Ultrasound Neuromodulation of an Anti-Inflammatory Pathway at the Spleen Improves Experimental Pulmonary Hypertension.

BACKGROUND: Inflammation is pathogenically implicated in pulmonary arterial hypertension; however, it has not been adequately targeted therapeutically. We investigated whether neuromodulation of an anti-inflammatory neuroimmune pathway involving the splenic nerve using noninvasive, focused ultrasound stimulation of the spleen (sFUS) can improve experimental pulmonary hypertension. METHODS: Pulmonary hypertension was induced in rats either by Sugen 5416 (20 mg/kg SQ) injection, followed by 21 (or 35) days of hypoxia (sugen/hypoxia model), or by monocrotaline (60 mg/kg IP) injection (monocrotaline model). Animals were randomized to receive either 12-minute-long sessions of sFUS daily or sham stimulation for 14 days. Catheterizations, echocardiography, indices of autonomic function, lung and heart histology and immunohistochemistry, spleen flow cytometry, and lung single-cell RNA sequencing were performed after treatment to assess the effects of sFUS. RESULTS: Splenic denervation right before induction of pulmonary hypertension results in a more severe disease phenotype. In both sugen/hypoxia and monocrotaline models, sFUS treatment reduces right ventricular systolic pressure by 25% to 30% compared with sham treatment, without affecting systemic pressure, and improves right ventricular function and autonomic indices. sFUS reduces wall thickness, apoptosis, and proliferation in small pulmonary arterioles, suppresses CD3+ and CD68+ cell infiltration in lungs and right ventricular fibrosis and hypertrophy and lowers BNP (brain natriuretic peptide). Beneficial effects persist for weeks after sFUS discontinuation and are more robust with early and longer treatment. Splenic denervation abolishes sFUS therapeutic benefits. sFUS partially normalizes CD68+ and CD8+ T-cell counts in the spleen and downregulates several inflammatory genes and pathways in nonclassical and classical monocytes and macrophages in the lung. Differentially expressed genes in those cell types are significantly enriched for human pulmonary arterial hypertension-associated genes. CONCLUSIONS: sFUS causes dose-dependent, sustained improvement of hemodynamic, autonomic, laboratory, and pathological manifestations in 2 models of experimental pulmonary hypertension. Mechanistically, sFUS normalizes immune cell populations in the spleen and downregulates inflammatory genes and pathways in the lung, many of which are relevant in human disease.

Vagus nerve stimulation modulates distinct acetylcholine receptors on B cells and limits the germinal center response.

Acetylcholine is produced in the spleen in response to vagus nerve activation; however, the effects on antibody production have been largely unexplored. Here, we use a chronic vagus nerve stimulation (VNS) mouse model to study the effect of VNS on T-dependent B cell responses. We observed lower titers of high-affinity IgG and fewer antigen-specific germinal center (GC) B cells. GC B cells from chronic VNS mice exhibited altered mRNA and protein expression suggesting increased apoptosis and impaired plasma cell differentiation. Follicular dendritic cell (FDC) cluster dispersal and altered gene expression suggested poor function. The absence of acetylcholine-producing CD4+ T cells diminished these alterations. In vitro studies revealed that α7 and α9 nicotinic acetylcholine receptors (nAChRs) directly regulated B cell production of TNF, a cytokine crucial to FDC clustering. α4 nAChR inhibited coligation of CD19 to the B cell receptor, presumably decreasing B cell survival. Thus, VNS-induced GC impairment can be attributed to distinct effects of nAChRs on B cells.

What can cause cancer patients to attempt suicide? Thiamine deficiency mimicking the symptoms of major depressive disorder.

OBJECTIVES: Thiamine deficiency (TD) presents with various physical and psychiatric symptoms, but no cases with depression-like symptoms have been reported. METHODS: We report a patient with cancer who appeared to attempt suicide as a consequence of depressive mood likely related to TD. RESULTS: The patient was a 58-year-old woman diagnosed with recurrent endometrial cancer, with lung metastasis and pelvic dissemination. The patient apparently attempted suicide was referred to the psycho-oncology department. At the time of the examination, major depressive disorder was suspected based on her mental symptoms, but when thiamine was administered intravenously in response to her poor dietary intake, her palpitations, dyspnea, anorexia, and insomnia improved, and her suicidal ideation disappeared at her reexamination 1 hour later after thiamine administration. SIGNIFICANCE OF RESULTS: It is likely that the observed palpitations, dyspnea, anorexia, and insomnia, as well as the severe depression and the attempted suicide, which were thought to be physical symptoms associated with depression, were actually related to TD. Suicidal ideation and attempted suicide are conspicuous as psychiatric symptoms. However, in such cases, rather than simply starting treatment for depression, it is necessary to consider reversible TD as a cause of these symptoms and perform differential diagnosis to confirm the physical illness.

Features and prognosis of patients with lupus nephritis receiving glucocorticoid treatment: a descriptive study using a Japanese claims database.

OBJECTIVE: To evaluate the status of lupus nephritis treatment particularly regarding the need for intensification of treatment in Japan from 2010 to 2019 using a large-scale claims database. METHODS: This descriptive study included adult lupus nephritis patients who were administered glucocorticoid equivalent to ≥15 mg prednisolone as the initial dose. After summarizing patient characteristics, we assessed the rate of treatment intensification using the Kaplan-Meier method among six groups based on initial dose of glucocorticoid. RESULTS: We identified 403 patients (mean age, 42.7 years; 68.5% women) with the median initial glucocorticoid dose of 30 mg/day prednisolone equivalent. We observed 56 treatment intensifications; the incidence rate was 71.3 per 1,000 person-years (95% confidence interval: 52.6-90.0). The rate in higher glucocorticoid dose groups was higher than that in lower glucocorticoid dose groups. CONCLUSIONS: We found that the rate of treatment intensification was higher in the high-dose glucocorticoid groups than in the low-dose glucocorticoid groups. Further studies are needed to clarify the relationship between the initial dose of glucocorticoids and the prognosis of lupus nephritis patients.

Recurrence of Large-Vessel Vasculitis Induced by Multiple Types of Granulocyte Colony-Stimulating Factor Preparation in Patient with Large-Cell Neuroendocrine Lung Carcinoma: A Case Report.

With the increased use of granulocyte colony-stimulating factor (G-CSF) preparations, there is concern about the increase in G-CSF-associated large-vessel vasculitis; however, there have been no previous reports of vasculitis caused by multiple types of G-CSF preparations. We experienced a case of drug-induced large-vessel vasculitis caused by two different G-CSF products, which was difficult to diagnose. When treating patients with a history of large-vessel vasculitis caused by pegfilgrastim, we need to pay attention to its recurrence when using other G-CSF preparations.

A patient with Marchiafava-Bignami disease type A transported by ambulance with impaired consciousness and malnutrition was successfully treated after early diagnosis by MRI.

Marchiafava-Bignami disease (MBD) is a very rare disorder characterized by demyelination and necrosis of the corpus callosum. A 53-year-old male was transported to the emergency room with impaired consciousness. On his arrival, he was quite emaciated. CT examination revealed no hemorrhagic lesions whereas MR images showed hyperintense areas throughout the corpus callosum, leading to a diagnosis of MBD. His impaired consciousness improved with treatment, including parenteral thiamine administration. When examining patients with impaired consciousness because of malnutrition, MBD should be taken in consideration and the incorporation of head MR imaging into the examination protocol enables early diagnosis and treatment, and may improve the prognosis.

Impact of immediate general anesthesia in the emergency room on prevention of rebleeding after subarachnoid hemorrhage.

BACKGROUND: Aneurysm rebleeding is fatal in patients with aneurysmal subarachnoid hemorrhage (aSAH). We aimed to investigate whether immediate general anesthesia (iGA) management in the emergency room, upon arrival, prevents rebleeding after admission and reduces mortality following aSAH. METHODS: The clinical data of 3033 patients with World Federation of Neurosurgical Societies (WFNS) grade 1, 2, or 3 aSAH from the Nagasaki SAH Registry Study between 2001 and 2018 were retrospectively analyzed. iGA was defined as sedation and analgesia using intravenous anesthetics and opioids combined with intubation induction. We calculated crude and adjusted odds ratios to evaluate the associations between iGA and the risk of rebleeding/death using multivariable logistic regression models with fully conditional specification for multiple imputations. In the analysis of the relationship between iGA and death, we excluded patients with aSAH who died within 3 days after the onset of symptoms. RESULTS: Of the 3033 patients with aSAH who met the eligibility criteria, 175 patients (5.8%) received iGA (mean age, 62.4 years; 49 were male). Heart disease, WFNS grade, and lack of iGA were independently associated with rebleeding in the multivariable analysis with multiple imputations. Among the 3033 patients, 15 were excluded due to death within 3 days after the onset of symptoms. After excluding these cases, our analysis revealed that age, diabetes mellitus, history of cerebrovascular disease, WFNS grade, Fisher grade, lack of iGA, rebleeding, postoperative rebleeding, no shunt operation, and symptomatic spasm were independently associated with mortality. CONCLUSIONS: Management by iGA was associated with a 0.28-fold decrease in the risks of both rebleeding and mortality in patients with aSAH, even after adjusting for the patient's history of diseases, comorbidities, and aSAH status. Thus, iGA can be a treatment for the prevention of rebleeding before aneurysmal obliteration treatment.

Incidence and factors associated with newly implemented do-not-attempt-resuscitation orders among deteriorating patients after rapid response system activation: A retrospective observational study using a Japanese multicenter database.

Aim: The rapid response system (RRS) was initially aimed to improve patient outcomes. Recently, some studies have implicated that RRS might facilitate do-not-attempt-resuscitation (DNAR) orders among patients, their families, and healthcare providers. This study aimed to examine the incidence and factors independently associated with DNAR orders newly implemented after RRS activation among deteriorating patients. Methods: This observational study assessed patients who required RRS activation between 2012 and 2021 in Japan. We investigated patients' characteristics and the incidence of new DNAR orders after RRS activation. Furthermore, we used multivariable hierarchical logistic regression models to explore independent predictors of new DNAR orders. Results: We identified 7904 patients (median age, 72 years; 59% male) who required RRS activation at 29 facilities. Of the 7066 patients without pre-existing DNAR orders before RRS activation, 394 (5.6%) had new DNAR orders. Multivariable hierarchical logistic regression analyses revealed that new DNAR orders were associated with age category (adjusted odds ratio [aOR], 1.56; 95% confidence interval, 1.12-2.17 [65-74 years old reference to 20-64 years old], aOR, 2.56; 1.92-3.42 [75-89 years old], and aOR, 6.58; 4.17-10.4 [90 years old]), malignancy (aOR, 1.82; 1.42-2.32), postoperative status (aOR, 0.45; 0.30-0.71), and National Early Warning Score 2 (aOR, 1.07; 1.02-1.12 [per 1 score]). Conclusion: The incidence of new DNAR orders was one in 18 patients after RRS activation. The factors associated with new DNAR orders were age, malignancy, postoperative status, and National Early Warning Score 2.

Investigation of Whole Blood Thiamine Concentration in Independently Ambulatory Residents of a Provincial Town in Japan: A Cross-Sectional Study.

Background Thiamine deficiency (TD) is an important public health problem in nutrition, occurring in 2-6% of the population in Europe and the US, whereas thiamine levels are reported to be significantly reduced by 36.6-40% in some populations of East Asia. However, there is little information available at present, regarding factors such as age, despite the continued aging of society. Further, studies such as those mentioned above have not yet been undertaken in Japan, the country in which population aging is most advanced. Objective To investigate TD in the Japanese community-dwelling individuals who are independently ambulatory. Methods We undertook an examination of TD in blood samples obtained from 270 citizens in a provincial town, aged 25-97 years, who were able to walk to the venue and provide informed consent for inclusion in this research and of whom 8.9% had a history of cancer. We summarized the demographic characteristics of the subjects. The whole-blood thiamine concentrations were measured using the high-performance liquid chromatography method. A value of 21.3 ng/ml or less was taken as low and a borderline value was set as less than 28 ng/ml. Results The mean (±SD) whole blood thiamine concentration was 47.6 ± 8.7 ng/ml. No TD was observed to exist participating in this study, with no subjects even showing show borderline values. Further, there was no significant difference in thiamine level between those aged 65 or older and those aged less than 65. Conclusions No cases of TD were observed among the subjects in this study, nor was the concentration of thiamine found to be related to age. It is possible that the frequency of TD might be very low in citizens who have a certain level of activity. In the future, it is necessary to expand the prevalence of TD to a wider range of subjects.

The prevalence of thiamine deficiency among elderly nursing home residents: A cross-sectional study.

Background: Although thiamine deficiency (TD) can lead to Wernicke encephalopathy, the characteristics associated with TD in the elderly have not yet been clarified. We sought to clarify the frequency of TD among an institutionalized elderly population with a controlled dietary intake and to identify possible factors related to TD. Method: We undertook a cross-sectional study of residents in three nursing homes for the elderly as of June 2020. Blood thiamine concentrations were measured using a high-performance liquid chromatography method, with TD defined as a concentration of <21.3 ng/mL. Basic data (age, sex, height, weight, and BMI), dietary intake for the previous 3 weeks, degree of care (DOC), degree of independence in daily life for elderly with dementia (DIDLED), and comorbidities were analyzed using descriptive statistical methods. Results: The mean age (±SD) was 86.9 years (±8.29), with 84 residents (70.0%) being female. The DIDLED varied from total independence to long-term care level 5 (full assistance), with 89.2% suffering dementia. The mean whole blood thiamine value was 36.18 (±17.58) ng/ml, with TD confirmed in 7 (5.8%) of the 120 residents. All TD patients suffered from dementia. No TD was observed in patients with a near-normal food intake, and no related factors were observed among the other items. Conclusion: Reduced food intake may at increase the risk of TD and symptoms of TD may be overlooked in those displaying symptoms of dementia; thus, it is important for clinicians working with the elderly to remain aware of the potential for TD.

Thiamine Deficiency in a Patient With Schizophrenia: Precautions and Countermeasures for Subclinical Thiamine Deficiency.

Patients with schizophrenia often experience problems associated with ordinary exercises of life due to their mental symptoms. Those experiencing problems related to feeding behavior, in particular, are considered to be susceptible to developing Wernicke encephalopathy due to a deficiency in thiamine, the physiological stores of which are limited; however, there are few reported cases, and most of them were accompanied by the classical triad of signs. We report our experience with asymptomatic thiamine deficiency (TD) in a schizophrenia patient. A 73-year-old female was receiving medication for schizophrenia as an outpatient. No symptoms such as hallucinations or delusions were observed, the patient had a sociable personality and was able to function at a level where she could live alone. Although there were no active complaints about eating by the patient, we investigated the situation due to reports of TD in schizophrenia patients. As results revealed a significant decrease in whole blood thiamine to 19 ng/mL (reference range: 24-66 ng/mL), we administered a large dose of thiamine. No changes were observed in psychosomatic symptoms before and after administration. Patients with schizophrenia experience problems that may lead to TD, such as dietary imbalances and disturbed feeding habits. Therefore, even if patients with schizophrenia do not actively complain about their feeding behavior, it may be necessary to take medical measures such as blood sampling in consideration of the potential for developing TD.

14- and 17-Membered Macrocycles Containing Amide, Amino, and Carbamate Groups in The Monocyclic Skeleton: An Accidental Byproduct Obtained from a Residue after Separation.

A 14-membered cyclic compound (3) containing amide, amino, and carbamate groups, which was serendipitously obtained in the oily residue after the separation of 4-benzyl-1,4,7,10-tetraazacyldododecane-2,6-dione (2a) and 4,16-dibenzyl-1,4,7,10,13,16,19,22-octaazacyclo-tetracosane-2,6,14,18-tetraone (2b), is reported. The structure of 3 is formally a CO2 insertion between positions 3 and 4 of the 12-membered ring in 2a. The CO2 insertion was confirmed in the synthesis of diethyl 2,2'-(benzylazanediyl)diacetate (1) by the reaction of benzylamine with ethyl bromoacetate using K2CO3 as the base. In addition, the selective synthesis of 3 and ethyl N-benzyl-N-((2-ethoxy-2-oxoethoxy)carbonyl)glycinate (5) and their kinetic behavior are reported. The reaction of 5 with triethylenetetramine afforded a 17-membered macrocycle (7), which was obtained in an 18% yield. Compounds 6 and 8 were prepared from 3 and 7 by introducing benzyl groups to improve their solubility in organic solvents. Titration experiments using 1H NMR showed that both 6 and 8 exhibit Li+ selectivity.

Impact of intraoperative fluid restriction on renal outcomes in patients undergoing robotic-assisted laparoscopic prostatectomy.

Robotic-assisted laparoscopic prostatectomy (RALP) requires intraoperative fluid restriction to maintain the optimal view of the operative field during vesicourethral anastomosis and to prevent upper airway edema that may occur due to the steep Trendelenburg position. The aim of this study was to demonstrate that our fluid restriction regimen would not increase postoperative serum creatinine (sCr) levels in patients undergoing RALP. The fluid regimen involved maintaining a crystalloid infusion at 1 ml/kg/h until completion of vesicourethral anastomosis, then rapid infusion of 15 ml/kg within 30 min, followed by maintenance at 1.5 ml/kg/h until post-operative day (POD) 1. The primary outcome of this study was the change in the sCr level from baseline to POD7. Secondary outcomes were the sCr levels on PODs 1 and 2, the surgical view during vesicourethral anastomosis, and the incidences of re-intubation and acute kidney injury (AKI). Sixty-six patients were eligible for the analysis. The paired t test for non-inferiority showed no significant difference in sCr levels between baseline and POD7 (mean ± standard deviation, 0.79 ± 0.14 vs. 0.80 ± 0.18 mg/dl, p < 0.001). Seven patients developed AKI on POD1, but all but one recovered on POD2. Ninety-seven percent of operations were rated as having a good view of the operative field. There were no cases of re-intubation. This study demonstrated that the fluid restriction regimen of 1 ml/kg/h until completion of vesicourethral anastomosis created a good view of the operative field during vesicourethral anastomosis without increasing postoperative sCr levels in patients undergoing RALP. Trial registration: This trial was registered in the University Hospital Medical Information Network under registration number UMIN000018088 (registration date; July 1, 2015).

Recent Trend of Using Computed Tomography to Diagnose Pediatric Appendicitis at the First Hospital Visit: A Descriptive Study Using a Medical Claims Database.

OBJECTIVE: We recognize that computed tomography (CT) should not be used to diagnosis pediatric appendicitis due to radiation exposure. However, few studies have recently shown a trend in its use. This study aimed to investigate the annual use of CT for the diagnosis of pediatric appendicitis at the first hospital visit. METHODS: This was a descriptive study using nationwide claims data. We extracted the data of children younger than 15 years who underwent imaging tests to diagnose acute and suspected appendicitis at the first visit between January 2008 and September 2018. We summarized the patient characteristics and the percentage of CT, ultrasonography (US), or CT/US utilization by year, age, and department. RESULTS: We identified 6658 children who underwent CT (2349 [35.8%]), US (53,57 [54.5%]), and CT/US (634 [9.7%]). The annual CT use dropped from 43.1% in 2012 to 29.4% in 2018. According to age group, the highest percentage of CT use in 2018 was 84.6% in preschool children, followed by adolescents (40.3%), upper-grade (26.0%), and lower-grade (15.0%) children. Data of annual CT use by department revealed that CT usage was much higher in internal and emergency medicine than in pediatrics. Furthermore, adolescents accounted for approximately 50% of CT use in internal medicine. CONCLUSIONS: The percentage of CT use for pediatric appendicitis at the first visit declined annually. However, CT use still tended to be higher in preschool- and adolescent-aged children, or in departments other than pediatrics. Further studies are required to clarify the clinical benefits of CT use to diagnose pediatric appendicitis.

Pseudoprogression during induction treatment with nivolumab plus ipilimumab combined with chemotherapy for metastatic lung adenocarcinoma: A case report.

The incidence rate of pseudoprogression during immune checkpoint inhibitor monotherapy for non-small cell lung cancer is reportedly 3.6%-6.9%, while pseudoprogression during chemoimmunotherapy is rare. Reports on pseudoprogression during dual immunotherapy combined with chemotherapy are lacking. Herein, a 55-year-old male with invasive mucinous adenocarcinoma (cT2aN2M1c [OTH, PUL], stage IVB, and programmed death-ligand 1 expression <1%), renal dysfunction, and disseminated intravascular coagulation was treated with carboplatin, solvent-based paclitaxel, nivolumab, and ipilimumab. After treatment initiation, computed tomography (CT) on day 14 showed disease progression. The patient was diagnosed with pseudoprogression because of a lack of symptoms, improved platelet count, and decreased fibrin/fibrinogen degradation product levels. CT on day 36 showed a reduction in the primary lesion size, multiple lung metastases, and mesenteric metastases. Therefore, pseudoprogression should be considered during dual immunotherapy with chemotherapy.

A long-acting anti-IL-8 antibody improves inflammation and fibrosis in endometriosis.

Current pharmacological treatments for endometriosis are limited to hormonal agents that can relieve pain but cannot cure the disease. Therefore, the development of a disease-modifying drug for endometriosis is an unmet medical need. By studying human endometriotic samples, we found that the progression of endometriosis was associated with the development of inflammation and fibrosis. In addition, IL-8 expression was highly up-regulated in endometriotic tissues and closely correlated with disease progression. We created a long-acting recycling antibody against IL-8 (AMY109) and evaluated its clinical potency. Because rodents do not produce IL-8 and do not experience menstruation, we analyzed the lesions in cynomolgus monkeys that spontaneously developed endometriosis and in a surgically induced endometriosis monkey model. Both spontaneously developed and surgically induced endometriotic lesions demonstrated pathophysiology that was highly similar to that of human endometriosis. Once-a-month subcutaneous injection of AMY109 to monkeys with surgically induced endometriosis reduced the volume of nodular lesions, lowered the Revised American Society for Reproductive Medicine score as modified for monkeys, and ameliorated fibrosis and adhesions. In addition, experiments using cells derived from human endometriosis revealed that AMY109 inhibited the recruitment of neutrophils to endometriotic lesions and the production of monocyte chemoattractant protein-1 from neutrophils. Thus, AMY109 may represent a disease-modifying therapy for patients with endometriosis.

Can depressed cancer patients with a borderline thiamine concentration develop deficiency within a short time period?

BACKGROUND: Despite increasing reports of thiamine deficiency (TD) among cancer patients, there remain some patients with borderline thiamine concentrations (BTC). However, it is unclear whether such patients subsequently develop TD. METHODS: Here, we report cases of cancer patients progressing to TD within a short time period after presentation with BTC (24-28 ng/ml). CASE 1: A 49-year-old female with lung cancer. During treatment for depression, the patient showed a decreased appetite, and a blood sample revealed BTC (25 ng/ml). Fourteen days later, she reported a continued loss of appetite, and despite the absence of the 3 classical signs of Wernicke encephalopathy (WE), additional testing showed a thiamine level of 23 ng/ml, leading to a diagnosis of TD. CASE 2: A 65-year-old female developed depression during chemotherapy for angiosarcoma. Her blood sample revealed BTC (25 ng/ml). Seven days later, despite the absence of the classical signs of WE, a further testing revealed a thiamine level of 20 ng/ml. CASE 3: A 41-year-old female developed depression during chemotherapy for ovarian cancer. No loss of appetite was observed, but a blood sample revealed BTC (25 ng/ml). Seven days later, despite the absence of the classical signs of WE or decreased appetite, further testing revealed a thiamine level of 19 ng/ml. SIGNIFICANCE OF RESULTS: Depressed cancer patients with BTC may develop TD within a short time frame. To prevent TD, health-care professionals should maintain an awareness of its potential and the need for regular testing of thiamine level or prophylactic replacement therapy.

The Association Between Hypouricemia and Cardiometabolic Diseases: Analyzing Nationwide Data From Medical Checkup and Health Insurance Records.

OBJECTIVES: The aims of this study were to evaluate the association between hypouricemia and cardiometabolic diseases, such as hypertension, dyslipidemia, and reduced kidney function, and to explore the sex-specific optimal range for serum uric acid (sUA) associated with the lowest risk for these diseases. METHODS: In this cross-sectional study, we identified individuals with sUA data between April 2018 and March 2019 and recorded the frequency of cardiometabolic comorbidities according to sUA. Univariable and multivariable logistic regression analyses were performed for the overall population and after classifying by sex to assess the association between sUA and cardiometabolic comorbidities. RESULTS: Among 796,508 individuals, a J-shaped association was observed between the sUA level and cardiometabolic diseases in the overall population. The adjusted odds ratios (95% confidence interval) for hypertension, dyslipidemia, and reduced renal function in individuals with sUA ≤1.0 mg/dL compared with those with sUA ranging between 2.1 and 3.0 mg/dL were 1.38 (1.13-1.69), 1.52 (1.30-1.78), and 2.17 (1.47-3.20), respectively. A J-shaped association between sUA and hypertension was observed only in women. The optimal range of sUA associated with the lowest risk for hypertension was assumed to be <6 mg/dL in men and 1-4 mg/dL in women. A J-shaped association between the sUA and dyslipidemia and reduced renal function was observed in both men and women. The optimal range of sUA for dyslipidemia and reduced renal function was approximately 2-5 mg/dL in men and 1-4 mg/dL in women. CONCLUSIONS: Excess and extremely low uric acid levels may be related to an increased cardiometabolic risk.