Visual Field Improvement and Electrode Extrusion Prevention by Extended Endaural Incision With Cavity Obliteration for Cochlear Implantation in Ears After Canal Wall-Down Mastoidectomy: Experience of Four Cases.

There is no global consensus on the surgical technique of cochlear implantation (CI) in ears with an open cavity after canal wall-down (CWD) mastoidectomy. Here, we report CI surgery with an endaural incision for the ears after CWD mastoidectomy. The endaural incision was extended upward to obliterate the open cavity of the temporal fascial flap. The endaural incision was extended downward to close the open cavity inlet. After inserting the implanted electrode, the open cavity was obliterated using a temporal fascial flap, and the cavity was closed at the inlet. We performed this type of CI surgery in four ears in three patients. This extended endaural incision provided an excellent view for pedicling the temporal fascial flap with the superficial temporal artery and for open cavity closure without any serious complications. This technique allowed us to opt for CI surgery of the ears after CWD mastoidectomy.

Extracting interpretable features for pathologists using weakly supervised learning to predict p16 expression in oropharyngeal cancer.

One drawback of existing artificial intelligence (AI)-based histopathological prediction models is the lack of interpretability. The objective of this study is to extract p16-positive oropharyngeal squamous cell carcinoma (OPSCC) features in a form that can be interpreted by pathologists using AI model. We constructed a model for predicting p16 expression using a dataset of whole-slide images from 114 OPSCC biopsy cases. We used the clustering-constrained attention-based multiple-instance learning (CLAM) model, a weakly supervised learning approach. To improve performance, we incorporated tumor annotation into the model (Annot-CLAM) and achieved the mean area under the receiver operating characteristic curve of 0.905. Utilizing the image patches on which the model focused, we examined the features of model interest via histopathologic morphological analysis and cycle-consistent adversarial network (CycleGAN) image translation. The histopathologic morphological analysis evaluated the histopathological characteristics of image patches, revealing significant differences in the numbers of nuclei, the perimeters of the nuclei, and the intercellular bridges between p16-negative and p16-positive image patches. By using the CycleGAN-converted images, we confirmed that the sizes and densities of nuclei are significantly converted. This novel approach improves interpretability in histopathological morphology-based AI models and contributes to the advancement of clinically valuable histopathological morphological features.

Utility of the endobronchial Watanabe spigot for intractable cancer-related pneumothorax: a retrospective observational study.

BACKGROUND: The use of endobronchial Watanabe spigots for intractable secondary pneumothorax in patients with cancer has not been adequate. This study aimed to investigate the use of endobronchial Watanabe spigots for intractable pneumothorax in patients with malignant tumors. METHODS: Consecutive patients with malignant tumors who underwent occlusion with an endobronchial Watanabe spigot for intractable pneumothorax associated with perioperative treatment or drug therapy at our institution between January 2014 and February 2022 were reviewed. RESULTS: Of the 32 cases in which an endobronchial Watanabe spigot was used, six were excluded; we thus evaluated 26 cases in which the chest tube was removed. Chest tubes were removed in 19 cases (73.1%) and could not be removed and required surgical treatment under general anesthesia in seven patients (26.9%), of which four (14.8%) underwent open-window thoracostomy. Half of the patients were treated with both an endobronchial Watanabe spigot and pleurodesis. Although thin-slice chest computed tomography revealed a fistula in 15 patients, the chest tube was removed in 11 (57.9%) patients. A significant difference was only observed in patients with a history of heavy smoking. CONCLUSIONS: The chest tube removal rate was comparable to those reported in previous studies. An endobronchial Watanabe spigot may be a useful treatment option for intractable cancer-related pneumothorax.

Effect of Average Relative Humidity on Epistaxis.

Background Epistaxis is a very common symptom. The occurrence of epistaxis may be affected by dry environments, but there are some differences among previous reports and this view is controversial. Objective We investigated the relationship between the number of epistaxes and daily average relative humidity. Methods Data on patients with epistaxis between March 2011 and February 2021 were collected from two hospitals. The daily average relative humidity was examined, and the change in the number of patients with epistaxis due to humidity was investigated using a generalized linear mixed model. Results A total of 4184 cases of epistaxis were identified. The number of epistaxis cases per day was significantly associated with the daily average relative humidity (p < 0.001). One percent increment in average relative humidity decreases the number of epistaxis cases per day by 1.1%. Conclusion A negative correlation was found to exist between daily average relative humidity and occurrences of epistaxis.

Endoscopic observation of pharyngeal mucosal suture healing process after total laryngectomy: case series.

BACKGROUND: Pharyngocutaneous fistula (PCF), a major complication of total laryngectomy, is caused by pharyngeal repair failure. OBJECTIVE: Assess the usefulness of endoscopic observation of the pharyngeal suture's healing process for the early detection of PCF development. METHODS: Pharyngeal mucosal sutures were endoscopically observed postoperatively in patients who underwent total laryngectomy with primary closure. RESULTS: Postoperatively, a white coat adhered to the pharyngeal mucosal suture of all patients. In most cases, the white coat gradually receded, which was considered to be a normal healing process. Thickening of the white coat and/or dehiscence of surgical wound were interpreted as 'poor healing conditions'. Three cases were judged to have developed poor healing conditions of the pharyngeal mucosal suture and one patient developed PCF. The other two patients did not develop PCF, possibly due to early detection of 'poor healing condition' and conservative approach, such as discontinuation of oral intake. CONCLUSIONS: Postoperative poor healing conditions of the pharyngeal mucosal suture may be precursors to PCF development. Endoscopic observation enables early detection of these conditions and may enable the prevention of PCF.

Elevation of C-reactive protein during concurrent chemoradiotherapy is a poor predictive factor for head and neck cancer.

OBJECTIVE: The prognostic role of pretreatment C-reactive protein (CRP) has been reported for head and neck cancer. However, little is known about the relationship between the changes in CRP levels during treatment and prognosis. This study aimed to investigate the correlation between CRP elevation during concurrent chemoradiotherapy (CCRT) and survival outcomes. METHODS: The medical records of patients with oropharyngeal, hypopharyngeal, and laryngeal cancer treated with CCRT at the University of Tsukuba Hospital and National Hospital Organization Mito Medical Center from April 2014 to December 2019 were retrospectively reviewed. Patients were divided into normal (<0.3 mg/dl) and elevated (≥0.3 mg/dl) CRP groups according to the CRP level after the first cycle of cisplatin. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 74 patients were enrolled, of whom 36 (49%) showed elevated CRP levels after the first cycle of cisplatin. The 3-year PFS was 83.3% and 61.0% in the normal and elevated CRP groups, respectively, showing significant differences between the two groups. CONCLUSION: Elevated CRP levels after the first cycle of cisplatin is an objective predictive marker for survival in patient with head and neck squamous cell carcinoma treated with CCRT.

Estradiol protects hair cells from cisplatin-induced ototoxicity via Nrf2 activation.

Cisplatin-induced ototoxicity is caused by reactive oxygen species. It has been recognized that estradiol (E2) regulates redox balance. However, little is known about the protective mechanisms of E2 against cisplatin-induced ototoxicity. In this study, we investigated the effect of E2 on nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated hair cell protection using the organ of Corti isolated from mice. The organ of Corti collected from C57BL/6 mice at 3-5 postnatal days was used in all experiments. The organ of Corti was exposed to 20 µM cisplatin with/without 100 nM E2 to examine the effect of E2 on cisplatin-induced hair cell loss. The mRNA expression of Nrf2 and the phase II detoxification gene after E2 and cisplatin treatment was analyzed using quantitative real-time PCR. E2 significantly reduces cisplatin-induced cochlear hair cell death. In addition, 100 nM E2 increased the mRNA expression of Nrf2 and phase II detoxification genes in the organ of Corti under cisplatin treatment. Our results suggest that E2 activates Nrf2, phase II detoxification enzymes and exerts a protective effect against cisplatin-induced ototoxicity.

The area of residual tumor predicts esophageal squamous cell carcinoma prognosis following neoadjuvant chemotherapy.

PURPOSE: To clarify the utility of the area of residual tumor for patients with esophageal squamous cell cancer treated with neoadjuvant chemotherapy. METHODS: We enrolled 186 patients with esophageal squamous cell cancer who underwent surgical resection following neoadjuvant chemotherapy at our hospital. Using digital images, we measured the area of residual tumor at the maximum plane of the specimen and divided the patient into three groups as follows: 0 (area = 0 mm2), low (area = 0-40 mm2), and high (area ≥ 40 mm2). The clinicopathological factors and prognosis were compared among these groups. RESULTS: The median area of the residual tumor was 15.0 mm2　(range 0-1,448.8 mm2). Compared with the 0 and low group, the high group was significantly associated with poorer recurrence-free survival (all P < .001) and overall survival (P < .001 [vs. 0] and P = .017 [vs low]). The area of residual tumor, ypN, tumor regression grade, and lymphovascular invasion were independent predictors of recurrence-free survival. By dividing the patients using a combination of the area of residual tumor and lymphovascular invasion, the high and/or lymphovascular invasion ( +) group displayed significantly poor recurrence-free survival than the 0 group and low/lymphovascular invasion ( -) group. However, there was no significant difference in the recurrence-free survival between the 0 group and low/lymphovascular invasion ( -) group. CONCLUSION: The area of residual tumor is a promising histopathological prognostic factor for patients with esophageal squamous cell cancer treated with neoadjuvant chemotherapy. Moreover, it is a possible candidate histopathological factor for postoperative chemotherapy selection.

Is elective neck dissection necessary for patients with cT3-4N0 parotid gland cancer?

OBJECTIVE: Management of the cervical lymph nodes in patients with cT3-4N0 parotid gland cancer (PGC) has been controversial. This study investigated the need for elective neck dissection (END) in patients with cT3-4N0 PGC. METHODS: We retrospectively examined cervical lymph node metastasis, overall survival (OS), and disease-free survival (DFS) rates in 40 patients with cT3-4N0 PGC according to whether or not END was performed. RESULTS: Cervical lymph node metastasis occurred in 27.5% of patients and level II was the most common area. Recurrence could be treated by salvage neck dissection. There was no significant difference in OS (P=0.581) or DFS (P=0.728) between the group that underwent END and the group that did not. CONCLUSION: END at level II is worth performing because of the occult lymph node metastasis rate. The area of neck dissection should be limited because there is no evidence that END improves the prognosis of cT3-4N0 PGC.

Efficacy of the pretreatment geriatric nutritional risk index for predicting severe adverse events in patients with head and neck cancer treated with chemoradiotherapy.

OBJECTIVE: The Geriatric Nutritional Risk Index (GNRI) is a simple and well-established nutritional assessment tool. Although concurrent chemoradiotherapy (CCRT), particularly cisplatin-based CCRT, is a standard treatment for locoregional advanced head and neck squamous cell carcinoma (HNSCC), the predictive factors of adverse events related to CCRT remain to be elucidated. The present study aimed to determine the association between GNRI and CCRT-related adverse events in patients of all ages with head and neck cancer (HNC) who underwent CCRT. METHODS: We retrospectively analyzed and compared the clinical characteristics and adverse events of 82 patients with HNC treated with CCRT according to their GNRI at the Department of Otolaryngology, Head and Neck Surgery, University of Tsukuba Hospital, between May 2014 and November 2019. The GNRI was calculated according to the equation: 1.489 × serum albumin (g/L) + 41.7 × (body weight/ideal body weight). We compared two groups: low GNRI (GNRI < 98) and normal GNRI (GNRI ≥ 98) groups. RESULTS: Eighty-two patients were enrolled in this study. There were 61 (76%) and 21 (26%) patients in the normal GNRI group and low GNRI group, respectively. There were significant differences in the incidence of grade ≥ 3 radiation mucositis, radiation dermatitis, and leukopenia between the low GNRI group and the normal GNRI groups. CONCLUSIONS: Patients with low GNRI scores were more likely to have severe adverse events. Pretreatment GNRI predicted severe CCRT-related adverse events in patients of all ages with HNC undergoing CCRT.

Construction and commissioning of mid-infrared self-amplified spontaneous emission free-electron laser at compact energy recovery linac.

The mid-infrared range is an important spectrum range where materials exhibit a characteristic response corresponding to their molecular structure. A free-electron laser (FEL) is a promising candidate for a high-power light source with wavelength tunability to investigate the nonlinear response of materials. Although the self-amplification spontaneous emission (SASE) scheme is not usually adopted in the mid-infrared wavelength range, it may have advantages such as layout simplicity, the possibility of producing a single pulse, and scalability to a short-wavelength facility. To demonstrate the operation of a mid-infrared SASE FEL system in an energy recovery linac (ERL) layout, we constructed an SASE FEL setup in cERL, a test facility of the superconducting linac with the ERL configuration. Despite the adverse circumstance of space charge effects due to the given boundary condition of the facility, we successfully established the beam condition at the undulators and observed FEL emission at a wavelength of 20 µm. The results show that the layout of cERL has the potential for serving as a mid-infrared light source.

The Geriatric Nutritional Risk Index as a Prognostic Factor in Patients with Advanced Head and Neck Cancer.

OBJECTIVE: The Geriatric Nutritional Risk Index (GNRI) is a simple and well-established nutritional assessment tool and is a significant prognostic factor in various cancers. However, the role of the GNRI in predicting clinical outcomes in patients with advanced head and neck cancer (AHNC) has not been investigated. The aim of the present study was to examine the association between the GNRI and prognosis in patients with AHNC. STUDY DESIGN: Retrospective cohort study. METHODS: Data collected between 2002 and 2013 from Tsukuba University Hospital were reviewed. The GNRI was calculated according to the equation, 1.489 × serum albumin (g/l) + 41.7 × (body weight/ideal body weight). Characteristics and prognosis were compared among three risk groups: high (GNRI <82); intermediate (GNRI 82-98); and normal (GNRI >98). The primary endpoint was overall survival. RESULTS: A total of 248 AHNC patients were enrolled, among whom 134 (54%) exhibited no nutritional risk, 53 (21%) had an intermediate risk for malnutrition, and 61 (25%) exhibited a high risk for malnutrition. Three-year survival rates according to the three-group GNRI scores for normal, intermediate, and high risk were 76.6%, 56.3%, and 19.5%, respectively. As the three-group GNRI score increased, the risk for mortality significantly increased (adjusted hazard ratio [HR] for intermediate to normal, 1.73 [95% CI, 1.02-2.92]; adjusted HR for high to normal, 4.31 [95% CI, 2.71-6.84]). CONCLUSIONS: The GNRI could be considered a useful prognostic factor in patients with AHNC. LEVEL OF EVIDENCE: 4 Laryngoscope, 131:E151-E156, 2021.

Cephalic Vein Cut-down for Totally Implantable Central Venous Access Devices With Preoperative Ultrasonography by Surgical Residents.

BACKGROUND/AIM: Cephalic vein (CV) cut-down for totally implantable central venous access devices (TICVADs) is not frequently used due to its low success rate. We compared the outcomes of CV cut-down using preoperative ultrasonography (US) performed by experienced surgeons versus surgical residents. PATIENTS AND METHODS: From December 2015 to December 2017, 10 surgeons implanted 212 TICVADs using CV cut-down with preoperative US. The surgeons were divided into two groups of five each: surgical residents (Group A, n=124 procedures) and experienced surgeons (Group B, n=88 procedures). Duration of operation time, completion rate, and complications were retrospectively analyzed. RESULTS: The completion rate was significantly higher in Group A (98.4% versus 92.0%, p=0.04). Duration of operation time (45.2±14.5 versus 42.0±13.1 minutes, p=0.22), rates of early complications (1.6% versus 1.1%, p=0.77) and late complications (3.2% versus 2.3%, p=0.68) were equivalent between the two groups. No fatal complications occurred in either group. CONCLUSION: CV cut-down can be safely performed by surgical residents under the use of preoperative US.

Discovery of colossal Seebeck effect in metallic Cu2Se.

Both electrical conductivity σ and Seebeck coefficient S are functions of carrier concentration being correlated with each other, and the value of power factor S2σ is generally limited to less than 0.01 W m-1 K-2. Here we report that, under the temperature gradient applied simultaneously to both parallel and perpendicular directions of measurement, a metallic copper selenide, Cu2Se, shows two sign reversals and colossal values of S exceeding ±2 mV K-1 in a narrow temperature range, 340 K < T < 400 K, where a structure phase transition takes place. The metallic behavior of σ possessing larger magnitude exceeding 600 S cm-1 leads to a colossal value of S2σ = 2.3 W m-1 K-2. The small thermal conductivity less than 2 W m-1 K-1 results in a huge dimensionless figure of merit exceeding 400. This unusual behavior is brought about by the self-tuning carrier concentration effect in the low-temperature phase assisted by the high-temperature phase.

Bilateral Adrenal Hemorrhage in a Patient with Antiphospholipid Syndrome during Chronic Graft-versus-host Disease.

We present the case of a 56-year-old man with an upper respiratory infection followed by fatigue, hypotension, and hyponatremia. Bilateral adrenal hemorrhage was confirmed, based on T2-weighted magnetic resonance imaging. The patient had previously undergone allogeneic hematopoietic stem cell transplantation and had been diagnosed with antiphospholipid syndrome (APS) during the development of chronic graft-versus-host disease. A prompt diagnosis and steroid replacement, in addition to anticoagulant therapy, resulted in a favorable outcome. Once the diagnosis of APS has been confirmed, which might be the sign of bilateral adrenal hemorrhage, the initial manifestations of adrenal insufficiency should never be overlooked.

Cardio-ankle vascular index predicts for the incidence of cardiovascular events in obese patients: a multicenter prospective cohort study (Japan Obesity and Metabolic Syndrome Study: JOMS).

OBJECTIVE: The cardio-ankle vascular index (CAVI) is an index of arterial stiffness less dependent on blood pressure and an indicator suitable for assessing the arterial dysfunction. However, it remains unclear whether CAVI can predict the outcome of cardiovascular diseases (CVD) in obese patients. METHODS: A total of 425 obese Japanese outpatients (189 men and 236 women, mean age: 51.5 years) were enrolled in a multicenter prospective cohort Japan, the Japan Obesity and Metabolic Syndrome Study (JOMS). Primary analysis regarding measurements of cardiovascular risk factors including CAVI and the occurrence of macrovascular complications was based on following the participants over a 5-year period. RESULTS: Of the eligible patients, 300 (78%) were followed into the fifth year. During the study period, 15 coronary heart disease, 7 stroke, and 6 arteriosclerosis obliterans events occurred. All events occurred in 28 patients, and CVD incidence rate was 15.8 per 1000 person-years. In the analysis of adjusted models for traditional risk factors, CAVI was a significant factor for the incidence of events. In addition, high CAVI and low HDL-cholesterol were significant factors for the incidence of events in Cox stepwise multivariate analysis when age- and sex-adjusted (CAVI [per 1]: HR = 1.44 [1.02-2.02], p = 0.037; HDL-cholesterol [per 1 mmol/L]: HR = 0.20 [0.06-0.69], p = 0.011). In addition, CAVI added value to atherosclerotic cardiovascular disease risk score in predicting the development of CVD. CONCLUSION: This study demonstrates for the first time that CAVI is an effective predictor of CVD events in obese patients.

Comparison of cystatin C- and creatinine-based estimated glomerular filtration rate to predict coronary heart disease risk in Japanese patients with obesity and diabetes.

The aim of this study is to determine which indicator of chronic kidney disease most closely correlates with 10-year Framingham coronary heart disease (CHD) risk among serum creatinine, serum cystatin C (S-CysC), urine albumin-creatinine ratio (UACR), estimated creatinine-based GFRs (eGFRcre), and estimated CysC-based GFRs (eGFRcys) in patients with obesity and diabetes. Serum creatinine, S-CysC, UACR, and cardio-ankle vascular index (CAVI) were examined in 468 outpatients with obesity and type 2 diabetes, free of severe renal dysfunction or previous history of cardiovascular disease, as a cross-sectional survey using baseline data from the multi-centered Japan Diabetes and Obesity Study. S-CysC and eGFRcys had significantly stronger correlations with the 10-year Framingham CHD risk than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.318; S-CysC, ρ = 0.497; UACR, ρ = 0.174; eGFRcre, ρ = -0.291; eGFRcys, ρ = -0.521; P < 0.01 by Fisher's z-test). S-CysC and eGFRcys had significantly stronger correlations with CAVI than serum creatinine, eGFRcre, and UACR (creatinine, ρ = 0.198; S-CysC, ρ = 0.383; UACR, ρ = 0.183; eGFRcre, ρ = -0.302; eGFRcys, ρ = -0.444; P < 0.05 by Fisher's z-test). The receiver operating characteristic curves to distinguish the high-risk patients for CHD revealed significantly larger areas under the curve of S-CysC and eGFRcys than those of serum creatinine, UACR, and eGFRcre (serum creatinine, 0.64; S-CysC, 0.75; UACR, 0.56; eGFRcre, 0.63; eGFRcys, 0.76; P < 0.01). The data suggested that eGFRcys can be more predictive of the 10-year CHD risk than eGFRcre in Japanese patients with obesity and diabetes.

Plasma free metanephrines in the diagnosis of pheochromocytoma: diagnostic accuracy and strategies for Japanese patients.

Measuring the levels of the plasma free metanephrines (PFMs) represents a recently developed and promising test for the diagnosis of pheochromocytoma in the United States and Europe. As this test has not yet been evaluated in Japan, it is necessary to evaluate the diagnostic efficacy of measuring the levels of PFMs compared with the standard measurement of the urinary excretion of metanephrines (uMNs) whose reliability is well established to detect of pheochromocytoma. A total of 101 Japanese subjects clinically suspected of having pheochromocytoma in were included in this study. Subsequently, we prospectively measured the PFMs levels in all patients, compared with those of biochemical markers of the catecholamine secretion and metabolisms in the plasma and urine. All subjects with adrenal tumors underwent tumor excision. Data were available for 84 of the 101 patients, 47 of whom had histopathologically proven pheochromocytoma and 37 were finally diagnosed with non-pheochromocytoma. The results of comparisons in the accuracy of measurement for diagnosis of pheochromocytoma between PFMs and the urinary excretion of metanephrines (uMNs) were 0.980 VS 0.951 for AUC of receiver operatorating characteristic (ROC) curve, 0.957 VS 0.894 for sensitivity, and 0.973 VS 0.946 for specificity, respectively. Although the differences were small, the results of our study definitely demonstrated that measurement of PFMs was not inferior to standard urinary metanephrines (uMNs) measurement, which is established to be the most reliable biochemical method to detect pheochromocytoma. This study clearly shows measuring the PFMs levels to be a reliable and efficient method for diagnosing pheochromocytoma in Japanese patients, as demonstrated in previous reports.

Perioperative sequential monitoring of hemodynamic parameters in patients with pheochromocytoma using the Non-Invasive Cardiac System (NICaS).

Surgical treatment of pheochromocytoma is associated with a high risk of hemodynamic instability. To reduce the risk of perioperative complications, adequate medical treatment to normalize blood pressure and restore blood volume is required. Accurate evaluation of the circulating blood volume (CBV) in perioperative patients with pheochromocytoma is clinically important. In the present study, we adopted whole-body bioimpedance monitoring technique using the Non-Invasive Cardiac System (NICaS), which can non-invasively measure cardiac output (CO) values. NICaS-derived CO values were evaluated in eight preoperative patients with pheochromocytoma and were compared with simultaneous CBV values measured by a conventional indicator dilution method using (131)I-labeled human serum albumin. In these patients with pheochromocytoma, the NICaS-derived CO values were significantly correlated with the CBV values measured by (131)I-labeled human serum albumin (4.86 ± 1.05 L/min vs 4.79 ± 1.02 L; r = 0.906; P = 0.002). Sequential NICaS-derived CO values confirmed that CBV increased after preoperative treatment with an α-blocker, with or without volume loading. The results of this study indicate that NICaS can be used to accurately and non-invasively evaluate the hemodynamic status. By sequential monitoring of NICaS-derived CO values, we are able to confirm whether adequate CBV in a patient with pheochromocytoma is obtained by preoperative medical treatment with α-blockers or volume loading, to avoid perioperative complications.

Behavioral and clinical correlates of serum bilirubin concentrations in Japanese men and women.

BACKGROUND: A considerable interest has been drawn to potential protective effects of bilirubin against oxidative stress-related diseases. Smoking is known to be associated with lower concentrations of serum bilirubin, but other behavioral correlates of serum bilirubin have not been well studied. In this cross-sectional study, we examined the associations of behavioral and clinical factors with serum total bilirubin in Japanese men and women. METHOD: The study subjects comprised of 4802 men and 6414 women aged 49-76 years who participated in the baseline survey of an ongoing cohort study on lifestyle-related diseases in Fukuoka, Japan. With consideration to time of the day of blood sampling and fasting hours, the associations with smoking, alcohol intake, body mass index, physical activity, coffee, tea, blood pressure, glycated hemoglobin (HbA1c), HDL cholesterol and non-HDL cholesterol with serum bilirubin were evaluated by analysis of covariance and multiple linear regression analysis. RESULTS: While smoking was negatively associated with serum bilirubin, alcohol consumption was positively associated with serum bilirubin in both men and women. Coffee consumption was associated with lower bilirubin concentrations in both sexes. In the multiple linear regression analysis, HDL cholesterol was positively and HbA1c was negatively associated with bilirubin in both men and women, and the associations were more evident in women. CONCLUSION: Smoking, alcohol use and coffee consumption were important behavioral correlates of serum bilirubin in Japanese men and women. Serum HDL cholesterol was a measurable clinical correlate of bilirubin in women.