Efficacy and tolerability of initial triple combination therapy with metformin, dapagliflozin and saxagliptin compared with stepwise add-on therapy in drug-naïve patients with type 2 diabetes (TRIPLE-AXEL study): A multicentre, randomized, 104-week, open-label, active-controlled trial.

AIM: To evaluate the efficacy and tolerability of an initial triple combination therapy (TCT) compared with conventional stepwise add-on therapy (SAT) in patients with newly diagnosed type 2 diabetes (T2D). MATERIALS AND METHODS: This multicentre, randomized, 104-week, open-label trial randomized 105 patients with drug-naïve T2D (with HbA1c level ≥ 8.0%, < 11.0%) to the TCT (1000 mg of metformin, 10 mg of dapagliflozin and 5 mg of saxagliptin once daily) or SAT (initiated with metformin, followed by glimepiride and sitagliptin) groups. The primary outcome was the proportion of patients who achieved an HbA1c level of less than 6.5% without hypoglycaemia, weight gain of 5% or higher, or discontinuation of drugs because of adverse events at week 104. RESULTS: HbA1c reduction from baseline at week 104 was similar between the groups (the least squares mean change was -2.56% in the TCT group vs. -2.75% in the SAT group). The primary outcome was achieved in 39.0% and 17.1% of the TCT and SAT groups, respectively, with a risk difference of 22.0 (95% confidence interval 3.0, 40.8; P = .027). HbA1c level less than 6.5% at week 104 was 46.3% in both the TCT and SAT groups, whereas the incidence of hypoglycaemia, weight gain, or discontinuation of drugs was 16.7% and 62.0% in the TCT and SAT groups, respectively (P < .001). TCT was well-tolerated and had fewer adverse events than SAT. CONCLUSIONS: Among newly diagnosed patients with T2D, initial TCT effectively lowered HbA1c levels with higher tolerability and safety than SAT for 104 weeks, suggesting a novel strategy for initial combination therapy in T2D patients.

Distribution of urinary trace element exposure and dietary sources in women over 50 in an agricultural region- A community-based KoGES cohort study.

BACKGROUND: There is a noticeable lack of information on the levels of both non-essential and essential trace elements in women aged over 50. The main objective of this study is to investigate trace element concentrations and explore the influence of sociodemographic factors and dietary sources of exposure in this demographic. METHODS: We analyzed 19 trace elements, including manganese, cobalt, copper, zinc, molybdenum, chromium, nickel, arsenic, strontium, cadmium, tin, antimony, cesium, barium, tungsten, mercury, thallium, lead, and uranium, using ICP-MS and mercury analyzer. Urine samples were obtained from a cohort of 851 women aged over 50 who participated in the 8th KoGES-Ansung study (2017-2018). Multiple linear models were employed to explore associations between urinary trace element concentrations and sociodemographic factors and dietary sources of exposure. We used K-means clustering to discern patterns of exposure to trace elements and identify contributing factors and sources. RESULTS: Our findings indicate higher concentrations of molybdenum (Mo), arsenic (As), cadmium (Cd), and lead (Pb) in our study population compared to women in previous studies. The study population were clustered into two distinct groups, characterized by lower or higher urinary concentrations. Significant correlations between age and urinary concentrations were observed in Ni. Smoking exhibited positive associations with urinary Cd and As. Associations with dietary sources of trace elements were more distinct in women in the high-exposure group. Urinary antimony (Sb) was positively linked to mushroom and egg intake, As to mushroom and fish, and Hg to egg, dairy products, fish, seaweed, and shellfish. CONCLUSIONS: Our study underscores the significant gap in understanding urinary concentrations of trace elements in women aged over 50. With higher concentrations of certain elements compared to previous studies and significant correlations between age, smoking, and specific food sources, it is imperative to address this gap through targeted dietary source-specific risk management.

Editorial Commentary: Artificial Intelligence Models Using Machine Learning Can Improve Preoperative Identification of Subscapularis Pathology.

Subscapularis pathology is difficult to diagnose, in part because of decreased sensitivity and accuracy in identifying tears with magnetic resonance imaging (MRI) when compared to other cuff tendons. Artificial intelligence evaluation of patient physical examination and MRI data using a machine learning model shows that arthroscopically confirmed partial- or full-thickness subscapularis tears are highly associated with abnormal subscapularis tendon length, long head of the biceps tears, and subscapularis fatty atrophy, and on physical examination, with weakness with internal rotation and positive lift-off, belly press, and bear hug tests. Today, physicians may use machine learning as a tool, but this model may not currently be sufficient to drastically change practice. However, with continued research and development, which is occurring rapidly, similar models could aid physicians in timely identification of pathology and optimization of preoperative planning, as well as physician training and education.

Pectoralis major tendon rupture repairs using intramedullary suture anchors shows high patient-reported outcomes in military service members.

BACKGROUND: In the general population, pectoralis major tendon ruptures are uncommon; however, it is a common injury in the military population. The military service members have greater physical demands than the general population. The purpose of this study is to critically assess the postoperative outcomes of pectoralis major tendon ruptures in military service members following a repair using intramedullary suture anchors. METHODS: A retrospective chart review was performed between 2014 and 2022, identifying patients who underwent a pectoralis major rupture repair performed by the senior surgeon using intramedullary suture anchors. Records were reviewed for age, gender, mechanism of injury, chronicity, visual analog scale, and Single Assessment Numeric Evaluation (SANE) scores. Patients who had less than 1 year of follow-up were excluded from the study. During the study period, 18 patients underwent surgical repair of their torn pectoralis major, and 15 patients were followed up >1 year postoperatively. Twelve of these 15 patients (80%) were successfully contacted, and patient-reported outcomes were collected. RESULTS: A total of 12 patients (12 male, 0 female) with a mean age of 34.5 years were identified. Average time from injury to surgery was 471.4 days. Average duration of follow-up was 3.7 years. There was a decrease in the preoperative average single repetition maximum (1RM) barbell bench press of 125.7 kg (277 lbs) to a postoperative average 1RM bench press of 101.8 kg (225 lbs) (P = .03). Mean change in average 1RM barbell bench press is a 19.04% decrease postoperatively. Postoperative SANE score was 80.8 and an American Shoulder and Elbow Surgeons Standardized Shoulder Assessment Form score of 86.9. Seven patients (58.3%) stated they were afraid to bench press at their previous weight because of fear of reinjury. None of the patients were medically discharged from the military owing to limitations from their repaired shoulder. Ten patients (83%) reported they were extremely satisfied with their shoulder function postoperatively. CONCLUSION: Repair of the pectoralis major tendon ruptures using intramedullary suture anchors has high rates of return to duty, patient satisfaction, and patient-reported outcomes. More than half of the patients reported they were afraid to bench press at their preinjury weight because of concerns of reinjury; the decrease in postoperative strength may be a result of the patients' fear of reinjury rather than physiologic limitations.

Receiver operating characteristics of computed tomography (CT) compared to cystoscopy in diagnosis of canine ectopic ureters: Thirty-five cases.

OBJECTIVE: The aim of the study was to determine receiver operating characteristics (ROC) of computed tomographic excretory urography (CTEU) in predicting cystoscopic findings of ureteral anatomy. STUDY DESIGN: Retrospective cohort study. ANIMALS: Thirty-five client-owned dogs. METHODS: The medical records of dogs referred for suspected ectopic ureters were reviewed. Inclusion criteria included CTEU findings reported by board-certified radiologists, followed by rigid cystoscopy with or without ureteral cystoscopic laser ablation (CLA). Data included signalment, urinary incontinence degree, body condition score, weight, degree of colon distension, CTEU and cystoscopy findings. ROC analysis was used to compare CT-predicted ureteral orthotopia/ectopia to cystoscopy findings. Additionally, ROC of CT predicted ureteral orifice locations was analyzed. Regression covariate analysis was performed to identify factors that may have influenced accuracy of diagnosis. RESULTS: The ability of CT to identify a normal and intra-or extramural ectopic ureters conclusively and correctly was 13/26 (50%) and 32/41(78%), respectively. Sensitivity and specificity of identifying extramural versus intramural ureters was 2/7 versus 30/46 (29 vs. 65%) and 61/63 versus 17/24 (97 vs. 71%), respectively. Ectopic orifice determination sensitivity and specificity varied widely depending on location from 0% to 76% and 67% to 97%, respectively. Covariate analysis failed to identify interfering factors. CONCLUSIONS: CT did not accurately predict anatomy of ureters; CT findings may need confirmation by cystoscopy and possibly intraoperative fluoroscopy prior to determining if CLA is indicated or not. CLINICAL SIGNIFICANCE: Our results may be of importance for surgeons interpreting the CTEU findings. CTEU prediction of the location of the ureteral orifice shows low sensitivity especially in or close to the urethral sphincter area.

Ecological factors affecting first-time mothers' satisfaction with Sanhujoriwons (postpartum care centres) from South Korea: a cross-sectional and correlational study.

BACKGROUND: In South Korea, commercial postpartum care centres, known as Sanhujoriwons, have emerged as important institutions aiding mothers' physical recovery after childbirth. Although previous studies have measured mothers' satisfaction level with Sanhujoriwons, this study applies Bronfenbrenner's ecological model to identify the factors influencing first-time mothers' satisfaction with Sanhujoriwons. METHODS: This descriptive correlational study involved 212 first-time mothers admitted to Sanhujoriwons for two weeks with their new-borns (healthy babies weighing at least 2.5 kg) after giving birth after 37 weeks of pregnancy. Data were collected using a self-report questionnaire at five postpartum care centres in the metropolitan area of South Korea from October to December 2021, on the day of the mothers' discharge. This study considered ecological factors such as perceived health status, postpartum depression, childcare stress, maternal identity at the individual level; partnership with Sanhujoriwon staff at the microsystem level; and the Sanhujoriwons' education support system at the exo-system level. The data were analysed using descriptive statistics, t-test, one-way ANOVA, correlation analysis, and hierarchical regression analysis using the SPSS 25.0 Win program. RESULTS: The mean score of satisfaction with Sanhujoriwons was 59.67 ± 10.14 out of 70, indicating a high level of satisfaction. The hierarchical regression analysis showed that satisfaction with Sanhujoriwons was significantly affected by the perceived health status (ß = 0.19, p < 0.001), partnership between mothers and the caregivers (ß = 0.26, p < 0.001), and education support system of the Sanhujoriwons (ß = 0.47, p < 0.001). The explanatory power of the model for these variables was 62.3%. CONCLUSIONS: Our results indicate that not only the mother's health status but also the educational support system of postpartum care centres and partnerships are important for improving first-time mothers' satisfaction with postpartum care centres. Thus, when developing an intervention program for postpartum care centres, practitioners should focus on developing various kinds of support and strategies to improve the physical health condition of mothers, build partnerships between mothers and care staff, and improve the quality of the educational support offered to mothers. Further studies to develop and test the effectiveness of such intervention programs are strongly suggested.

Area Measurement Percentile of 3-Dimensional Computed Tomography Has the Highest Interobserver Reliability When Measuring Anterior Glenoid Bone Loss.

PURPOSE: To determine the accuracy of glenoid bone loss measurement and the difference between 3 methods of measurement, as well as the measurements application to previously published studies. METHODS: A list of patients with anterior bony glenoid defects was created through a search of electronic medical records. Three surgeons reviewed each patient's advanced imaging (computed tomography [CT], 3-dimensional [3D] CT, or magnetic resonance imaging), and glenoid bone loss was measured by 3 different methods: (1) linear measurement percentile (LMP), (2) area measurement percentile (AMP), and (3) circle-line method (CLM). The intraclass correlation coefficients between reviewers and mathematical differences between measurement techniques were calculated. RESULTS: The images of 125 patients with anterior glenoid bone loss were measured. For all imaging studies, the intraclass correlation coefficient was greatest with the AMP (0.738) and CT with 3D reconstruction (0.735). Within the entire sample, average bone loss measured 21.3% (range, 5.6%-43.5%) by the LMP method, 15.7% (range, 1.6%-42.2%) by the CLM, and 16.5% (range, 2.3%-40.3%) by the AMP method. On average, the difference between the LMP and AMP methods was 4.8%. When the AMP and LMP methods were compared, the greatest difference in measurement was 5.9%, and this occurred at an LMP of 19.1%, which was an AMP of 13.2%. CONCLUSIONS: When measuring anterior glenoid bone loss, CT with 3D reconstruction and the AMP method have the greatest interobserver reliability. Furthermore, the greatest difference between the LMP and AMP methods occurs at an LMP between 18.3% and 20.0% and an AMP between 12.4% and 14.2%, with the difference ranging from 5.7% to 5.9%. CLINICAL RELEVANCE: When measuring anterior glenoid bone loss, evaluation of CT with 3D reconstruction is more reliable than magnetic resonance imaging evaluation. Furthermore, the AMP method has the greatest interobserver reliability when compared with the LMP method and CLM.

Surgical treatment of shoulder instability in active-duty service members with subcritical glenoid bone loss: Bankart vs. Latarjet.

INTRODUCTION: Subcritical bone loss has been identified as a risk factor for potentially inferior outcomes following typical arthroscopic soft tissue repair. One alternative that has been presented as an option for patients with bone loss is the Latarjet, an ipsilateral coracoid transfer to the anteroinferior glenoid. The purpose of this study is to compare the outcomes between the arthroscopic Bankart repair and the open Latarjet for the treatment of anterior shoulder instability in patients with subcritical bone loss. We hypothesize that the open Latarjet will provide higher patient-reported outcome measure scores and lower rates of dislocation. METHODS: A retrospective cohort comparison of patients with anterior glenohumeral instability procedures was performed. Inclusion criteria included symptomatic anterior shoulder instability, subcritical glenoid bone loss (13.5%-24%), surgical treatment with arthroscopic Bankart repair or open Latarjet, and minimum follow-up of 2 years. Outcomes included recurrent instability (defined as postoperative dislocation or subjective subluxation), permanent physical restrictions, Western Ontario Shoulder Index (WOSI), and Single Assessment Numeric Evaluation (SANE) scores. RESULTS: Forty-seven patients were included, 25 of whom underwent an arthroscopic Bankart repair and 23 patients an open Latarjet. The average bone loss was 17.8% and 19.3%, respectively. Overall, 8 patients experienced recurrent instability, 6 in the arthroscopic Bankart group and 2 in the open Latarjet group (P = .162). The average postoperative SANE score for arthroscopic Bankart group was 48% and for the open Latarjet group, 84% (P < .001). The average postoperative WOSI score for the arthroscopic Bankart group was 53.6% and for the open Latarjet group, 67.9% (P = .069). There were significantly more patients placed on permanent physical restrictions in the arthroscopic Bankart repair group (16) compared with open Latarjet (3) (P < .001). CONCLUSION: In patients with subcritical glenoid bone loss (defined as 13.5%-24%), patients treated with an open Latarjet have insignificantly higher SANE and WOSI scores and lower permanent physical restrictions than patients treated with an arthroscopic Bankart repair. We found no statistically significant difference in recurrent instability rates between the open Latarjet and arthroscopic Bankart repair (P = .162).

Sex, menopause, and age differences in the associations of persistent organic pollutants with thyroid hormones, thyroxine-binding globulin, and peripheral deiodinase activity: A cross-sectional study of the general Korean adult population.

Persistent organic pollutants (POPs) can disrupt the thyroid hormone system in humans. We assessed the associations of several POPs with serum thyroid hormones (T3 and T4) and thyroid-stimulating hormone, and investigated the modulating effects of sex, menopausal status, and age on these associations, in a subgroup of the adult population (n = 1250) from the Korean National Environmental Health Survey. PCB105 and PCB118 were negatively associated with total T4 in premenopausal females and males aged <50, whereas the associations were insignificant in other groups. PCB180, p,p'-DDE, and p,p'-DDT showed positive associations with total T3 in postmenopausal females; however, among males aged ≥50, PCB118, PCB138, and p,p'-DDE showed negative associations with total T3. The effects of exposure to multiple POPs were examined in multi-factor analyses. Factor 2 comprised PCB52, hexachlorobenzene, and BDE-47 was associated with an increase in free T4 in premenopausal females (ß = 0.015, p = 0.024), while Factor 1, which contained most POPs, was associated with a change in total T3 in postmenopausal females (ß = 0.032, p = 0.040) and males aged ≥50 (ß = -0.039, p = 0.023). Changes in total T4 or total T3 could be explained by differences in thyroxine-binding globulin (TBG) and peripheral deiodinase activity (GD). Negative associations of TBG with PCB105 in premenopausal females and PCB153 in males aged <50 may mediate the effect of decreasing total T4. PCB180, p,p'-DDE, p,p'-DDT, and Factor 1 were positively associated with GD, which is consistent with an increased total T3 in postmenopausal females. PCB118 was negatively associated with GD and total T3 in males aged ≥50. BDE-47 and ß-hexachlorocyclohexane were associated with thyroid autoantibodies in premenopausal females and males aged <50. Our observations suggest that the thyroid-disrupting effects of POPs may differ by sex, sex hormonal status, and age, and may be mediated by TBG and GD.

Lead, mercury, and cadmium exposures are associated with obesity but not with diabetes mellitus: Korean National Environmental Health Survey (KoNEHS) 2015-2017.

BACKGROUND: Associations of heavy metal exposures with obesity and obesity-related traits have been suggested, while those with nonalcoholic fatty liver disease (NAFLD) and diabetes mellitus (DM) are often inconsistent. METHODS: This study included 3787 adults aged ≥19 years who participated in the Korean National Environmental Health Survey 2015-2017, and investigated the association of toxic heavy metals with metabolic diseases. Lead (Pb), mercury (Hg), and cadmium (Cd) were measured either in urine (uHg, uCd) or total blood (bPb, bHg). Body mass index (BMI) was calculated, and DM cases were identified through a self-answered medication history. Hepatic Steatosis Index (HSI) as a surrogating index of NAFLD, was calculated using hepatic enzyme measurements, including aspartate aminotransferase (AST) and alanine aminotransferase (ALT). RESULTS: Adults in the highest quartile of bPb, bHg, and uHg showed significantly elevated odds of obesity (BMI ≥25 kg/m2), compared to the lowest quartile (OR 1.58 for bPb, 1.92 for bHg, and 1.81 for uHg). HSI was positively correlated with bHg, uHg, and uCd concentrations. The odds of NAFLD (HSI ≥36) were also increased with increasing quartile of bHg, uHg, and uCd concentrations. For DM, bPb showed a significant negative association, while bHg and uCd exhibited non-monotonic and inconclusive associations. CONCLUSIONS: Among the general adult population of Korea, both Pb and Hg exposures were associated with an increased risk of obesity. In addition, both Hg and Cd exposures were associated with increased odds of NAFLD. These metals, however, were not associated with an increased risk of DM.

Surgical treatment of anterior shoulder instability with glenoid bone loss with the Latarjet procedure in active-duty military service members.

INTRODUCTION: The arthroscopic Bankart repair in the setting of glenoid bone loss has high rates of failure. In patients with anterior glenoid bone loss, the Latarjet provides glenohumeral stability through restoration of the glenoid bone, the conjoint tendon acting as a sling on the subscapularis, and anterior capsulolabral repair. Active-duty military personnel are at high risk for glenohumeral instability and have been equated to the contact athlete; most are young, male, and engage in contact sports. The purpose of this study is to assess the return to full-duty rates in active-duty military personnel following the Latarjet for anterior glenohumeral instability with glenoid bone loss. METHODS: A retrospective review of all glenohumeral instability procedures were reviewed at a tertiary training hospital from June 2014 to June 2019. The patient population consisted of active-duty military personnel with glenoid bone loss and anterior glenohumeral instability, who were treated with a Latarjet. The primary outcome was return to full-duty status. RESULTS: There were 50 patients identified for the study. Four patients were lost to follow-up, leaving 46 of 50 patients (92.0%) eligible for this study. The average age at the time of the index procedure was 23.1 years. The average percentage bone loss was 18.4%. Forty-one patients (89.1%) were able to return to full-duty status. Four patients (8.7%) sustained a recurrent dislocation following the Latarjet; all 4 dislocations occurred during a combat deployment. Four patients (8.7%) reported episodes of subluxation without dislocation. Forty-one patients (89.1%) reported that their shoulders felt stable, and we found an average return to full duty at 5.3 months CONCLUSION: In our active-duty military cohort, we found an 8.7% rate of recurrent instability after a Latarjet procedure, and 41 patients (89.1%) were able to return to full-duty status. In conclusion, the Latarjet procedure in the active-duty military population with anterior glenoid bone loss resulted in a high rate of return to duty, excellent functional outcomes, low rate of recurrent instability, and a low overall complication rate.

Muscle strength, an independent determinant of glycemic control in older adults with long-standing type 2 diabetes: a prospective cohort study.

BACKGROUND: Although the proportion of older patients with type 2 diabetes mellitus (T2DM) has increased, few studies have reported the factors affecting glucose levels in older patients with long-standing T2DM. This study assessed the determinants of glycemic control in older adults with T2DM of a duration of ≥10 years, including muscle mass, muscle quality, and ß-cell function. METHODS: This was a prospective study of older patients aged ≥60 years with a T2DM duration of ≥10 years. The Homeostatic Model Assessment of Insulin Resistance (HOMA-IR) index, handgrip strength (HGS), and body composition through bioelectrical impedance analysis were assessed. The primary outcome was a composite of: (i) increment of glycated hemoglobin (HbA1c) from the baseline ≥0.6% and (ii) HbA1c ≥ 9% at any time point during the follow-up period. To find the predicting determinants of the outcome, we performed the Cox proportional hazard analysis. RESULTS: Among 100 patients (mean age, 64.0 ± 8.6 years; median duration of diabetes, 20 [interquartile range (IQR), 17-23] years; median HbA1c at baseline, 7.1 [IQR, 6.7-7.4] %), the primary outcome was observed in 40 (40.0%) patients during 4.0 (IQR 2.3-5.0) years of follow-up. A Cox proportional hazards model adjusted for age, sex, baseline HbA1c, obesity, duration of DM and anti-diabetic medication at baseline showed that low HGS and insulin resistance at the baseline were independent determinants of the primary outcome (hazard ratio [HR] = 2.23 [95% confidence interval (CI), 1.06-4.72] and 2.39 [95% CI, 1.18-4.83], respectively). Sex stratification confirmed that HGS and muscle mass were independent determinants of the primary outcome only in women (HR per quartile, 0.58 [95% CI, 0.37-0.93] and 0.46 [95% CI, 0.25-0.85], respectively). `. CONCLUSIONS: Low HGS and insulin resistance were independent risk factors for aggravated glycemic control among older patients with long standing T2DM.

Prediction Models for the Clinical Severity of Patients With COVID-19 in Korea: Retrospective Multicenter Cohort Study.

BACKGROUND: Limited information is available about the present characteristics and dynamic clinical changes that occur in patients with COVID-19 during the early phase of the illness. OBJECTIVE: This study aimed to develop and validate machine learning models based on clinical features to assess the risk of severe disease and triage for COVID-19 patients upon hospital admission. METHODS: This retrospective multicenter cohort study included patients with COVID-19 who were released from quarantine until April 30, 2020, in Korea. A total of 5628 patients were included in the training and testing cohorts to train and validate the models that predict clinical severity and the duration of hospitalization, and the clinical severity score was defined at four levels: mild, moderate, severe, and critical. RESULTS: Out of a total of 5601 patients, 4455 (79.5%), 330 (5.9%), 512 (9.1%), and 301 (5.4%) were included in the mild, moderate, severe, and critical levels, respectively. As risk factors for predicting critical patients, we selected older age, shortness of breath, a high white blood cell count, low hemoglobin levels, a low lymphocyte count, and a low platelet count. We developed 3 prediction models to classify clinical severity levels. For example, the prediction model with 6 variables yielded a predictive power of >0.93 for the area under the receiver operating characteristic curve. We developed a web-based nomogram, using these models. CONCLUSIONS: Our prediction models, along with the web-based nomogram, are expected to be useful for the assessment of the onset of severe and critical illness among patients with COVID-19 and triage patients upon hospital admission.

Evaluation of acute and subacute toxicity of sodium taurodeoxycholate in rats.

Taurodeoxycholate (TDCA) inhibits various inflammatory responses suggesting potential clinical application. However, the toxicity of TDCA has not been evaluated in detail in vivo. We investigated the acute toxicity and 4-week repeated-dose toxicity of TDCA following intravenous infusion under Good Laboratory Practice regulations. In the sighting study of acute toxicity, one of two rats (one male and one female) treated with 300 mg/kg TDCA died with hepatotoxicity, suggesting that the approximate 50% lethal dose of TDCA is 300 mg/kg. Edema and discoloration were observed at the injection sites of tails when rats were infused with 150 mg/kg or higher amount of TDCA once. In 4-week repeated-dose toxicity study, no treatment-related mortality or systemic changes in hematology and serum biochemistry, organ weights, gross pathology, or histopathology were observed. However, the tail injection site showed redness, discharge, hardening, and crust formation along with histopathological changes such as ulceration, edema, fibrosis, and thrombosis when rats were infused with 20 mg/kg TDCA. Taken together, TDCA induced no systemic toxicity or macroscopic lesions at the injection site at a dose of 10 mg/kg/day, which is 33 times higher than the median effective dose observed in a mouse sepsis model. These findings suggest that TDCA might have a favorable therapeutic index in clinical applications.

Nonclinical toxicology studies with sodium taurodeoxycholate: acute and subacute toxicity in dogs.

Sodium taurodeoxycholate (TDCA) has been investigated for various inflammatory disorders such as sepsis. We recently evaluated nonclinical safety profile of TDCA using rats infused intravenously. As a series of preclinical safety investigations, we further conducted toxicity studies with TDCA delivered to dogs via intravenous administration under Good Laboratory Practice regulation in this study. In dose range-finding study (dose escalation study), dogs given with TDCA at a dose of 150 mg/kg showed marked changes in clinical signs, hematology, and serum biochemistry. And biochemical markers of liver damage and local skin lesions were observed following intravenous infusion of 100 mg/kg TDCA, suggesting that 100 mg/kg was chosen as the highest dose of TDCA for 4-week repeated-dose toxicity study using dogs. Despite no treatment-related significant changes in body weight, food consumption, ophthalmoscopy, and urinalysis, skin lesions were observed at the injection site of animals administered with higher than 50 mg/kg of TDCA along with biochemical and histopathological changes associated with liver injury. However, most of off-target effects were found to be reversible since these were recovered after stopping TDCA infusion. These findings indicate that the no-observed-adverse-effect-level (NOAEL) for TDCA in dogs was considered to be 5 mg/kg/d. Taken together, our results provide important toxicological profiles regarding the safe dose of TDCA for drug development or clinical application.

Bone resorption of the greater tuberosity after open reduction and internal fixation of complex proximal humeral fractures: fragment characteristics and intraoperative risk factors.

HYPOTHESIS AND BACKGROUND: In complex proximal humeral fractures, bone resorption of the greater tuberosity is sometimes observed after open reduction and internal fixation (ORIF). However, this has not been well characterized, and risk factors for resorption are not completely understood. We aimed (1) to identify the risk factors associated with bone resorption of the greater tuberosity and (2) to quantify the geometric and bone density characteristics associated with bone resorption using 3-dimensional computed tomography models in complex proximal humeral fractures treated with ORIF. METHODS: We identified a retrospective cohort of 136 patients who underwent ORIF of 3- or 4-part proximal humeral fractures; greater tuberosity resorption developed after ORIF in 30 of these patients. We collected demographic, fracture-related, and surgery-related characteristics and performed multivariable logistic regression analysis to identify factors independently associated with the development of greater tuberosity resorption. Furthermore, we identified 30 age- and sex-matched patients by use of propensity score matching to perform quantitative fragment-specific analysis using 3-dimensional computed tomography models. After the fragment of the greater tuberosity was identified, the number of fragments, the relative fragment volume to the humeral head, and the relative bone density to the coracoid process were calculated. Measurements were compared between matched case-control groups. RESULTS: We found that an unreduced greater tuberosity (odds ratio [OR], 10.9; P < .001), inadequate medial support at the calcar (OR, 15.0; P < .001), and the use of an intramedullary fibular strut (OR, 4.5; P = .018) were independently associated with a higher risk of bone resorption. Quantitative fragment-specific analysis showed that greater tuberosities with a larger number of fragments (5 ± 2 vs. 3 ± 2, P = .021), smaller fragments (9.9% ± 3.8% vs. 18.6% ± 4.7%, P < .001), and fragments with a lower bone density (66.4% ± 14.3% vs. 88.0% ± 18.4%, P = .001) had higher rates of resorption. DISCUSSION AND CONCLUSION: An unreduced greater tuberosity or inadequate medial support increases the risk of greater tuberosity resorption, as do a larger number of fracture fragments, smaller fragments, and lower bone density. Additionally, fibular strut grafting is an independent risk factor for tuberosity resorption. Further study is needed, but alternatives to strut grafting such as femoral head allograft may warrant serious consideration.

Predicting reoperation after operative treatment of proximal humerus fractures.

PURPOSE: The current understanding of the factors associated with a second surgery or loss of alignment after operative treatment of a proximal humerus fracture has relied on small sample studies with stepwise regression analysis. In this study, we used a powerful regression analysis over a large sample and with many variables to test the null hypothesis that there are no factors associated with a revision surgery or loss of alignment after operative treatment of proximal humerus fractures. METHODS: A retrospective review of all surgically treated proximal humerus fractures from January 1, 2000, to December 31, 2015, was performed at a tertiary level hospital. We extracted longitudinal medical records for all patients, and the data were organized into two categories of predictors: fracture/operative characteristics and patient characteristics. RESULTS: During the study period, 423 patients met the inclusion criteria. Three hundred and fourteen of the fractures underwent Open Reduction Internal Fixation (ORIF) and 109 underwent Hemiarthroplasty. Thirty-three patients underwent revision surgery (8%). Seventy-nine patients treated with ORIF had loss of alignment (25%). Across the entire cohort, the least absolute shrinkage selection operator (LASSO) analysis found that patients between 40 and 60 years of age had a higher odds of revision surgery (OR = 1.6). In patients treated with ORIF, the LASSO regression found an unreduced calcar to be the strongest predictor of loss of alignment (OR = 5.5), followed by osteoporosis (OR = 1.3), prior radiation treatment (OR = 1.3), unreduced greater tuberosity (OR = 1.2) and age over 80 years (OR = 1.2). CONCLUSION: Reoperation after proximal humerus surgery is infrequent even though loss of alignment is common. In our cohort, not all patients who had a loss of alignment underwent revision surgery; consequently, obtaining the best possible reduction at the index surgery is paramount.

Peripheral arterial endothelial dysfunction predicts future cardiovascular events in diabetic patients with albuminuria: a prospective cohort study.

BACKGROUND: Reactive hyperemia-peripheral arterial tonometry (RH-PAT) is a noninvasive and simple test for evaluating the endothelial function. There has been sparse evidence on the usefulness of the RH-PAT index (RHI) in predicting future cardiovascular diseases among diabetic patients. METHODS: Asymptomatic diabetic patients with albuminuria were selected; their medical history and laboratory findings were evaluated every 3 to 4 months, respectively. The primary outcome was a composite of three-point major adverse cardiovascular events (3-point MACE): death from cardiovascular causes, acute coronary events, or nonfatal stroke. On the contrary, secondary outcomes included a composite of 3-point MACE, hospitalization for heart failure, or chronic kidney disease (CKD) progression. RHI was measured using the Endo-PAT2000 at the baseline. RHI < 1.67 was considered to indicate peripheral endothelial dysfunction (PED). RESULTS: In total, 149 subjects were included (mean age, 61.8 ± 9.2 years; duration of diabetes was 12 years). During the follow-up period (median, 49.7 months), of the 149 subjects, primary outcomes were detected in 12 (1 [2.3%] and 11 [10.5%] of those without and with PED, respectively). The presence of PED in baseline measurements significantly increased both primary and secondary outcomes, following adjustment for age, sex, hypertension, glycated hemoglobin, low-density lipoprotein cholesterol, triglyceride, systolic blood pressure, baseline estimated glomerular filtration rate, overt proteinuria, duration of diabetes, premedical history of ischemic events, anti-platelet agents, and smoking history (hazard ratio [HR]: 10.95; 95% confidence interval CI 1.00-119.91 for the primary outcome; HR, 4.12; 95% CI 1.37-12.41 for secondary outcome). In addition, PED could predict secondary outcomes independent of the risk score according to the American College of Cardiology/American Heart Association (HR: 3.24; 95% CI 1.14-9.17). CONCLUSIONS: PED can independently predict future cardiovascular events among diabetic patients with albuminuria.

Prenatal sonographic markers of the outcome in fetuses with bronchopulmonary sequestration.

PURPOSE: To evaluate the prenatal sonographic predictive markers of the outcome in fetuses with bronchopulmonary sequestration (BPS). METHODS: BPS size and diameter of the feeding artery (FA) were measured prenatally and postnatally. Velocity of the FA and the left ventricular-modified myocardial performance index (LV mod-MPI) were also evaluated prenatally. RESULTS: Forty-seven women were included in the study. Mean gestational age, mass size, diameter and velocity of the FA, and LV mod-MPI at prenatal diagnosis were 23.5 ± 2.2 weeks, 3.6 ± 8.3 cm, 2.3 ± 0.6 mm, 46.6 ± 15.4 cm/s, and 0.46 ± 0.06, respectively. Mean mass diameter and FA diameter measured on postnatal CT examinations were 3.8 ± 1.0 cm and 2.3 ± 0.7 mm, respectively. Five patients had respiratory symptoms after birth. Twenty children (43%) underwent or were scheduled to undergo mass excision, and the remaining 27 (57%) were doing well without any intervention. There was no neonatal death. LV mod-MPI at diagnosis, the FA diameter after birth and the serial change in the FA size were significantly associated with postnatal mass excision. CONCLUSION: The FA diameter and LV mod-MPI may be additional markers for predicting whether fetuses with BPS should undergo mass excision in early childhood or conservative care.

Effect of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes.

OBJECTIVE: We investigated the effects of sodium-glucose cotransporter 2 inhibitor, empagliflozin, and α-glucosidase inhibitor, voglibose, on hepatic steatosis in an animal model of type 2 diabetes (T2DM). METHODS: Empagliflozin (OLETF-EMPA) or voglibose (OLETF-VOG) was administered to Otsuka Long-Evans Tokushima fatty (OLETF) rats once daily for 12 weeks. Control Long-Evans Tokushima Otsuka (LETO) and OLETF (OLETF-C) rats received saline. RESULTS: Blood glucose levels were significantly suppressed in OLETF-EMPA and OLETF-VOG compared with the OLETF-C group. The liver fat content was significantly higher in the OLETF-C group than in the OLETF-EMPA and OLETF-VOG. Hepatic gene expressions involved in gluconeogenesis (glucose 6-phosphatase [G6Pase], fructose-1,6-bisphosphatase [FBP1], and phosphoenolpyruvate carboxykinase [PEPCK]) and lipogenesis (acetyl-CoA carboxylase [ACC], fatty acid synthase [FAS], and sterol regulatory element-binding transcription factor 1c [SREBP-1c]) were significantly decreased in the OLETF-EMPA group compared with other OLETF groups (OLETF-C and OLETF-VOG). Sirtuin 1 (SIRT1) expression level and SIRT1 activity were markedly reduced in OLETF-C rats; however, its expression increased in the OLETF-EMPA and OLETF-VOG. AMP-activated protein kinase (AMPK) phosphorylation level was remarkably increased by empagliflozin treatment in OLETF rats compared with other OLETF groups. Long-term empagliflozin and voglibose treatment reduced hepatic steatosis with suppression of gluconeogenesis and lipogenesis pathway in OLETF rats. CONCLUSION: We suggest that this metabolic improvement might be related to SIRT1 and AMPK pathway in T2DM. But empagliflozin is thought to have more advantage to prevent hepatic steatosis than voglibose in T2DM.