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Skeletal muscle is a major regulator of glycemic control at rest, and glucose utilization increases drastically during exercise. Sustaining a high glucose utilization via glycolysis requires efficient replenishment of NAD+ in the cytosol. Apoptosis-inducing mitochondrion-associated factor 2 (AIFM2) was previously shown to be a NADH oxidoreductase domain-containing flavoprotein that promotes glycolysis for diet and cold-induced thermogenesis. Here, we find that AIFM2 is selectively and highly induced in glycolytic extensor digitorum longus (EDL) muscle during exercise. Overexpression (OE) of AIFM2 in myotubes is sufficient to elevate the NAD+-to-NADH ratio, increasing the glycolytic rate. Thus, OE of AIFM2 in skeletal muscle greatly increases exercise capacity, with increased glucose utilization. Conversely, muscle-specific Aifm2 depletion via in vivo transfection of hairpins against Aifm2 or tamoxifen-inducible haploinsufficiency of Aifm2 in muscles decreases exercise capacity and glucose utilization in mice. Moreover, muscle-specific introduction of NDE1, Saccharomyces cerevisiae external NADH dehydrogenase (NDE), ameliorates impairment in glucose utilization and exercise intolerance of the muscle-specific Aifm2 haploinsufficient mice. Together, we show a novel role for AIFM2 as a critical metabolic regulator for efficient utilization of glucose in glycolytic EDL muscles.

Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF), a multiorgan disease that is characterized by diverse metabolic defects. However, other than specific CFTR mutations, the factors that influence disease progression and severity remain poorly understood. Aberrant metabolite levels have been reported, but whether CFTR loss itself or secondary abnormalities (infection, inflammation, malnutrition, and various treatments) drive metabolic defects is uncertain. Here, we implemented comprehensive arteriovenous metabolomics in newborn CF pigs, and the results revealed CFTR as a bona fide regulator of metabolism. CFTR loss impaired metabolite exchange across organs, including disruption of lung uptake of fatty acids, yet enhancement of uptake of arachidonic acid, a precursor of proinflammatory cytokines. CFTR loss also impaired kidney reabsorption of amino acids and lactate and abolished renal glucose homeostasis. These and additional unexpected metabolic defects prior to disease manifestations reveal a fundamental role for CFTR in controlling multiorgan metabolism. Such discovery informs a basic understanding of CF, provides a foundation for future investigation, and has implications for developing therapies targeting only a single tissue., Introduction Cystic fibrosis (CF) is an autosomal recessive disease caused by loss-of-function mutations in the gene encoding the CF transmembrane conductance regulator (CFTR) anion channel (1-4). The clinical phenotype is [...]

Background: Understanding the economic value of deucravacitinib and apremilast could assist treatment decision-making for patients with moderate to severe plaque psoriasis. Objective: This study compared the cost per response (CPR) for US patients initiating deucravacitinib versus apremilast for moderate to severe plaque psoriasis. Methods: A CPR model using pharmacy and administration costs was developed from a US payer perspective. Response was defined as a 75% reduction from baseline in Psoriasis Area and Severity Index (PASI 75) at weeks 16 and 24. Long-term response was defined as the cumulative benefit over 52 weeks, measured as area under the curve; subsequent treatment was included. Scenario analyses explored varying the efficacy measure or choices of subsequent treatments and limiting discontinuation. Results: The CPR for deucravacitinib versus apremilast was lower at 16 weeks (difference: –$3796 [95% confidence interval (CI): –$6140 to –$1659]) and 24 weeks (difference: –$12,784 [95% CI: –$16,674 to –$9369]). At 52 weeks, the cost per cumulative benefit was lower for patients who initiated deucravacitinib, regardless of initial treatment period duration (16 or 24 weeks). Conclusions: Scenario analyses found mainly consistent results. This study showed that the CPR is lower when initiating deucravacitinib versus apremilast in moderate to severe plaque psoriasis. [ABSTRACT FROM AUTHOR]

We tested whether skin tone would influence pain estimation and whether a colour stereotype (i.e., "darker‐is‐stronger") moderates the relationship. We manipulated targets' skin tone into three levels (darker/medium/lighter). Participants estimated how much physical or emotional pain the targets would feel in various adverse situations and answered how much they believed objects with darker colours are stronger. Although the differences in estimated pain between the three skin tone conditions were not statistically significant, we found the moderation effect of the colour stereotype on the relationship between skin tone and pain estimation (for physical pain only). Specifically, participants with a stronger colour stereotype expected that darker‐skinned targets would feel less physical pain than lighter skinned ones. [ABSTRACT FROM AUTHOR]

Emotions are increasingly being recognised as important aspects of prejudice and intergroup behaviour. Specifically, emotional mediators play a key role in the process by which intergroup contact reduces prejudice towards outgroups. However, which particular emotions are most important for prejudice reduction, as well as the consistency and generality of emotion-prejudice relations across different in-group-out-group relations, remain uncertain. To address these issues, in Study 1 we examined six distinct positive and negative emotions as mediators of the contact-prejudice relations using representative samples of U.S. White, Black, and Asian American respondents (N = 639). Admiration and anger (but not other emotions) were significant mediators of the effects of previous contact on prejudice, consistently across different perceiver and target ethnic groups. Study 2 examined the same relations with student participants and gay men as the out-group. Admiration and disgust mediated the effect of past contact on attitude. The findings confirm that not only negative emotions (anger or disgust, based on the specific types of threat perceived to be posed by an out-group), but also positive, status- and esteem-related emotions (admiration) mediate effects of contact on prejudice, robustly across several different respondent and target groups.

Purpose: This real-world study investigated the impact of patient-reported disease burden and health-related quality of life (HRQoL) on switching from systemic nonbiologic to biologic therapy in patients with plaque psoriasis. Patients and Methods: Biologic therapy–naive (biologic-naive) patients aged ≥ 18 years who were using systemic nonbiologic treatment and who enrolled in the CorEvitas Psoriasis Registry between April 2015 and August 2022 were included. Measures of patient-reported disease burden and HRQoL were collected at Registry enrollment. The primary outcome of interest was initiation of biologic therapy within 45 days of enrollment. Multivariable logistic regression models were fitted separately for each patient-reported measure, adjusting for patient, disease, and treatment characteristics, including physician-rated disease severity. Adjusted odds ratios of switching to biologic therapy were estimated for greater versus lesser burden for each measure. Results: Of 848 included patients, 323 (38.1%) switched to biologic treatment. Greater patient-reported burden was independently associated with switching, with significantly higher adjusted odds ratios (95% confidence interval) for greater versus lesser burden as measured by the Dermatology Life Quality Index (1.55 [1.08– 2.23], P=0.017), visual analog scale (VAS) for itch (2.14 [1.49– 3.08], P< 0.001), VAS for skin pain (2.18 [1.45– 3.29], P< 0.001), VAS for fatigue (1.66 [1.15– 2.40], P=0.007), Patient Global Assessment-VAS (3.09 [1.94– 4.91], P< 0.001), and with activities impairment on the Work Productivity and Activity Impairment questionnaire (2.51 [1.72– 3.65], P< 0.001). Conclusion: In addition to clinically assessed disease severity, patient-reported disease burden and quality of life may drive the switch to biologic treatment in real-world patients with plaque psoriasis. [ABSTRACT FROM AUTHOR]

Research on skin tone bias (i.e., bias against members of the same racial group with different skin tones) has been conducted mostly with Black/White targets. We tested skin tone bias with East Asian (Korean) targets and investigated its possible mechanisms. In Study 1, comparisons of impressions between targets with different skin tones (darker‐, medium‐, and lighter‐skinned) showed statistically significant differences in warmth, competence, morality, cleanliness, dangerousness, strongness, and social status. Study 2 revealed that lighter‐skinned Koreans were perceived to be more similar to Whites (vs. Blacks or South Asians), but this perceived similarity did not explain the effect of skin tone on impression ratings. In Study 3, participants showed associations of darker (vs. lighter) skin with rural (vs. urban) areas and with blue‐collar (vs. white‐collar) jobs. However, these associations explained only the skin tone effects on dangerousness. This research demonstrated skin tone bias with East Asian participants and targets. [ABSTRACT FROM AUTHOR]