Phase III study of bilayer sustained-release tramadol tablets in patients with cancer pain: a double-blind parallel-group, non-inferiority study with immediate-release tramadol capsules as an active comparator.

PURPOSE: We investigated whether twice-daily administration of a bilayer tablet formulation of tramadol (35% immediate-release [IR] and 65% sustained-release) is as effective as four-times-daily IR tramadol capsules for managing cancer pain. METHODS: This randomized, double-blind, double-dummy, active-comparator, non-inferiority study enrolled opioid-naïve patients using non-steroidal anti-inflammatory drugs or acetaminophen (paracetamol) to manage cancer pain and self-reported pain (mean value over 3 days ≥ 25 mm on a 100-mm visual analog scale [VAS]). Patients were randomized to either bilayer tablets or IR capsules for 14 days. The starting dose was 100 mg/day and could be escalated to 300 mg/day. The primary endpoint was the change in VAS (averaged over 3 days) for pain at rest from baseline to end of treatment/discontinuation. RESULTS: Overall, 251 patients were randomized. The baseline mean VAS at rest was 47.67 mm (range: 25.6-82.7 mm). In the full analysis set, the adjusted mean change in VAS was - 22.07 and - 19.08 mm in the bilayer tablet (n = 124) and IR capsule (n = 120) groups, respectively. The adjusted mean difference was - 2.99 mm (95% confidence interval [CI] - 7.96 to 1.99 mm). The upper 95% CI was less than the predefined non-inferiority margin of 7.5 mm. Other efficacy outcomes were similar in both groups. Adverse events were reported for 97/126 (77.0%) and 101/125 (80.8%) patients in the bilayer tablet and IR capsule groups, respectively. CONCLUSION: Twice-daily administration of bilayer tramadol tablets was as effective as four-times-daily administration of IR capsules regarding the improvement in pain VAS, with comparable safety outcomes. CLINICAL TRIAL REGISTRATION: JapicCTI-184143/jRCT2080224082 (October 5, 2018).

Predictors of In-Hospital Death in Patients With Acute Myocardial Infarction.

OBJECTIVE: Factors such as age, vital signs, renal function, Killip class, cardiac arrest, elevated cardiac biomarker levels, and ST deviation predict survival in patients with acute myocardial infarction (AMI). However, the existing risk assessment tools lack comprehensive consideration of catheter-related factors, and short-term prognostic predictors are unknown. This study aimed to clarify in-hospital prognostic predictors in hospitalized patients with AMI. METHODS: Five hundred and thirty-six patients who underwent percutaneous coronary intervention (PCI) for AMI were divided into non-survivor (n = 36) and survivor (n = 500) groups. Coronary risk factors, laboratory findings, angiographic findings, and clinical courses were compared between the two groups. Multiple logistic regression was used to analyze in-hospital death in pre- and post-PCI phases. RESULTS: In the pre-PCI phase, multiple logistic regression analysis revealed several predictors of in-hospital death, including systolic blood pressure [odds ratio (OR) = 0.985, p = 0.023)], Killip class ≥2 (OR = 14.051, p <0.001), and chronic kidney disease (OR = 4.859, p = 0.040). In the post-PCI phase, multiple logistic regression analysis revealed additional predictors of in-hospital death, including Killip class ≥2 (OR = 5.982, p = 0.039), presence of lesions in the left main trunk (OR = 51.381, p = 0.044), utilization of intra-aortic balloon pumps and percutaneous cardiopulmonary support (OR = 6.141, p = 0.016), and presence of multi-vessel disease (OR = 6.323, p = 0.022). CONCLUSION: Predictors of in-hospital death in AMI extend beyond conventional risk factors to include culprit lesions, mechanical support, and multi-vessel disease that manifest post-PCI.

A Noonan-like pediatric patient with a de novo CBL pathogenic variant and an RNF213 polymorphism p.R4810K presenting with cardiopulmonary arrest due to left main coronary artery ostial atresia.

Left main coronary artery ostial atresia (LMCAOA) is an extremely rare condition. Here, we report the case of a 14-year-old boy with Noonan syndrome-like disorder in whom LMCAOA was detected following cardiopulmonary arrest. The patient had been diagnosed with Noonan syndrome-like disorder with a pathogenic splice site variant of CBL c.1228-2 A > G. He suddenly collapsed when he was running. After administering two electric shocks using an automated external defibrillator, the patient's heartbeat resumed. Cardiac catheterization confirmed the diagnosis of LMCAOA. Left main coronary artery angioplasty was performed. The patient was discharged without neurological sequelae. Brain magnetic resonance imaging revealed asymptomatic Moyamoya disease. In addition, RNF213 c.14429 G > A p.R4810K was identified. There are no reports on congenital coronary malformations of compound variations of RNF213 and CBL. In contrast, the RNF213 p.R4810K polymorphism has been established as a risk factor for angina pectoris and myocardial infarction in adults, and several congenital coronary malformations due to genetic abnormalities within the RAS/MAPK signaling pathway have been reported. This report aims to highlight the risk of sudden death in patients with RASopathy and RNF213 p.R4810K polymorphism and emphasize the significance of actively searching for coronary artery morphological abnormalities in these patients.

Heat Stroke-Induced Takotsubo Cardiomyopathy With a Concomitant Transient Brugada-Like Electrocardiogram.

A 79-year-old man presented with impaired consciousness, fever with a body temperature of 41.1°C, and an electrocardiogram showing significant ST segment elevation in leads V1-6, coved-type ST elevation in leads V1-3, and partial right bundle branch block. Echocardiography revealed notable left ventricle dysfunction with apex-based akinesis. Coronary angiography confirmed severe obstructive lesions but left ventriculography displayed the distinct apical ballooning of takotsubo cardiomyopathy (TC). This case highlights the presence of atypical electrocardiographic patterns in TC influenced by comorbidities, supporting the diagnosis of TC despite concurrent obstructive coronary artery disease.

Anammox-Mediated Hydroxyapatite Granules: Physicochemical Properties, 3D Hierarchy, and Biofilm Thickness.

Biomineralization inspired the development of simultaneous biological transformations and chemical precipitation for simultaneous nitrogen removal and phosphorus recovery from wastewater, which could compensate for the incapacity of phosphorus management in the new biological route of anaerobic ammonium oxidation (anammox). In this study, we strengthened anammox-mediated biomineralization by long-term feeding of concentrated N, P, and Ca substrates, and a self-assembled matrix of anammox bacteria and hydroxyapatite (HAP) was fabricated in a granular shape, defined as HAP-anammox granules. HAP was identified as the dominant mineral using elemental analysis, X-ray diffraction, and Raman spectroscopy. The intensive precipitation of HAP resulted in a higher inorganic fraction and substantially improved settleability of anammox biomass, which facilitated HAP precipitation by acting as nucleation and metabolically elevated pH. By using X-ray microcomputed tomography, we visually represented the hybrid texture of interwoven HAP pellets and biomass, the core-shell layered architecture of different-sized HAP-anammox granules, and their homogeneously regulated thickness of the outer biofilm (from 118 to 635 µm). This unique architecture endows HAP-anammox granules with outstanding settleability, active biofilm, and tightly bonded biofilm with the carrier, which may explain the excellent performance of these HAP-anammox granules under various challenging operational conditions in previous studies.

An Escherichia coli-Induced Distal Arch Aneurysm Presenting With Hemoptysis.

Infected thoracic aneurysms are a rare and potentially life-threatening condition that present with non-specific symptoms. We describe here a case of an 83-year-old female who presented to the emergency department with the chief complaint of vomiting blood. The patient had presented to the emergency department 40 days earlier with abdominal pain, fever, and leukocytosis. She had a medical history of traumatic liver injury resulting in bile duct stenosis, necessitating percutaneous transhepatic gallbladder drainage and subsequent bile duct-jejunal anastomosis 25 years ago. Emergency contrast-enhanced computed tomography (CT) revealed an irregular distal arch aneurysm. According to the patient's present symptoms, CT findings, and medical history, infected thoracic aneurysm was suspected. Total arch replacement was performed promptly, followed by thorough antibiotic therapy. Following successful treatment, the patient's condition stabilized, and she was transferred to a rehabilitation facility for further recovery.

Conservative Treatment for Isolated Superior Mesenteric Artery Dissection With Severely Narrowed True Lumen.

A 59-year-old male presented to the emergency department with distressing epigastric pain after seeking medical attention at a nearby clinic three hours prior. Upon examination, the attending physician noticed edematous changes in the proximal segment of the superior mesenteric artery, and a subsequent enhanced computed tomography (CT) scan confirmed the diagnosis of an isolated dissection of the artery. Notably, the true lumen of the vessel was significantly narrowed, raising concerns for potential vascular compromise. After extensive consultation between a vascular surgeon and a radiologist, a decision was made to adopt a conservative management approach. The patient was closely monitored with meticulous bowel rest, hydration management, and carefully curated dietary modifications. Over time, subsequent CT scans revealed progressive enlargement of the true lumen, which was highly reassuring to the medical team. As a result of the expert management and diligent care provided, the patient was eventually discharged home without any adverse events or complications. This case highlights the critical role of a multidisciplinary approach in managing complex vascular pathology and underscores the importance of thoughtful clinical decision-making and meticulous monitoring in achieving favorable outcomes.

Electrocardiographic QRS Findings Upon Admission Can Predict Prognosis of Acute Myocardial Infarction Caused by Occlusion of Left Main Coronary Artery.

BACKGROUND: Acute myocardial infarction (AMI) caused by left main coronary artery (LMCA) occlusion is associated with a severe clinical course and catastrophic consequences. HYPOTHESIS: We sought to clarify ECG predictors of prognosis in AMI caused by LMCA occlusion. METHODS: We examined 20 consecutive patients with AMI caused by LMCA occlusion that was treated by primary stenting. The patients were assigned to either a group that survived (S) and was discharged from hospital, or a group that did not survive (NS) and died in hospital. We compared ECG findings upon admission, angiographic findings, laboratory data and clinical outcomes. RESULTS: The rate of having Thrombolysis In Myocardial Infarction (TIMI) grade > 2 coronary flow before PCI and of achieving TIMI grade 3 after PCI was significantly lower in the NS than the S group (14.3% vs. 83.3%, p = 0.003 and 35.7% vs. 100%, p = 0.008). The ECG findings showed longer QRS interval in the NS than in the S group (150.5 ± 37.9 vs. 105.2 ± 15.4, p = 0.022). A QRS interval ≥ 120 msec predicted in-hospital mortality with sensitivity, specificity and positive and negative predictive values of 78.5%, 100%, 100% and 66.7%, respectively, in this population. CONCLUSIONS: The QRS duration upon admission was a good predictor of in-hospital mortality among patients with AMI caused by LMCA occlusion. This ECG sign could be useful in the emergency clinical setting.

Partial Arch Replacement Using Common Trunk Perfusion in Type A Acute Aortic Dissection.

An 80-year-old woman was referred to our hospital following a syncope. Contrast-enhanced computed tomography revealed an acute type A aortic dissection with a bovine aortic arch and an enlarged innominate artery. The dissection affected only the ascending aorta and not the common trunk, which is composed of the innominate and left common carotid arteries. Cardiopulmonary bypass was established using common trunk perfusion and vena cava drainage. Following a thorough evaluation, a surgical intervention involving the replacement of the ascending aorta and partial arch, accompanied by the excision of the dilated innominate artery, was meticulously carried out. In instances where the common trunk remains unaffected by the dissection, it presents as a viable alternative perfusion site. Therefore, opting for an approach involving the resection of the common trunk followed by the separate reconstruction of the innominate and left common carotid arteries during the replacement of the ascending aorta and partial arch may serve as a preventative measure against potential vascular events in the future.

Earlobe Creases as a Marker of the Risk for Coronary Atherosclerosis Before Angiography in Elderly and Non-elderly Patients.

Background The close relationship between earlobe creases (ELC) and the presence of coronary artery disease (CAD) has been reported. In addition, this study aimed to determine associations between ELC and the presence, extent, and severity of coronary atherosclerosis assessed by coronary angiography in non-elderly and elderly patients. Methods We assessed 1,086 consecutive patients with suspected CAD by coronary angiography. We defined severe CAD as Gensini scores > 20. Multiple logistic regression analysis was adjusted for age, sex, hypertension, diabetes mellitus, smoking status, lipid profiles, and body mass index (BMI) to assess the presence or absence of CAD, multivessel disease, and severe CAD in elderly (age ≥ 60 years) and non-elderly (age < 60 years) patients. Results ELC was a significantly positive determinant of CAD (odds ratio (OR) = 3.074, p < 0.001), multivessel disease (OR = 3.101, p < 0.001), and severe CAD (OR = 2.823, p < 0.001) in all patients. ELC was also a predictor of CAD, multivessel disease, and severe CAD not only in patients aged ≥ 60 years (OR = 3.095, p < 0.001; OR = 3.071, p < 0.001; OR = 2.761, p < 0.001, respectively) but also in those aged < 60 years (OR = 2.749, p = 0.035; OR = 2.634, p = 0.038; OR = 2.766, p = 0.006, respectively). Conclusions ELC was independently associated with the presence of CAD, multivessel disease, and severe CAD in both elderly and non-elderly patients who were assessed by coronary angiography.

Dysmegakaryopoiesis and Transient Mild Increase in Bone Marrow Blasts in Patients With Aplastic Anemia Treated With Eltrombopag May Be Signs of Hematologic Improvement and Not Portend Clonal Evolution.

OBJECTIVES: Eltrombopag, a thrombopoietin-receptor agonist, stimulates hematopoiesis in patients with acquired aplastic anemia (AA). Cytomorphologic changes in bone marrow after eltrombopag administration are still unclear. This study examined the effect of eltrombopag on cytomorphologic findings using data from prior phase 2 studies (E1201 and E1202). METHODS: Microscopic examinations were performed in 31 patients with AA (E1201 [n = 21], E1202 [n = 10]). The relationship between hematologic improvement and morphologic findings was also investigated. RESULTS: In 5 patients (E1201 [n = 3], E1202 [n = 2]), the bone marrow blast count increased after initiation of eltrombopag treatment compared with screening values. The blast count was less than 5%, and the increase in bone marrow blasts was transient in all 4 patients who had bone marrow examinations at follow-up. In 8 patients (E1201 [n = 5], E1202 [n = 3]), dysplastic forms of megakaryocytes were found in the bone marrow following treatment initiation. Dysmegakaryopoiesis of 10% or more was found in 3 patients. None of the patients revealed micromegakaryocytes. Ten patients showed an increase in bone marrow blasts and/or dysmegakaryopoiesis following treatment initiation. Nine of 10 patients showed hematologic improvement in 1 or more lineages. CONCLUSIONS: Dysmegakaryopoiesis without micromegakaryocytes and a transient increase of less than 5% in bone marrow blast count may be signs of hematologic improvement with eltrombopag for patients with AA.

Prediction of energy balance from milk traits of Holsteins in Japan.

We predicted the energy balance (EB) of Holstein cows in Japan from milk traits obtained by herd testing. Records covered 156 lactations of 102 cows. The number of artificial inseminations was highest, and the first conception rate was lowest in the low-EB group. Four prediction models were developed-for the whole lactation and for the early, middle, and late stages of lactation-with 20 variables, covering days in milk (DIM), milk yield, and milk composition traits. The actual and predicted EB means agreed well within DIM classes; the means of the residuals were smaller in the lactation stage models than in the all-lactation model, but the standard deviations (SDs) of the residuals were similar among models. After data reduction, the SDs of the residuals for 100 iterations were <1 throughout lactation in both types of models when n = 100. After model reduction, including the daily change of milk yield as a variable minimized the SDs of the residuals. Our equations for herd-level EB prediction have potential for use in genetic evaluation.

Simulation of the lifetime productivity of a dairy herd in Japan according to the number of days to first service of cows.

To determine the optimal voluntary waiting period to first service after calving for maximizing the lifetime productivity of cows in a dairy herd, we simulated the changes in lifetime productivity due to increasing the number of days from calving to first service. We also assessed the effects of changes in the maximum number of services within a lactation, maximum number of calvings, and calf sale prices on lifetime productivity. We evaluated lifetime productivity as lifetime average productivity, that is, the sum of daily revenues from milk and calf sales from first calving to culling. The lifetime productivity at ≤65 days to first service was low because of the low conception rate during early lactation. In addition, lifetime productivity at ≥185 days to first service decreased as the number of days to first service increased. The number of days to first service for maximum lifetime productivity decreased as the maximum number of calvings increased. Furthermore, the decrease in lifetime productivity associated with decreasing the maximum number of services within a lactation from five to four was greater than that when the maximum number of calvings was decreased from six to five.

Oral histone deacetylase inhibitor tucidinostat (HBI-8000) in patients with relapsed or refractory adult T-cell leukemia/lymphoma: Phase IIb results.

This multicenter, prospective phase IIb trial evaluating the efficacy and safety of tucidinostat (HBI-8000) in patients with relapsed or refractory (R/R) adult T-cell leukemia/lymphoma (ATLL) was undertaken in Japan. Eligible patients had R/R ATLL and had failed standard of care treatment with chemotherapy and with mogamulizumab. Twenty-three patients received tucidinostat 40 mg orally twice per week and were included in efficacy and safety analyses. The primary end-point was objective response rate (ORR) assessed by an independent committee. The ORR was 30.4% (95% confidence interval [CI], 13.2, 52.9]. Median progression-free survival was 1.7 months (95% CI, 0.8, 7.4), median duration of response was 9.2 months (95% CI, 2.6, not reached), and median overall survival was 7.9 months (95% CI, 2.3, 18.0). All patients experienced adverse events (AEs), which were predominantly hematologic and gastrointestinal. Incidence of grade 3 or higher AEs was 78.3%; most were laboratory abnormalities (decreases in platelets, neutrophils, white blood cells, and hemoglobin). Tucidinostat was well tolerated with AEs that could be mostly managed with supportive care and dose modifications. Tucidinostat is a meaningful treatment option for R/R ATLL patients; further investigation is warranted.

A Cardiac Arrest Case due to Left Coronary Artery Compression in Congenital Heart Disease-Associated Pulmonary Arterial Hypertension.

We report the case of an adult who had a cardiac arrest in the setting of pulmonary hypertension and a previously repaired intermediate atrioventricular septal defect, with left main coronary trunk stenosis due to dilatation of the main pulmonary artery. In patients with pulmonary hypertension exhibiting anginal symptoms, it is advisable to perform chest contrast computed tomography to confirm the pulmonary artery diameter and the presence of coronary artery compression. In addition, our case highlights the importance of early collaboration among specialists during the transition from adolescence to adulthood.

Nous décrivons le cas d'un adulte ayant subi un arrêt cardiaque alors qu'il présentait une hypertension pulmonaire et qu'il avait déjà subi la réparation d'une communication septale auriculoventriculaire intermédiaire, avec sténose de l'artère coronaire gauche principale causée par la dilatation de l'artère pulmonaire principale. Chez les patients atteints d'hypertension pulmonaire qui présentent des symptômes angineux, il est recommandé d'effectuer une tomodensitométrie thoracique avec produit de contraste pour confirmer le diamètre de l'artère pulmonaire et la présence d'une compression de l'artère coronaire. Notre cas souligne également l'importance d'établir sans tarder une collaboration entre spécialistes lors de la transition entre l'adolescence et l'âge adulte.

Decrease in volume and density of foraminiferal shells with progressing ocean acidification.

Rapid increases in anthropogenic atmospheric CO2 partial pressure have led to a decrease in the pH of seawater. Calcifying organisms generally respond negatively to ocean acidification. Foraminifera are one of the major carbonate producers in the ocean; however, whether calcification reduction by ocean acidification affects either foraminiferal shell volume or density, or both, has yet to be investigated. In this study, we cultured asexually reproducing specimens of Amphisorus kudakajimensis, a dinoflagellate endosymbiont-bearing large benthic foraminifera (LBF), under different pH conditions (pH 7.7-8.3, NBS scale). The results suggest that changes in seawater pH would affect not only the quantity (i.e., shell volume) but also the quality (i.e., shell density) of foraminiferal calcification. We proposed that pH and temperature affect these growth parameters differently because (1) they have differences in the contribution to the calcification process (e.g., Ca2+-ATPase and Ω) and (2) pH mainly affects calcification and temperature mainly affects photosynthesis. Our findings also suggest that, under the IPCC RCP8.5 scenario, both ocean acidification and warming will have a significant impact on reef foraminiferal carbonate production by the end of this century, even in the tropics.

Left ventricular inflow obstruction due to a coronary arteriovenous fistula: a paediatric case report.

BACKGROUND: We report a rare case of left ventricular inflow obstruction from a branch of the left circumflex coronary artery to the right atrium caused by a coronary arteriovenous fistula (CAVF) in a young Japanese male child. CASE PRESENTATION: The patient was diagnosed with CAVF following a heart murmur shortly after birth. The left-to-right shunt caused right ventricular volume overload and pulmonary congestion. An emergency surgical intervention was performed for the CAVF on day 6 after birth. However, by 5 years of age, his left ventricular inflow obstruction worsened. We found an abnormal blood vessel originating from the proximal part of a branch of the left circumflex coronary artery, circling the outside of the mitral valve annulus along the medial side of the coronary sinus. As the child gets older, the blood inflow into the left ventricle might get restricted further, resulting in left-sided heart failure. CONCLUSION: Our findings suggest that even after CAVF closure surgery, it is essential to monitor for complications caused by progressive dilatation of a persistent CAVF.

Atypical electrocardiographic findings in severe hyperkalemia with slow clinical course.

A 77-year-old woman walked into the emergency department with an episode of syncope and vomiting. She had visited at an orthopedic clinic with weakness of the lower extremities 6 weeks before, but cervical and lumbar MRI findings were unremarkable. Thereafter, she developed fingertip numbness and appetite loss at 7 and 3 days, respectively, before admission. She had been prescribed with RAS inhibitors for years. Electrocardiography while in the emergency department revealed bradycardia with normal QRS and a tented T wave. Laboratory findings revealed serum potassium 9.2 mEq/L. We discontinued RAS inhibitors and ß-blockers and added glucose-insulin therapy. Thereafter, her general condition gradually recovered, and her symptoms completely disappeared. Elderly patients with chronic kidney disease treated with RAS inhibitors might develop slowly progressive symptoms of hyperkalemia. Electrocardiographic findings could be atypical and inconsistent with serum potassium values.

Total Anomalous Pulmonary Venous Connection with Lethal Pulmonary Venous Obstruction Managed by Multidisciplinary Cooperation.

BACKGROUND: Total anomalous pulmonary venous connection (TAPVC) is a critical congenital heart disease for which emergency surgery is required after birth. In cases of no intervention, TAPVC is associated with a high mortality rate in the first year of life. Although foetal echocardiographic techniques for diagnosing TAPVC have improved, TAPVC remains one of the most difficult congenital heart diseases to diagnose via foetal echocardiography. Here, we report a case of TAPVC with pulmonary venous obstruction (PVO), which was diagnosed via foetal echocardiography. Case Presentation. On foetal echocardiography at 32 weeks' gestation, a large atrial septal defect, enlarged superior vena cava, and continuous flow pattern in the vertical vein from the common chamber were observed in the foetus. Paediatric cardiologists and cardiac surgeons, neonatologists, and obstetricians planned to perform a caesarean section and emergency heart surgery. The male infant was born at 37 weeks' gestation via caesarean section, and postnatal echocardiography revealed PVO at the confluence of the superior vena cava and common chamber. Similarly, chest computed tomography confirmed the foetal diagnosis. The postnatal diagnoses were TAPVC type Ib, PVO, atrial septal defect, and patent ductus arteriosus. Surgical repair of the TAPVC was initiated within the first 3 hours of life. Screening brain echocardiography and head computed tomography revealed intracranial haemorrhage and hydrocephalus. Therefore, the patient underwent emergency bilateral external drainage on day 13. On day 48, a ventriculoperitoneal shunt was inserted owing to progressive brain ventricular dilatation. The patient was discharged home on postoperative day 68. CONCLUSIONS: Although the prognosis of TAPVC with PVO remains poor, continuous observation through foetal echocardiography and early interdepartmental collaboration can result in good outcomes.