Machine learning-based risk model using 123I-metaiodobenzylguanidine to differentially predict modes of cardiac death in heart failure.

BACKGROUND: Cardiac sympathetic dysfunction is closely associated with cardiac mortality in patients with chronic heart failure (CHF). We analyzed the ability of machine learning incorporating 123I-metaiodobenzylguanidine (MIBG) to differentially predict risk of life-threatening arrhythmic events (ArE) and heart failure death (HFD). METHODS AND RESULTS: A model was created based on patients with documented 2-year outcomes of CHF (n = 526; age, 66 ± 14 years). Classifiers were trained using 13 variables including age, gender, NYHA functional class, left ventricular ejection fraction and planar 123I-MIBG heart-to-mediastinum ratio (HMR). ArE comprised arrhythmic death and appropriate therapy with an implantable cardioverter defibrillator. The probability of ArE and HFD at 2 years was separately calculated based on appropriate classifiers. The probability of HFD significantly increased as HMR decreased when any variables were combined. However, the probability of arrhythmic events was maximal when HMR was intermediate (1.5-2.0 for patients with NYHA class III). Actual rates of ArE were 3% (10/379) and 18% (27/147) in patients at low- (≤ 11%) and high- (> 11%) risk of developing ArE (P < .0001), respectively, whereas those of HFD were 2% (6/328) and 49% (98/198) in patients at low-(≤ 15%) and high-(> 15%) risk of HFD (P < .0001). CONCLUSION: A risk model based on machine learning using clinical variables and 123I-MIBG differentially predicted ArE and HFD as causes of cardiac death.

Mutational concordance analysis provides supportive information for double cancer diagnosis.

BACKGROUND: Mutation analysis using next-generation sequencing highlights the features of tumors with somatic alterations. However, the mutation profile of double cancer remains unclear. Here, we analyzed tumors derived from the same patient using whole exome sequencing (WES) to investigate the coherence of somatic mutations in double cancer. METHODS: First, the tumor mutational burden (TMB) was investigated using WES of 5521 tumor specimens from a Japanese pan-cancer cohort. The frequencies of mutation concordance were then compared in these cancers. Finally, we calculated the expected value of mutational concordance fitting a Poisson distribution to determine the relationship between double and metastatic cancers. RESULTS: In all, 44, 58, and 121 paired samples were diagnosed as double cancer, multifocal lesions (derived from identical tissues), and metastasis, respectively. Our analysis revealed that common somatic mutations were almost entirely absent in double cancer, whereas primary tumors and metastatic foci harbored several identical alterations. Concordance of the mutation profile in the same patient reflects the tumor origin and development, suggesting the potential for identifying double cancer based on common somatic mutations. Furthermore, according to a Poisson distribution, double cancer could be discriminated based on paired samples from the same patient. The probability of double cancer with more than 10 mutations was ≤1 part-per-billion (ppb, 10- 9). In multifocal lesions, 74% of tumor pairs accumulated ≤10 common mutations, implying a difference in tumor origin within identical tissues. CONCLUSIONS: These findings indicate that counting common somatic mutations can indicate the differences in origin between tumors derived from the same patient. Our mutation coherence analysis can thus provide beneficial information for diagnosing double cancer.

Preoperative Magnetic Resonance Imaging (MRI) for Predicting Thromboembolic Complications during Endovascular Treatment for Iliac Artery Occlusions.

BACKGROUND: Preoperative prediction of thromboembolic complications using magnetic resonance imaging (MRI) in coronary arteries and carotid arteries has been established. However, the technique has not been applied in peripheral arteries. This study aimed to assess the relationship between thromboembolic complications during endovascular treatment (EVT) for iliac artery occlusion and signal intensity on MRI. METHODS: This single-institution study included 52 iliac artery occlusions in 51 patients (mean age, 70.4 years) who underwent successful EVT between January 2010 and March 2018. MRI using an inversion recovery-prepared, steady-state free precession technique was performed preoperatively. Thromboembolic complications were defined as distal embolization and in-stent protrusion greater than 25% of the stent cross-sectional area confirmed by angiography and intravascular ultrasonography, regardless of symptoms. The highest signal intensity of iliac artery occlusion divided by the signal intensity of adjacent iliopsoas muscle (target-to-muscle ratio, TMR) was measured on MR images. Multivariate analysis was performed to clarify the predictors of thromboembolic complications during EVT. RESULTS: Thromboembolic complications observed in 11 vessels (21.2%) from 11 patients comprised distal embolization (n = 4) and in-stent protrusion (n = 7). A TMR cutoff value > 2.57 had a sensitivity of 90.9%, specificity of 78.0%, positive predictive value of 52.6%, and negative predictive value of 97.0% for detecting thromboembolic complications during EVT. In the multivariate analysis, TMR >2.57 was the only independent factor associated with thromboembolic complications (odds ratio, 30.10; 95% confidence interval, 3.26-278.00; P = 0.003). CONCLUSIONS: The presence of higher signal intensity in iliac artery occlusion on MRI is useful for predicting thromboembolic complications during EVT.

Characterization of tumors with ultralow tumor mutational burden in Japanese cancer patients.

Tumor mutational burden analysis using whole-exome sequencing highlights features of tumors with various mutations or known driver alterations. Cancers with few changes in the exon regions have unclear characteristics, even though low-mutated tumors are often detected in pan-cancer analysis. In the present study, we analyzed tumors with low tumor mutational burden listed in the Japanese version of The Cancer Genome Atlas, a data set of 5020 primary solid tumors. Our analysis revealed that detection rates of known driver mutations and copy number variation were decreased in samples with tumor mutational burden below 1.0 (ultralow tumor), compared with those in samples with low tumor mutational burden (≤5 mutations/Mb). This trend was also observed in The Cancer Genome Atlas data set. In the ultralow tumor mutational burden tumors, expression analysis showed decreased TP53 inactivation and chromosomal instability. TP53 inactivation frequently correlated with PI3K/mTOR-related gene expression, implying suppression of the PI3K/mTOR pathway in ultralow tumor mutational burden tumors. In common with mutational burden, the T cell-inflamed gene expression profiling signature was a potential marker for prediction of an immune checkpoint inhibitor response, and some ultralow tumor mutational burden tumor populations highly expressed this signature. Our analysis focused on how these tumors could provide insight into tumors with low somatic alteration that are difficult to detect solely using whole-exome sequencing.

Japanese version of The Cancer Genome Atlas, JCGA, established using fresh frozen tumors obtained from 5143 cancer patients.

This study aimed to establish the Japanese Cancer Genome Atlas (JCGA) using data from fresh frozen tumor tissues obtained from 5143 Japanese cancer patients, including those with colorectal cancer (31.6%), lung cancer (16.5%), gastric cancer (10.8%) and other cancers (41.1%). The results are part of a single-center study called "High-tech Omics-based Patient Evaluation" or "Project HOPE" conducted at the Shizuoka Cancer Center, Japan. All DNA samples and most RNA samples were analyzed using whole-exome sequencing, cancer gene panel sequencing, fusion gene panel sequencing and microarray gene expression profiling, and the results were annotated using an analysis pipeline termed "Shizuoka Multi-omics Analysis Protocol" developed in-house. Somatic driver alterations were identified in 72.2% of samples in 362 genes (average, 2.3 driver events per sample). Actionable information on drugs that is applicable in the current clinical setting was associated with 11.3% of samples. When including those drugs that are used for investigative purposes, actionable information was assigned to 55.0% of samples. Germline analysis revealed pathogenic mutations in hereditary cancer genes in 9.2% of samples, among which 12.2% were confirmed as pathogenic mutations by confirmatory test. Pathogenic mutations associated with non-cancerous hereditary diseases were detected in 0.4% of samples. Tumor mutation burden (TMB) analysis revealed 5.4% of samples as having the hypermutator phenotype (TMB ≥ 20). Clonal hematopoiesis was observed in 8.4% of samples. Thus, the JCGA dataset and the analytical procedures constitute a fundamental resource for genomic medicine for Japanese cancer patients.

Improved Visualization and Identification of the Right Adrenal Vein in 70-kVp Contrast-Enhanced Computed Tomography.

OBJECTIVE: The aim of this study was to assess the utility of 70-kilovoltage-peak (kVp) contrast-enhanced computed tomography (CECT) for visualization and identification of the right adrenal vein (RAV) in comparison with that of conventional 120-kVp CECT. METHODS: This retrospective study included patients who underwent adrenal venous sampling with concurrent biphasic 120-kVp (120-kVp group, n = 43) or 70-kVp (70-kVp group, n = 47) CECT. Signal-to-noise ratios, contrast-to-noise ratios, longitudinal lengths, conspicuity scores, RAV detection rates, and size-specific dose estimates were compared between the 2 groups. RESULTS: In comparison with the 120-kVp group, the 70-kVp group had significantly higher signal-to-noise and contrast-to-noise ratios (P < 0.001-P = 0.033), greater longitudinal lengths (P < 0.001-P = 0.002), superior conspicuity scores for the RAV (P < 0.001), higher RAV detection rates (P = 0.015-P = 0.033), and lower size-specific dose estimates (P < 0.001). CONCLUSIONS: Seventy-kilovoltage-peak CECT has advantages over conventional 120-kVp CECT and is potentially useful for noninvasive assessment of the precise anatomy of the RAV.

Plastic/Ferroelectric Crystals with Easily Switchable Polarization: Low-Voltage Operation, Unprecedentedly High Pyroelectric Performance, and Large Piezoelectric Effect in Polycrystalline Forms.

Molecular ferroelectric crystals have attracted growing interest as potential alternatives to conventional lead-based ceramic ferroelectrics. We have recently discovered that a class of compounds known as plastic crystals can show multiaxial ferroelectricity, which allows ferroelectric performance even in polycrystalline forms. Here, we report new plastic/ferroelectric ionic molecular crystals that exhibit remarkably small coercive electric fields at room temperature. The easily switchable ferroelectric polarization enables low-voltage switching operations and high-frequency performance. Such ferroelectric crystals can be readily processed into bulk polycrystalline forms with desired shapes that are characterized by unprecedentedly high pyroelectric figures of merit and large piezoelectricity. These multifunctional molecular crystals represent highly attractive prospects for device elements with a diverse range of applications, which will significantly boost the development of molecular ferroelectric crystals.

Mutational burden and signatures in 4000 Japanese cancers provide insights into tumorigenesis and response to therapy.

Tumor mutational burden (TMB) and mutational signatures reflect the process of mutation accumulation in cancer. However, the significance of these emerging characteristics remains unclear. In the present study, we used whole-exome sequencing to analyze the TMB and mutational signature in solid tumors of 4046 Japanese patients. Eight predominant signatures-microsatellite instability, smoking, POLE, APOBEC, UV, mismatch repair, double-strand break repair, and Signature 16-were observed in tumors with TMB higher than 1.0 mutation/Mb, whereas POLE and UV signatures only showed moderate correlation with TMB, suggesting the extensive accumulation of mutations due to defective POLE and UV exposure. The contribution ratio of Signature 16, which is associated with hepatocellular carcinoma in drinkers, was increased in hypopharynx cancer. Tumors with predominant microsatellite instability signature were potential candidates for treatment with immune checkpoint inhibitors such as pembrolizumab and were found in 2.8% of cases. Furthermore, based on microarray analysis, tumors with predominant signatures were classified into 2 subgroups depending on the expression of immune-related genes reflecting differences in the immune context of the tumor microenvironment. Tumor subpopulations differing in the content of infiltrating immune cells might respond differently to immunotherapeutics. An understanding of cancer characteristics based on TMB and mutational signatures could provide new insights into mutation-driven tumorigenesis.

Tumor cell enrichment by tissue suspension improves sensitivity to copy number variation in diffuse gastric cancer with low tumor content.

The detection of copy number variations (CNVs) and somatic mutations in cancer is important for the selection of specific drugs for patients with cancer. In cancers with sporadic tumor cells, low tumor content prevents the accurate detection of somatic alterations using targeted sequencing. To efficiently identify CNVs, we performed tumor cell enrichment using tissue suspensions of formalin-fixed paraffin-embedded (FFPE) tissue sections with low tumor cell content. Tumor-enriched and residual fractions were separated from FFPE tissue suspensions of intestinal and diffuse-type gastric cancers containing sporadic tumor cells, and targeted sequencing was performed on 225 cancer-related genes. Sequencing of a targeted panel of cancer-related genes using tumor-enriched fractions increased the number of detectable CNVs and the copy number of amplified genes. Furthermore, CNV analysis using the normal cell-enriched residual fraction as a reference for CNV scoring allowed targeted sequencing to detect CNV characteristics of diffuse-type gastric cancer with low tumor content. Our approach improves the CNV detection rate in targeted sequencing with tumor enrichment and the accuracy of CNV detection in archival samples without paired blood.

Improved diagnosis of histological capsule in hepatocallular carcinoma by using nonenhancing capsule appearance in addition to enhancing capsule appearance in gadoxetic acid-enhanced MRI.

To assess the value of nonenhancing capsule by adding to enhancing capsule in gadoxetic acid-enhanced MRI (EOB-MRI) in comparison with contrast-enhanced CT (CE-CT) for diagnosing histological capsule in hepatocellular carcinoma (HCC). One-hundred fifty-one patients with HCC who underwent both CE-CT and EOB-MRI were retrospectively reviewed. Liver Imaging-Reporting and Data System (LI-RADS) v2018 imaging features, including enhancing and nonenhancing capsule were evaluated by two readers in CE-CT and EOB-MRI. Frequencies of each imaging feature were compared between CE-CT and EOB-MRI. The area under the receiver operating characteristic (AUC) curve for the diagnosis of histological capsule was compared across the following three imaging criteria: (1) enhancing capsule in CE-CT, (2) enhancing capsule in EOB-MRI, and (3) enhancing/nonenhancing capsule in EOB-MRI. Enhancing capsule in EOB-MRI was significantly less frequently depicted than that in CE-CT (p < 0.001 and = 0.016 for reader 1 and 2). Enhancing/nonenhancing capsule in EOB-MRI achieved a similar frequency of enhancing in CE-CT (p = 0.590 and 0.465 for reader 1 and 2). Adding nonenhancing capsule to enhancing capsule in EOB-MRI significantly increased AUCs (p < 0.001 for both readers) and achieved similar AUCs compared with enhancing capsule in CE-CT (p = 0.470 and 0.666 for reader 1 and 2). Adding nonenhancing capsule to the definition of capsule appearance can improve the diagnosis of capsule in EOB-MRI for the diagnosis of histological capsule in HCC and decrease discordance of capsule appearance between EOB-MRI and CE-CT.

False-positive 123I-metaiodobenzylguanidine scintigraphy in a patient with a gastrointestinal stromal tumor presenting as a left adrenal incidentaloma.

Summary: A 47-year-old man was diagnosed with a left adrenal incidentaloma at 40 years of age. The tumor had irregular margins and grew from 18 mm to 30 mm in maximum diameter over 7 years. On computed tomography scan, the mass appeared to localize within the tip of the lateral limb of the left adrenal gland, and between the left adrenal gland and the posterior wall of the stomach. The plasma corticotropin and cortisol concentrations and the 24-h urine fractionated metanephrine levels were normal. 123I-metaiodobenzylguanidine scintigraphy showed tumor avidity consistent with a hormonally inactive pheochromocytoma. A laparoscopic left adrenalectomy was performed; however, no tumor was present in the resected specimen. Abdominal computed tomography postoperatively showed that the tumor remained intact and appeared to connect to the posterior wall of the stomach. A laparotomy was performed and the tumor was removed. The tumor was localized to the intraperitoneal space and isolated from the posterior wall of the stomach. The pathological diagnosis was a gastrointestinal stromal tumor. Clinicians need to be aware of the limitations of diagnostic imaging studies in diagnosing non-functioning adrenal incidentalomas, which require a pathological analysis for the final diagnosis. Moreover, clinicians need to provide patients with sufficient informed consent when deciding on treatment strategies. Learning points: Anatomic structures and tumors that develop in neighboring tissues to the adrenal glands may be confused with primary adrenal tumors. 123I- metaiodobenzylguanidine (MIBG) scintigraphy is specific for diagnosing pheochromocytomas and paragangliomas; however, it has been reported that 123I-MIBG may accumulate in neuroendocrine tumors as well as other tumors. Clinicians should recognize the limitations of imaging studies and the uncertainty of an imaging-based preoperative diagnosis.

Comparative analysis of tumor content estimation methods based on simu- lated tumor samples identified their impact on somatic variant detection in cancer whole genome sequencing.

Whole genome sequencing (WGS) in cancer genomics has become widespread with recent technological innovations, and the amount and types of information obtained from WGS are increasing rapidly. Appropriate interpretation of results is becoming increasingly important in clinical applications. This study aimed to evaluate the accuracy of tumor content estimation and its impact on somatic variant detection, using 100 simulated tumor samples covering 10-100% tumor content constructed from the sequencing data of cell line models. Extensive analysis revealed that the estimation results varied among computational analytical methods. Notably, there was a large discrepancy in low tumor content (≤ 30%). The reproducibility decreased in cases wherein chromosome-scale copy number changes were observed in normal cells. The minimum tumor content required to detect somatic alterations was estimated to be 10-30%. Identification of whole genome doubling was achieved with the lowest tumor content, followed by single nucleotide variation/insertion or deletion, structural variation, and copy number variation. Tumor content had a significantly higher impact on the false negatives than the false positives in variant calls. Results should be interpreted cautiously for samples wherein tumor content is a concern. These results can form the basis of developing important guidelines for evaluating cancer WGS.

Impact of somatic mutations and transcriptomic alterations on cancer aneuploidy.

Aneuploidy has been recognized as one of hallmark of tumorigenesis since the early 20th century. Recent developments in structural variation analysis in the human genome have revealed the diversity of aneuploidy in cancer. However, the effects of gene mutation and expression in tumors on aneuploidy remain poorly understood. Here, we performed whole exome analysis of over 5,000 Japanese cancer cases and investigated the impact of somatic mutations and gene expression alterations on aneuploidy. First, we evaluated tumor content and genomic alterations that could influence aneuploidy. Next, we compared the aneuploidy frequency in 18 cancer types and observed that TP53 mutations were associated with the aneuploidy on specific chromosomes in colorectal and gastric cancers. Finally, we used expression analysis to isolate pathways involved in aneuploidy accumulation from tumors without TP53 mutations. Chromosomal instability and cell cycle aberration were associated with aneuploidy in TP53 wild-type tumors, and 26 commonly upregulated genes were identified in aneuploidy-high solid tumors without TP53 mutations. Among them, two cancer-related genes (CENPA and PBK) were involved in aneuploidy. Our integrated analysis revealed that both TP53 mutations and transcriptomic alterations independent of somatic mutations affect aneuploidy accumulation. Our findings will facilitate further understanding of diverse aneuploidies in the tumorigenesis.

Quality of life after total pancreatectomy with islet autotransplantation for chronic pancreatitis in Japan.

BACKGROUND: Patients with chronic pancreatitis (CP) often have severe and intractable abdominal pain, leading to decreased quality of life (QOL), inability to work or attend school, and increased health care costs due to repeated emergency room visits and hospitalizations. METHODS: We evaluated the efficacy of total pancreatectomy and islet autotransplantation (TPIAT) in terms of pain control and QOL in CP patients treated at our center in Japan. To evaluate QOL, we used the Short-Form 36 Health Survey version 2 (SF-36v2® Standard, Japanese), European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30), and Quality of Life Questionnaire-Pancreatic Modification (QLQ-PAN28). RESULTS: Between August 2016 and June 2019, we performed this procedure in 5 patients. All patients were followed up for 12 months and all transplanted islets were still functioning at the 1-year follow-up. The major adverse events were abdominal wall hemorrhage, intestinal obstruction, intra-abdominal abscess, and abdominal pain requiring hospitalization; no case had sequelae. No major complications were due to islet transplantation. Pain scores improved postoperatively in all patients. Three QOL item dimensions role-physical (p = 0.03125), general health perception (p = 0.03125) and vitality (p = 0.03125) in the SF-36 were significantly improved 12 months after TPIAT. Mean values of many other QOL items improved, though not significantly. CONCLUSION: The QOL improvement after TPIAT for CP suggests its effectiveness in the Japanese population.

Nuclear Cardiology Data Analyzed Using Machine Learning.

Machine learning has become popular in clinical practice, and the amount of research that uses artificial intelligence is rapidly increasing. In contrast to conventional statistical and rule-based methods, machine learning creates algorithms based only on combinations of input and output databases. Basic understanding of the internal workings of artificial intelligence, its structures and need for appropriate databases, as well as its strengths and weaknesses is important for efficient machine learning application. The cardiological applications of machine learning include diagnosing coronary artery diseases and heart failure, and examples are addressed herein. A preliminary application of machine learning to a 123I-metaiodobenzylguanidine-based risk model appears promising, and further studies using similar approaches are anticipated. Nuclear medicine physicians and cardiologists should play key roles in developing machine learning-based methods to ensure practical and reliable decisions.

Diagnosis of Parkinson syndrome and Lewy-body disease using 123I-ioflupane images and a model with image features based on machine learning.

OBJECTIVES: 123I-ioflupane has been clinically applied to dopamine transporter imaging and visual interpretation assisted by region-of-interest (ROI)-based parameters. We aimed to build a multivariable model incorporating machine learning (ML) that could accurately differentiate abnormal profiles on 123I-ioflupane images and diagnose Parkinson syndrome or disease and dementia with Lewy bodies (PS/PD/DLB). METHODS: We assessed 123I-ioflupane images from 239 patients with suspected neurodegenerative diseases or dementia and classified them as having PS/PD/DLB or non-PS/PD/DLB. The image features of high or low uptake (F1), symmetry or asymmetry (F2), and comma- or dot-like patterns of caudate and putamen uptake (F3) were analyzed on 137 images from one hospital for training. Direct judgement of normal or abnormal profiles (F4) was also examined. Machine learning methods included logistic regression (LR), k-nearest neighbors (kNNs), and gradient boosted trees (GBTs) that were assessed using fourfold cross-validation. We generated the following multivariable models for the test database (n = 102 from another hospital): Model 1, ROI-based measurements of specific binding ratios and asymmetry indices; Model 2, ML-based judgement of abnormalities (F4); and Model 3, features F1, F2 and F3, plus patient age. Diagnostic accuracy was compared using areas under receiver-operating characteristics curves (AUC). RESULTS: The AUC was high with all ML methods (0.92-0.96) for high or low uptake. The AUC was the highest for symmetry or asymmetry with the kNN method (AUC 0.75) and the comma-dot feature with the GBT method (AUC 0.94). Based on the test data set, the diagnostic accuracy for a diagnosis of PS/PD/DLB was 0.86 ± 0.04 (SE), 0.87 ± 0.04, and 0.93 ± 0.02 for Models 1, 2 and 3, respectively. The AUC was optimal for Model 3, and significantly differed between Models 3 and 1 (p = 0.027), and 3 and 2 (p = 0.029). CONCLUSIONS: Image features such as high or low uptake, symmetry or asymmetry, and comma- or dot-like profiles can be determined using ML. The diagnostic accuracy of differentiating PS/PD/DLB was the highest for the multivariate model with three features and age compared with the conventional ROI-based method.

Perilla frutescens seed oil combined with Anredera cordifolia leaf powder attenuates age-related cognitive decline by reducing serum triglyceride and glucose levels in healthy elderly Japanese individuals: a possible supplement for brain health.

We have shown that Anredera cordifolia extract improves learning and memory in a senescence-accelerated mouse model, and that α-linolenic acid (ALA)-rich Perilla frutescens seed oil (PO) improves brain function in healthy Japanese adults and elderly individuals. Herein, we present a 12-month, randomised, double-blind, parallel-armed intervention trial examining the effects of PO supplementation alone or in combination with A. cordifolia leaf powder on brain function in healthy elderly Japanese individuals. Participants were randomly divided into two groups: the PO group received 1.47 mL PO (0.88 g ALA) daily via soft gelatine capsules, and the POAC group received 1.47 mL PO and 1.12 g A. cordifolia leaf powder (1.46 mg vitexin and 1.12 mg adenosine) daily. After 12 months of intervention, the POAC group showed generally higher cognitive index scores than the PO group. The beneficial effects of combined supplementation on cognitive function were associated with increased ALA and eicosapentaenoic acid levels in red blood cell plasma membranes, increased serum biological antioxidant potential, and decreased serum triglyceride, glucose, and N-(epsilon)-carboxymethyl-lysine (CML), an advanced glycation end-product and biochemical marker of oxidative stress levels. The effects of combined supplementation on cognitive function also showed a significant negative correlation with serum CML levels after 12 months of intervention. Our findings suggest that combined long-term supplementation with PO and A. cordifolia more effectively ameliorates age-related cognitive decline than PO alone. These findings may serve as a basis for the development of new supplements for brain health. Clinical Trial Registry, UMIN000040863.

Perilla seed oil in combination with nobiletin-rich ponkan powder enhances cognitive function in healthy elderly Japanese individuals: a possible supplement for brain health in the elderly.

Perilla (Perilla frutescens) seed oil (PO), rich in α-linolenic acid (ALA), can improve cognitive function in healthy elderly Japanese people. Here, supplements containing either PO alone or PO with nobiletin-rich air-dried immature ponkan powder were examined for their effects on cognitive function in 49 healthy elderly Japanese individuals. Patients were enrolled in a 12-month randomized, double-blind, parallel-armed study. Randomized participants in the PO group received soft gelatin capsules containing 1.47 mL (0.88 g of ALA) of PO daily, and those in the PO + ponkan powder (POPP) group received soft gelatin capsules containing both 1.47 mL of PO and 1.12 g ponkan powder (2.91 mg of nobiletin) daily. At the end of intervention, the POPP group showed significantly higher cognitive index scores than the PO group. The pro-cognitive effects of POPP treatment were accompanied by increases in ALA and docosahexaenoic acid levels in red blood cell plasma membranes, serum brain-derived neurotropic factor (BDNF) levels, and biological antioxidant potential. We demonstrate that 12-month intervention with POPP enhances serum BDNF and antioxidant potential, and may improve age-related cognitive impairment in healthy elderly people by increasing red blood cell ω-3 fatty acid levels. Clinical Trial Registry, UMIN000040863.

Do heel-unloading orthoses improve clinical outcomes in patients after surgical treatment of calcaneal fracture? A propensity-matched, multicenter analysis of the TRON database.

BACKGROUND: Postoperative protocols after surgical treatment of calcaneal fracture have not been standardized to date. There are only a few reports on the efficacy of heel-unloading orthoses (HUOs; Mars shoe, Graffin orthosis), and thier efficacy is uncertain. OBJECTIVES: The purpose of this study was to compare postoperative radiologic and clinical outcomes in patients with calcaneal fractures who used Graffin orthosis. STUDY DESIGN: Multicenter retrospective study. METHODS: We finally extracted 182 patients from a database of the Trauma Research Group of Nagoya and divided them into two groups: group C (underwent casting or splinting only) and group O (Graffin orthosis was used). A propensity score algorithm was used to match group C to group O in a 1:1 ratio. We evaluated American Orthopaedic Foot and Ankle Society (AOFAS) score at three and six months after surgery and at final follow-up. Differences in reduction of the Böhler angle between the two groups were evaluated radiographically. All data were analyzed with a t-test or Fisher's exact test. P < .05 was considered statistically significant. RESULTS: The AOFAS score 3 months after surgery in group O was significantly higher than that in group C (69.57 vs. 77.22; P = .004). However, there were no statistically significant differences between group C vs. group O in AOFAS scores at 6 months after surgery and at final follow-up (81.92 vs. 85.67 and 89.18 vs. 88.13; P = .087 and 0.597, respectively). There was no significant statistical difference in the reduction of the Böhler angle (5.07 vs. 5.89; P = .529). CONCLUSIONS: At 3 months postoperatively, the orthosis group showed predominantly better functional results. We believe that heel-unloading orthoses are useful for patients who require an early return to work and to daily life.