients do reasonably well, with 70.0% of subjects returning to work. [Orthopedics. 2021;44(1):e43-e49.].

Molecular classification of the placebo effect in nausea.

In this proof-of-concept study, we tested whether placebo effects can be monitored and predicted by plasma proteins. In a randomized controlled design, 90 participants were exposed to a nauseating stimulus on two separate days and were randomly allocated to placebo treatment or no treatment on the second day. Significant placebo effects on nausea, motion sickness, and (in females) gastric activity could be verified. Using label-free tandem mass spectrometry, 74 differentially regulated proteins were identified as correlates of the placebo effect. Gene ontology (GO) enrichment analyses identified acute-phase proteins and microinflammatory proteins to be involved, and the identified GO signatures predicted day-adjusted scores of nausea indices in the placebo group. We also performed GO enrichment analyses of specific plasma proteins predictable by the experimental factors or their interactions and identified 'grooming behavior' as a prominent hit. Finally, Receiver Operator Characteristics (ROC) allowed to identify plasma proteins differentiating placebo responders from non-responders, comprising immunoglobulins and proteins involved in oxidation reduction processes and complement activation. Plasma proteomics is a promising tool to identify molecular correlates and predictors of the placebo effect in humans.

The central melanocortin system mediates the benefits of time-restricted feeding on energy balance.

OBJECTIVE: Recent decades have seen a marked increase in the prevalence of obesity and its associated comorbidities. This increase correlates with greater access to calorie-dense food that is often consumed later in the active phase of the day. Studies in high-fat diet-induced obese (DIO) mice indicate that restricting food access to their active (dark) phase is sufficient to reduce obesity. However, the specific mechanisms mediating these beneficial metabolic effects of dark restricted feeding (DRF) remain unknown. METHODS: We examined the impact of DRF on the response to peripheral signals regulating the central melanocortin system of DIO mice and on Mc4r-/- mice. RESULTS: The body weight loss following DRF has an acute onset that is sustained over time. This effect is contributed by a reduction on food intake that requires a functional central melanocortin system. Specifically, DRF impacts the circadian expression of melanocortin system genes in the arcuate nucleus of the hypothalamus (ARC). Consistent with this, DRF significantly increases the effectiveness of the fasting-feeding signals ghrelin and leptin that interact with the melanocortin system to regulate energy balance. Importantly, DRF did not reduce or prevent obesity in Mc4r-/- mice. CONCLUSIONS: Taken together, our data reveal a critical role of brain melanocortin signaling in mediating the beneficial effects of timed feeding on metabolic control, supporting potential meaningful benefits in combining timed feeding with pharmacological targeting of the melanocortin signaling for the treatment of obesity.

The scaffold protein p62 regulates adaptive thermogenesis through ATF2 nuclear target activation.

During ß-adrenergic stimulation of brown adipose tissue (BAT), p38 phosphorylates the activating transcription factor 2 (ATF2) which then translocates to the nucleus to activate the expression of Ucp1 and Pgc-1α. The mechanisms underlying ATF2 target activation are unknown. Here we demonstrate that p62 (Sqstm1) binds to ATF2 to orchestrate activation of the Ucp1 enhancer and Pgc-1α promoter. P62Δ69-251 mice show reduced expression of Ucp1 and Pgc-1α with impaired ATF2 genomic binding. Modulation of Ucp1 and Pgc-1α expression through p62 regulation of ATF2 signaling is demonstrated in vitro and in vivo in p62Δ69-251 mice, global p62-/- and Ucp1-Cre p62flx/flx mice. BAT dysfunction resulting from p62 deficiency is manifest after birth and obesity subsequently develops despite normal food intake, intestinal nutrient absorption and locomotor activity. In summary, our data identify p62 as a master regulator of BAT function in that it controls the Ucp1 pathway through regulation of ATF2 genomic binding.

Grey literature citations in top nursing journals: a bibliometric study.

OBJECTIVE: As access to information grows in tandem with the growth of the Internet, access to grey literature also increases. Because little is known about the use of grey literature in nursing journals, the authors investigated the prevalence and types of grey literature citations in top nursing journals. METHODS: We analyzed all citations (n=52,116) from articles published in 2011 in 6 top nursing journals selected from the Medical Library Association's Nursing and Allied Health Resource Section's 2012 "Selected List of Nursing Journals." Grey literature citations were identified and categorized by type. RESULTS: Grey literature accounted for 10.4% of citations across all 6 journals. Publications from governments (54.3%) and corporate organizations (26.8%) were the most common types of grey literature. CONCLUSION: The substantial citation of grey literature in nursing journals shows that nursing scholars seek and use this category of information. These findings have implications for teaching and learning among nursing researchers and the information professionals who serve the nursing research community.

Individual differences in biological regulation: Predicting vulnerability to drug addiction, obesity, and other dysregulatory disorders.

Physiological regulation is so fundamental to survival that natural selection has greatly favored the evolution of robust regulatory systems that use both reactive and preemptive responses to mitigate the disruptive impact of biological and environmental challenges on physiological function. In good health, robust regulatory systems provide little insight into the typically hidden complex array of sensor-effector interactions that accomplish successful regulation. Numerous health disorders have been traced to defective regulatory mechanisms, and generations of scientists have worked to discover ways to correct these defects and restore normal physiological function. Despite progress, numerous chronic health disorders remain resistant to treatment, and indeed for some disorders the incidence is increasing. We propose that an individual's susceptibility to acquire certain persistent dysregulatory disorders can be traced to interindividual variation in how that individual's regulatory system responds to challenges. Preexisting reliable individual differences among regulatory systems are typically unrecognized until appropriate regulatory challenges (e.g., exposure to a drug of abuse) lead to dysregulation (e.g., drug addiction). Specific characteristics of an individual's regulatory responsiveness may include etiological factors that participate in the acquisition, escalation and maintenance of health disorders characterized by dysregulation. By appropriately challenging a healthy individual's regulatory systems to identify its underlying characteristics, it is possible to ascertain whether an individual has an elevated risk for acquiring a dysregulated health condition and thereby enable strategies designed to prevent, rather than treat, the condition. This model is applied to drug addiction, and in addition we relate this approach to other dysregulated conditions such as obesity. (PsycInfo Database Record (c) 2020 APA, all rights reserved).

Shorter Time to Surgery Is Associated With Better Outcomes for Spondylolisthesis in the Workers' Compensation Population.

This study sought to determine the impact of time to surgery on clinical outcomes in patients with spondylolisthesis in the workers' compensation (WC) population. There is conflicting evidence regarding the effect of time to surgery on patients with spondylolisthesis. Patients receiving WC are known to have worse outcomes following spine surgery compared with the general population. A total of 791 patients from the Ohio Bureau of Workers' Compensation were identified who underwent lumbar fusion for spondylolisthesis between 1993 and 2013. The patients were divided into those who had surgery within 2 years of injury date and after 2 years. Confounding factors were corrected for in a multivariate logistic regression to determine predictors of return to work (RTW) status. Multivariate logistic regression determined that longer time to surgery (P=.003; odds ratio, 0.89 per year), age at index fusion (P=.003; odds ratio, 0.98 per year), and use of physical therapy before fusion (P=.008; odds ratio, 0.54) were negative predictors of RTW status. Patients who had surgery within 2 years were more likely to RTW and have fewer days absent from work, lower medical costs, and fewer sessions of psychotherapy, physical therapy, and chiropractor care. The authors demonstrated that for WC patients with spondylolisthesis, longer time to surgery was a negative predictor of RTW status. Patients who had surgery within 2 years of injury date were significantly more likely to RTW compared with after 2 years. [Orthopedics. 2020;43(3):154-160.].

How Our Work Influences Who We Are: Testing a Theory of Vocational and Personality Development over Fifty Years.

This study examines the developmental influences of occupational environments on personality traits from childhood to adulthood. We test aspects of a theory of vocational and personality development, proposing that traits develop in response to work experience following corresponsive and noncorresponsive mechanisms. We describe these pathways in the context of situations of vocational gravitation and inhabitation. In a sample from the Hawaii personality and health cohort (N = 596), we examined associations of childhood and adulthood personality traits, with occupational environments profiled on the RIASEC model. Mediations tests confirmed that work influenced personality development from childhood to adulthood for Openness/Intellect. We observed multiple reactivity effects of occupation environments on adulthood traits that were not associated with corresponding selection effects.

A Brain-Melanocortin-Vagus Axis Mediates Adipose Tissue Expansion Independently of Energy Intake.

The melanocortin system is a brain circuit that influences energy balance by regulating energy intake and expenditure. In addition, the brain-melanocortin system controls adipose tissue metabolism to optimize fuel mobilization and storage. Specifically, increased brain-melanocortin signaling or negative energy balance promotes lipid mobilization by increasing sympathetic nervous system input to adipose tissue. In contrast, calorie-independent mechanisms favoring energy storage are less understood. Here, we demonstrate that reduction of brain-melanocortin signaling actively promotes fat mass gain by activating the lipogenic program and adipocyte and endothelial cell proliferation in white fat depots independently of caloric intake via efferent nerve fibers conveyed by the common hepatic branch of the vagus nerve. Those vagally regulated obesogenic signals also contribute to the fat mass gain following chronic high-fat diet feeding. These data reveal a physiological mechanism whereby the brain controls energy stores that may contribute to increased susceptibility to obesity.

The restorative effect of work after unemployment: An intraindividual analysis of subjective well-being recovery through reemployment.

Previous research shows that unemployment has lasting detrimental effects on individuals' subjective well-being. However, the issue of how well-being evolves after individuals switch back into the labor force has received little theoretical and empirical attention. This study examines the extent to which reemployment restores individuals' subjective well-being following a period of unemployment. Applying fixed effects models to the large-scale longitudinal data from the British Household Panel Survey, we find that recovery of subjective well-being upon reemployment is fast, complete and enduring, even when individuals take less favorable employment options to return to work. By contrast, transitions into economic inactivity following unemployment are accompanied by persistent scars on subsequent well-being trajectories. This study advances our understanding of well-being development over the entire employment-unemployment-reemployment cycle. (PsycINFO Database Record (c) 2019 APA, all rights reserved).