Asian flush is a potential protective factor against COVID-19: a web-based retrospective survey in Japan.

BACKGROUND: Coronavirus disease 2019 (COVID-19), first reported in December 2019, spread worldwide in a short period, resulting in numerous cases and associated deaths; however, the toll was relatively low in East Asia. A genetic polymorphism unique to East Asians, Aldehyde dehydrogenase 2 rs671, has been reported to confer protection against infections. METHOD: We retrospectively investigated the association between the surrogate marker of the rs671 variant, the skin flushing phenomenon after alcohol consumption, and the timing of COVID-19 incidence using a web-based survey tool to test any protective effects of rs671 against COVID-19. RESULTS: A total of 807 valid responses were received from 362 non-flushers and 445 flushers. During the 42 months, from 12/1/2019 to 5/31/2023, 40.6% of non-flushers and 35.7% of flushers experienced COVID-19. Flushers tended to have a later onset (Spearman's partial rank correlation test, p = 0.057, adjusted for sex and age). Similarly, 2.5% of non-flushers and 0.5% of flushers were hospitalized because of COVID-19. Survival analysis estimated lower risks of COVID-19 and associated hospitalization among flushers (p = 0.03 and <0.01, respectively; generalized Wilcoxon test). With the Cox proportional hazards model covering 21 months till 8/31/2021, when approximately half of the Japanese population had received two doses of COVID-19 vaccine, the hazard ratio (95% confidence interval) of COVID-19 incidence was estimated to be 0.21 (0.10-0.46) for flusher versus non-flusher, with adjustment for sex, age, steroid use, and area of residence. CONCLUSIONS: Our study suggests an association between the flushing phenomenon after drinking and a decreased risk of COVID-19 morbidity and hospitalization, suggesting that the rs671 variant is a protective factor. This study provides valuable information for infection control and helps understand the unique constitutional diversity of East Asians.

Structure-guided engineering of biased-agonism in the human niacin receptor via single amino acid substitution.

The Hydroxycarboxylic acid receptor 2 (HCA2), also known as the niacin receptor or GPR109A, is a prototypical GPCR that plays a central role in the inhibition of lipolytic and atherogenic activities. Its activation also results in vasodilation that is linked to the side-effect of flushing associated with dyslipidemia drugs such as niacin. GPR109A continues to be a target for developing potential therapeutics in dyslipidemia with minimized flushing response. Here, we present cryo-EM structures of the GPR109A in complex with dyslipidemia drugs, niacin or acipimox, non-flushing agonists, MK6892 or GSK256073, and recently approved psoriasis drug, monomethyl fumarate (MMF). These structures elucidate the binding mechanism of agonists, molecular basis of receptor activation, and insights into biased signaling elicited by some of the agonists. The structural framework also allows us to engineer receptor mutants that exhibit G-protein signaling bias, and therefore, our study may help in structure-guided drug discovery efforts targeting this receptor.

Brain death determination in patients with veno-arterial extracorporeal membrane oxygenation: A systematic study to address the Harlequin syndrome.

PURPOSE: The Harlequin syndrome may occur in patients treated with venoarterial extracorporal membrane oxygenation (VA-ECMO), in whom blood from the left ventricle and the ECMO system supply different parts of the body with different paCO2-levels. The purpose of this study was to compare two variants of paCO2-analysis to account for the Harlequin syndrome during apnea testing (AT) in brain death (BD) determination. MATERIALS AND METHODS: Twenty-seven patients (median age 48 years, 26-76 years; male n = 19) with VA-ECMO treatment were included who underwent BD determination. In variant 1, simultaneous arterial blood gas (ABG) samples were drawn from the right and the left radial artery. In variant 2, simultaneous ABG samples were drawn from the right radial artery and the postoxygenator ECMO circuit. Differences in paCO2-levels were analysed for both variants. RESULTS: At the start of AT, median paCO2-difference between right and left radial artery (variant 1) was 0.90 mmHg (95%-confidence intervall [CI]: 0.7-1.3 mmHg). Median paCO2-difference between right radial artery and postoxygenator ECMO circuit (variant 2) was 3.3 mmHg (95%-CI: 1.5-6.0 mmHg) and thereby significantly higher compared to variant 1 (p = 0.001). At the end of AT, paCO2-difference according to variant 1 remained unchanged with 1.1 mmHg (95%-CI: 0.9-1.8 mmHg). In contrast, paCO2-difference according to variant 2 increased to 9.9 mmHg (95%-CI: 3.5-19.2 mmHg; p = 0.002). CONCLUSIONS: Simultaneous paCO2-analysis from right and left distal arterial lines is the method of choice to reduce the risk of adverse effects (e.g. severe respiratory acidosis) while performing AT in VA-ECMO patients during BD determination.

Efficacy of Botulinum Toxin in the Treatment of Cutaneous Flushing: A Systematic Review and Meta-Analysis.

BACKGROUND: Flushing is a common dermatologic complaint and can be resistant to many treatments. As the utility of botulinum toxin continues to expand, recent data suggest that it may also be a therapeutic option for flushing. OBJECTIVE: To evaluate the efficacy of botulinum toxin for the treatment of cutaneous flushing. MATERIALS AND METHODS: A systematic search of Medline, Embase, Cochrane CENTRAL, CINAHL, Scopus, and Web of Science databases was conducted to identify studies evaluating the effect of botulinum toxin on flushing 1 month after treatment. Prespecified outcome measures included a clinical flushing score, dermatology life quality index (DLQI), and erythema index (EI). Meta-analysis was performed to calculate the mean differences in these outcomes before and after treatment at 1-month follow-up. RESULTS: Nine studies (132 patients) were included in the analysis of this study (2 randomized controlled trials and 7 nonrandomized studies). All studies had a low risk of bias (high quality). The most frequent outcome reported was a clinical flushing score, which significantly decreased by 1.25 points overall (95% confidence interval [CI]: -2.47; -0.04) 1 month after treatment with botulinum toxin. Mean DLQI scores decreased (i.e., improved) by 9.02 points (95% CI: -19.81; 1.77) 1 month after botulinum toxin injections. The EI (measured by Mexameter) before and after botulinum toxin was evaluated in 2 studies; however, not enough statistical information was provided to analyze with meta-analytic techniques. CONCLUSION: Based on this meta-analysis, botulinum toxin significantly improves clinical flushing scores 1 month after treatment.

Diagnostic value of niacin skin blunting response in adolescent patients with depression.

OBJECTIVE: To investigate the differences in the niacin skin flushing response of adolescent depressed patients and healthy adolescents and its diagnostic value in adolescent depression. METHODS: Thirty-eight cases of acute episodes of depression in unmedicated adolescents and 47 age- and sex-matched healthy controls were included as study subjects, and sociodemographic and clinical data were collected, all of which were stimulated with six concentration gradients (up to 60 mmol/L, followed by sequential 3-fold gradient dilution to a minimum of 0.25 mmol/L) of niacin solution on the forearm skin, and the skin flushing area was applied as an assessment index. RESULTS: The total area of redness of the skin in response to niacin was significantly lower in the adolescent depression group than in the healthy adolescent group (Z=-3.36, p = 0.001) and was able to distinguish the adolescent depression group from the healthy adolescent group (area under curve = 0.713, sensitivity 51.1%, specificity 83.2%). CONCLUSIONS: Niacin sensitivity is reduced in adolescent depressed patients, and the niacin skin flush response has potential clinical value as a diagnostic biomarker for adolescent depression.

Genetic influences on alcohol flushing in East Asian populations.

BACKGROUND: Although it is known that variation in the aldehyde dehydrogenase 2 (ALDH2) gene family influences the East Asian alcohol flushing response, knowledge about other genetic variants that affect flushing symptoms is limited. METHODS: We performed a genome-wide association study meta-analysis and heritability analysis of alcohol flushing in 15,105 males of East Asian ancestry (Koreans and Chinese) to identify genetic associations with alcohol flushing. We also evaluated whether self-reported flushing can be used as an instrumental variable for alcohol intake. RESULTS: We identified variants in the region of ALDH2 strongly associated with alcohol flushing, replicating previous studies conducted in East Asian populations. Additionally, we identified variants in the alcohol dehydrogenase 1B (ADH1B) gene region associated with alcohol flushing. Several novel variants were identified after adjustment for the lead variants (ALDH2-rs671 and ADH1B-rs1229984), which need to be confirmed in larger studies. The estimated SNP-heritability on the liability scale was 13% (S.E. = 4%) for flushing, but the heritability estimate decreased to 6% (S.E. = 4%) when the effects of the lead variants were controlled for. Genetic instrumentation of higher alcohol intake using these variants recapitulated known associations of alcohol intake with hypertension. Using self-reported alcohol flushing as an instrument gave a similar association pattern of higher alcohol intake and cardiovascular disease-related traits (e.g. stroke). CONCLUSION: This study confirms that ALDH2-rs671 and ADH1B-rs1229984 are associated with alcohol flushing in East Asian populations. Our findings also suggest that self-reported alcohol flushing can be used as an instrumental variable in future studies of alcohol consumption.

Regulation of synthesis of polyamines by progesterone, estradiol, and their receptors in uteri of cyclic ewes†.

Progesterone (P4), estradiol (E2), and expression of their receptors (PGR and ESR1, respectively) by cells of the uterus regulate reproductive performance of mammals through effects on secretion and transport of nutrients into the uterine lumen. This study investigated the effect of changes in P4, E2, PGR, and ESR1 on expression of enzymes for the synthesis and secretion of polyamines. Suffolk ewes (n = 13) were synchronized to estrus (Day 0) and then, on either Day 1 (early metestrus), Day 9 (early diestrus), or Day 14 (late diestrus) of the estrous cycle, maternal blood samples were collected, and ewes were euthanized before obtaining uterine samples and uterine flushings. Endometrial expression of MAT2B and SMS mRNAs increased in late diestrus (P < 0.05). Expression of ODC1 and SMOX mRNAs decreased from early metestrus to early diestrus, and expression of ASL mRNA was lower in late diestrus than in early metestrus (P < 0.05). Immunoreactive PAOX, SAT1, and SMS proteins were localized to uterine luminal, superficial glandular, and glandular epithelia, stromal cells, myometrium, and blood vessels. Concentrations of spermidine and spermine in maternal plasma decreased from early metestrus to early diestrus and decreased further in late diestrus (P < 0.05). The abundances of spermidine and spermine in uterine flushings were less in late diestrus than early metestrus (P < 0.05). These results indicate that synthesis and secretion of polyamines are affected by P4 and E2, as well as the expression of PGR and ESR1 in the endometria of cyclic ewes.

Placement of High Dose Neurotoxins for Treatment-Resistant Rosacea.

Rosacea is a chronic inflammatory skin condition characterized by facial flushing, erythema, telangiectasias, and papulopustular lesions. Treatment for rosacea includes limiting inciting factors and reducing inflammation with topical and oral therapies. Traditional therapies primarily focus on the papulopustular or background erythematotelangiectatic component of rosacea, leaving symptoms of flushing poorly controlled and profoundly impacting the quality of life of patients. Neuromodulators have been speculated to improve the flushing component of rosacea by reducing mast cell degranulation and the release of neuropeptides. However, its use for symptomatic relief in refractory flushing rosacea has been limited by side effects such as facial muscle weakness or paralysis. We present the use of strategic placement of high-dose neuromodulators for treatment-resistant rosacea. This approach has resulted in the gradual stabilization of symptoms, improved quality of life, and superior side effect profile. Silence C, Kourosh AS, Gilbert E. Placement of high-dose neurotoxins for treatment-resistant rosacea. J Drugs Dermatol. 2023;22(6):605-606. doi:10.36849/JDD.7237.

64-year-old woman • hot flashes, facial flushing, excessive sweating, and palpitations • daily headaches • history of hypertension • Dx?

► hot flashes, facial flushing, excessive sweating, and palpitations ► daily headaches ► history of hypertension.

Is Asian flushing syndrome a disadvantage in the labor market?

A large fraction of people in East Asia are incapable of digesting alcohol because of a genetic deficiency. This study examines whether the variation in alcohol tolerance contributes to inequality in the labor market. We conduct our original surveys in Japan, Taiwan, and Korea with the measurement of respondents' degree of alcohol tolerance by a bio-marker test. We find that alcohol-tolerant men consume significantly more alcohol, but their earnings and hours worked do not differ from those of alcohol-intolerant men. Despite a prevalent view that drinking alcohol is indispensable to establish good relationships with colleagues and business partners, our results suggest that there is no systematic impact of alcohol tolerance on labor market outcomes.

Health-Related Habits and Health Promotion Behaviors in People With Alcohol Flushing.

There is limited investigation on health-related behaviors by alcohol flushing. A nationwide cross-sectional study was conducted using data from the Korea Community Health Survey. The final analysis included 130 192 adults with available information on alcohol flushing assessed by a self-reported questionnaire. About a quarter of participants were classified into alcohol flushers. After considering demographics, comorbidities, mental health, and perceived health status, multivariable logistic regression analysis revealed that flushers smoked or drank less and received vaccination or screening more than nonflushers. In conclusion, flushers have healthier behaviors than nonflushers.

Harlequin Syndrome Related to Perioperative Intercostal Blockade: A Case Report.

Harlequin syndrome is a rare syndrome characterized by hemifacial flushing and altered facial sweating, with only a few case reports related to intercostal blockades. We present a case of Harlequin syndrome in a 65-year-old woman after intercostal blockade for video-assisted thoracoscopic lobectomy. One hour postoperatively, the patient became nauseated and presented with flushing of the right half of the face with a clear line of demarcation. Within 3 hours, the flushing disappeared. In this case report, we discuss Harlequin syndrome in relation to intercostal blockade and encourage clinicians to consider this syndrome in the differential diagnosis when encountering similar symptoms.

Laser Speckle Contrast Imaging-based diagnosis of severe mesenteric traction syndrome: Hemodynamics and prostacyclin - A prospective cohort study.

BRIEF ABSTRACT: Today, the diagnosis and grading of mesenteric traction syndrome relies on a subjective assessment of facial flushing. However, this method has several limitations. In this study, Laser Speckle Contrast Imaging and a predefined cut-off value are assessed and validated for the objective identification of severe mesenteric traction syndrome. BACKGROUND: Severe mesenteric traction syndrome (MTS) is associated with increased postoperative morbidity. The diagnosis is based on an assessment of the developed facial flushing. Today this is performed subjectively, as no objective method exists. One possible objective method is Laser Speckle Contrast Imaging (LSCI), which has been used to show significantly higher facial skin blood flow in patients developing severe MTS. Using these data, a cut-off value has been identified. This study aimed to validate our predefined LSCI cut-off value for identifying severe MTS. METHODS: A prospective cohort study was performed on patients planned for open esophagectomy or pancreatic surgery from March 2021 to April 2022. All patients underwent continuous measurement of forehead skin blood flow using LSCI during the first hour of surgery. Using the predefined cut-off value, the severity of MTS was graded. In addition, blood samples for prostacyclin (PGI2) analysis and hemodynamics were collected at predefined time points to validate the cut-off value. MAIN RESULTS: Sixty patients were included in the study. Using our predefined LSCI cut-off value, 21 (35 %) patients were identified as developing severe MTS. These patients were found to have higher concentrations of 6-Keto-PGFaα (p = 0.002), lower SVR (p < 0.001), lower MAP (p = 0.004), and higher CO (p < 0.001) 15 min into surgery, as compared with patients not developing severe MTS. CONCLUSION: This study validated our LSCI cut-off value for the objective identification of severe MTS patients as this group developed increased concentrations of PGI2 and more pronounced hemodynamic alterations compared with patients not developing severe MTS.

Association between psychomotor function and ALDH2 genotype after consuming barley shochu: A randomized crossover trial.

Sustained exposure to acetaldehyde, the major metabolite of ethanol, may influence psychomotor performance even after the breath ethanol level significantly drops several hours following ethanol consumption. We examined the relationship between psychomotor function and changes in exhaled ethanol and acetaldehyde concentrations after consuming a low dose (0.33 g/kg) of barley shochu, a traditional Japanese distilled alcohol beverage, at the point when the exhaled ethanol concentrations dropped below 78,000 parts per billion (0.15 mg/L), the standard threshold for driving under the influence of alcohol in Japan. We assessed how the genetic polymorphisms of rs671 G/G homozygous (*1/*1) and G/A heterozygous (*1/*2) of ALDH2 influenced the kinetics of ethanol and acetaldehyde in exhaled air and psychomotor dynamics using the Digit Symbol Substitution Test (DSST), Critical Flicker Fusion Test (CFFT), and visual analogue scale (VAS) up to 12 h after shochu or water intake. There was no significant difference in DSST and CFFT scores depending on genotype; however, the time required for the DSST to attain the level prior to drinking was longer in the ALDH2 *1/*2 group than in the *1/*1 group. In the VAS test, facial flushing and mood elevation tended to be higher in the *1/*2 group after shochu consumption. VAS scores for mood elevation and facial flushing correlated with acetaldehyde concentration in exhaled breath. These results indicate that DSST recovery tends to be slower and mood elevation higher in the ALDH2 *1/*2 group even when exposed to a low dose of alcohol.

Identification of adolescent patients with depression via assessment of the niacin skin flushing response.

BACKGROUND: Depressive disorder (DD) affects approximately 20 % of adolescents worldwide, but it is underdiagnosed due to the lack of objective biomarkers. Niacin skin flushing response (NSFR) is an objective and noninvasive biomarker of adult depression; however, its effectiveness has not been assessed in adolescents. METHODS: This study included 198 adolescents with 50 % healthy controls (HC). Linear mixed-effects model and multiple linear regression analyses were performed to assess differences in NSFR between the DD and HC groups. Logistic regression models based on NSFR were constructed, and the area under curve (AUC) was calculated to evaluate the performance of models. Spearman correlations were calculated to assess the relationships between NSFR and disease duration and hormone levels associated with puberty. RESULTS: Adolescents with DD displayed significantly attenuated and delayed NSFR compared to HC. NSFR effectively distinguished DD patients from HC with AUC values of 0.719 (sensitivity = 0.844) and 0.721 (sensitivity = 0.829) determined in the discovery and validation sets, respectively. Within the DD group, the maximum degree of NSFR was negatively correlated with the disease duration (r = -0.28, p = 0.011), and the overall degree of NSFR was positively associated with prolactin (r = 0.29, p = 0.039) and thyroxine (r = 0.29, p = 0.027) levels. LIMITATIONS: Future investigations will be necessary to confirm our results in an independent sample set. CONCLUSIONS: This study provides the first evidence of the utility of NSFR as an objective auxiliary diagnostic biomarker for adolescent depression. It provides new clues to understand the pathophysiology of the disease, and helps promote precise diagnosis, treatment, and prognostic evaluation of adolescent depression.