Prognostic impact of MRI-derived feature tracking myocardial strain in patients with non-ischaemic dilated cardiomyopathy: a systematic review and meta-analysis.

AIM: To evaluate the clinical utility of feature tracking (FT)-derived myocardial strain in patients with non-ischaemic dilated cardiomyopathy (NIDCM). MATERIALS AND METHODS: Electronic database searches of PubMed, Web of Science Core Collection, Cochrane advanced search, and EMBASE were performed. Studies on NIDCM were divided into categories according to left ventricular ejection fraction (LVEF; <30%, 30-40%, >40%), and correlations between strains and prevalence of late gadolinium enhancement (LGE) were evaluated by weighted correlation coefficients. Global longitudinal strain (GLS) hazard ratios were also integrated for prediction of future adverse events. RESULTS: The present meta-analysis analysed data from 5,767 patients with NIDCM from 30 eligible studies. GLS and global circumferential strain significantly differed across the three LVEF categories (all p<0.05); however, global radial strain did not. Only GLS showed a strong correlation with the prevalence of LGE (Spearman's correlation coefficient = 0.61). The pooled HR of GLS for predicting adverse events was 1.15 (95% confidence interval [CI]: 1.07-1.23, p<0.001). CONCLUSION: In this meta-analysis, FT-derived GLS was strongly correlated with myocardial fibrosis and was an important predictor of future adverse events. These results suggest that FT-derived GLS may be useful in the pathological evaluation and risk stratification of NIDCM.

Faster acquisition of magnetic resonance imaging sequences of the knee via deep learning reconstruction: a volunteer study.

AIM: To evaluate whether deep learning reconstruction (DLR) can accelerate the acquisition of magnetic resonance imaging (MRI) sequences of the knee for clinical use. MATERIALS AND METHODS: Using a 1.5-T MRI scanner, sagittal fat-suppressed T2-weighted imaging (fs-T2WI), coronal proton density-weighted imaging (PDWI), and coronal T1-weighted imaging (T1WI) were performed. DLR was applied to images with a number of signal averages (NSA) of 1 to obtain 1DLR images. Then 1NSA, 1DLR, and 4NSA images were compared subjectively, and by noise (standard deviation of intra-articular water or medial meniscus) and contrast-to-noise ratio between two anatomical structures or between an anatomical structure and intra-articular water. RESULTS: Twenty-seven healthy volunteers (age: 40.6 ± 11.9 years) were enrolled. Three 1DLR image sequences were obtained within 200 s (approximately 12 minutes for 4NSA image). According to objective evaluations, PDWI 1DLR images showed the smallest noise and significantly higher contrast than 1NSA and 4NSA images. For fs-T2WI, smaller noise and higher contrast were observed in the order of 4NSA, 1DLR, and 1NSA images. According to the subjective analysis, structure visibility, image noise, and overall image quality were significantly better for PDWI 1DLR than 1NSA images; moreover, the visibility of the meniscus and bone, image noise, and overall image quality were significantly better for 1DLR than 4NSA images. Fs-T2WI and T1WI 1DLR images showed no difference between 1DLR and 4NSA images. CONCLUSION: Compared to PDWI 4NSA images, PDWI 1DLR images were of higher quality, while the quality of fs-T2WI and T1WI 1DLR images was similar to that of 4NSA images.

Cancer: slaying the nine-headed Hydra.

Modern medicine continues to evolve, and the treatment armamentarium for various diseases grows more individualized across a breadth of medical disciplines. Cure rates for infectious diseases that were previously pan-fatal approach 100% because of the identification of the specific pathogen(s) involved and the use of appropriate combinations of drugs, where needed, to completely extinguish infection and hence prevent emergence of resistant strains. Similarly, with the assistance of technologies such as next-generation sequencing and immunomic analysis as part of the contemporary oncology armory, therapies can be tailored to each tumor. Importantly, molecular interrogation has revealed that metastatic cancers are distinct from each other and complex. Therefore, it is conceivable that rational personalized drug combinations will be needed to eradicate cancers, and eradication will be necessary to mitigate clonal evolution and resistance.

Denosumab-related osteonecrosis of the jaw after tooth extraction and the effects of a short drug holiday in cancer patients: a multicenter retrospective study.

Pre-existing inflammation, corticosteroid therapy, periapical periodontitis, longer duration of denosumab therapy, and female sex were significantly associated with an increased risk of denosumab-related osteonecrosis of the jaw after tooth extraction in patients with cancer on oncologic doses of denosumab. A short drug holiday did not protect against this complication. INTRODUCTION: This study retrospectively investigated the relationship between various risk factors, including brief discontinuation of denosumab, and development of denosumab-related osteonecrosis of the jaw (DRONJ) after tooth extraction in patients with cancer who were receiving oncologic doses of this agent. METHODS: Data were collected on demographic characteristics, duration of denosumab therapy, whether or not denosumab was discontinued before tooth extraction (drug holiday), duration of discontinuation, presence of pre-existing inflammation, and whether or not additional surgical procedures were performed. Risk factors for DRONJ after tooth extraction were evaluated by univariate and multivariate analyses. RESULTS: A total of 136 dental extractions were performed in 72 patients (31 men, 41 women) with cancer who were receiving oncologic doses of denosumab. Post-extraction DRONJ was diagnosed in 39 teeth (28.7%) in 25 patients. Tooth extraction was significantly associated with development of DRONJ only in patients with pre-existing inflammation (odds ratio [OR] 243.77), those on corticosteroid therapy (OR 73.50), those with periapical periodontitis (OR 14.13), those who had been taking oncologic doses of denosumab for a longer period (OR 4.69), and in women (OR 1.04). There was no significant difference in the occurrence of DRONJ between patients who had a drug holiday before tooth extraction and those who did not. CONCLUSIONS: These findings suggest that inflamed teeth should be extracted immediately in patients with cancer who are receiving oncologic doses of denosumab. Drug holidays have no significant impact on the risk of DRONJ.

Gamma-Ray Observation of the Cygnus Region in the 100-TeV Energy Region.

We report observations of gamma-ray emissions with energies in the 100-TeV energy region from the Cygnus region in our Galaxy. Two sources are significantly detected in the directions of the Cygnus OB1 and OB2 associations. Based on their positional coincidences, we associate one with a pulsar PSR J2032+4127 and the other mainly with a pulsar wind nebula PWN G75.2+0.1, with the pulsar moving away from its original birthplace situated around the centroid of the observed gamma-ray emission. This work would stimulate further studies of particle acceleration mechanisms at these gamma-ray sources.

First Detection of sub-PeV Diffuse Gamma Rays from the Galactic Disk: Evidence for Ubiquitous Galactic Cosmic Rays beyond PeV Energies.

We report, for the first time, the long-awaited detection of diffuse gamma rays with energies between 100 TeV and 1 PeV in the Galactic disk. Particularly, all gamma rays above 398 TeV are observed apart from known TeV gamma-ray sources and compatible with expectations from the hadronic emission scenario in which gamma rays originate from the decay of π^{0}'s produced through the interaction of protons with the interstellar medium in the Galaxy. This is strong evidence that cosmic rays are accelerated beyond PeV energies in our Galaxy and spread over the Galactic disk.

Bone strength of the proximal femur in healthy subjects with ossification of the posterior longitudinal ligament.

We compared the bone strength measured via quantitative computed tomography-based finite element method (QCT/FEM) between healthy adults with and without ossification of the posterior longitudinal ligament (OPLL). No statistically significant difference was observed in the bone strength between healthy adults with and without OPLL. Hyperostosis of the posterior longitudinal ligament in OPLL may not be associated with the systemic bone strength. INTRODUCTION: Although patients with OPLL have been reportedly associated with increased level of bone mineral density (BMD) using dual-energy X-ray absorptiometry (DXA), little is known about the bone strength in OPLL subjects. The aim of this study is to investigate the bone strength measured via QCT/FEM in healthy subjects with OPLL using the medical check-up data, including whole-body CT scans. METHODS: We examined 796 participants (529 men and 267 women) who underwent CT scans in a single health center between January 2008 and May 2009. We identified OPLL in whole spine and divided the subjects into two groups: non-OPLL and OPLL groups. We calculated the predicted bone strength (PBS) of the proximal femur using QCT/FEM and examined the bone mineral status of the calcaneus using quantitative ultrasound (QUS). We compared the PBS and the QUS parameters between the non-OPLL and OPLL groups. RESULTS: Seventy-four subjects (9.3%; 57 men and 17 women) were diagnosed with OPLL in the whole spine. The OPLL group was significantly older than the non-OPLL group. No statistically significant difference was observed in the PBS and the QUS parameters between the non-OPLL and OPLL groups in both sexes. Furthermore, no statistically significant difference was noted in the PBS and the QUS parameters between two groups in age- and gender-matched analysis. CONCLUSIONS: Our results suggest that hyperostosis of the posterior longitudinal ligament in OPLL may not be associated with bone strength and bone mineral status at the extremities.

Ultra-low-loss nanofiber Fabry-Perot cavities optimized for cavity quantum electrodynamics.

We demonstrate the fabrication of ultra-low-loss, all-fiber Fabry-Perot cavities that contain a nanofiber section, optimized for cavity quantum electrodynamics. By continuously monitoring the finesse and fiber radius during the fabrication of a nanofiber between two fiber Bragg gratings, we were able to precisely evaluate taper transmission as a function of radius. The resulting cavities have an internal round-trip loss of only 0.31% at a nanofiber waist radius of 207 nm, with a total finesse of 1380, and a maximum expected internal cooperativity of ∼1050 for a cesium atom on the nanofiber surface. Our ability to fabricate such high-finesse nanofiber cavities may open the door for the realization of high-fidelity scalable quantum networks.

Which is more important in the management of splenic flexure colon cancer: strict central lymph node dissection or adequate bowel resection margin?

BACKGROUND: What qualifies as optimal lymph node (LN) dissection in the surgical management of splenic flexure colon cancer (SFCC) still remains controversial because few studies have evaluated the distribution of LN metastasis of SFCC. The aim of this study was to clarify detailed distribution of LN metastasis and long-term outcomes of SFCC. METHODS: This retrospective study enrolled patients who had curative colectomy for primary transverse or descending colon cancer of pathological stage I, II, or III at a single high-volume cancer center between April 2002 and December 2018. The 538 eligible patients were divided into three groups: patients with SFCC (SFCC group, n = 168), patients with proximal transverse colon cancer (PTCC group, n = 290), and patients with distal descending colon cancer (DDCC group, n = 80). LNs were classified into horizontal (pericolic) and vertical (intermediate and main) nodes. Intermediate and main LN station numbers were defined according to the Japanese Society for Cancer of the Colon and Rectum classification. Distributions of LN metastasis and long-term outcomes were compared. RESULTS: In the SFCC group, the mean age was 67.3 ± 10.5 years and 110 patients (65.5%) were male. The proportion of patients with LN metastasis in the intermediate or main region was significantly lower in the SFCC group (8%) than in the PTCC (37%) (p < 0.01) or DDCC group (29%) (p < 0.01) in pathological stage III patients. In the SFCC group, the incidence of pericolic LN metastasis on the oral side of tumor (43%) was significantly higher than in the PTCC group (21%) (p < 0.01) and was similar to that in the DDCC group (42%) (p = 0.51), while in the SFCC group, the incidence of pericolic LN metastasis on the anal side of tumor (17%) was lower than in the PTCC group (31%) and was also similar to that in the DDCC group (21%). There were no significant differences in disease-specific survival rates among all groups. CONCLUSIONS: LN metastasis occurred mainly in the pericolic region, especially on the oral side of the tumor in SFCC. It may, therefore, be important to have an adequate bowel resection margin, especially on the oral side, for SFCC.

Novel patterns of response under immunotherapy.

Novel patterns of response and progression to immunotherapy have been reported that are not observed with conventional cytotoxic or targeted anticancer treatments. A major breakthrough with immunotherapy is its potential to achieve durable responses in a subset of patients with advanced cancer that can be maintained several years even after stopping the treatment. No standardized definition of durable response exists in the literature, and the optimal duration of treatment in case of durable response is not clearly established. However, the majority of patients do not respond to immunotherapy. Initially reported in advanced melanoma patients, pseudoprogression occurs when tumor index lesions regress after initial progression, supporting the concept of treating some patients beyond progression. Overall, reported rates of pseudoprogression never exceeded 10%, meaning that the large majority of patients who have a disease progression will not eventually respond to treatment. The decision to pursue treatment beyond progression must therefore only be taken in carefully selected patients with clinical benefit, who did not experience severe toxicities with immunotherapy. Conversely, rapid progressions, called hyperprogressions, were reported by several teams with rates ranging from 4% to 29%. These observations need to be confirmed from randomized trials. It is essential to interrupt the treatment in patients with hyperprogression, in order to switch to another potentially active treatment. Finally, some patients experience dissociated responses, with some lesions shrinking and others growing. Local treatment with surgery or radiotherapy for growing lesions may be considered. Several immune-specific-related response criteria were developed to better capture benefits of immunotherapy. These criteria only address the pseudoprogression pattern of response, and do not capture the other patterns of response such as hyperprogression and dissociated response. The classic RECIST remains a reasonable and meaningful method to assess response to immunotherapy in the clinic.

First Detection of Photons with Energy beyond 100 TeV from an Astrophysical Source.

We report on the highest energy photons from the Crab Nebula observed by the Tibet air shower array with the underground water-Cherenkov-type muon detector array. Based on the criterion of a muon number measured in an air shower, we successfully suppress 99.92% of the cosmic-ray background events with energies E>100 TeV. As a result, we observed 24 photonlike events with E>100 TeV against 5.5 background events, which corresponds to a 5.6σ statistical significance. This is the first detection of photons with E>100 TeV from an astrophysical source.

Copy number elevation of 22q11.2 genes arrests the developmental maturation of working memory capacity and adult hippocampal neurogenesis.

Working memory capacity, a critical component of executive function, expands developmentally from childhood through adulthood. Anomalies in this developmental process are seen in individuals with autism spectrum disorder (ASD), schizophrenia and intellectual disabilities (ID), implicating this atypical process in the trajectory of developmental neuropsychiatric disorders. However, the cellular and neuronal substrates underlying this process are not understood. Duplication and triplication of copy number variants of 22q11.2 are consistently and robustly associated with cognitive deficits of ASD and ID in humans, and overexpression of small 22q11.2 segments recapitulates dimensional aspects of developmental neuropsychiatric disorders in mice. We capitalized on these two lines of evidence to delve into the cellular substrates for this atypical development of working memory. Using a region- and cell-type-selective gene expression approach, we demonstrated that copy number elevations of catechol-O-methyl-transferase (COMT) or Tbx1, two genes encoded in the two small 22q11.2 segments, in adult neural stem/progenitor cells in the hippocampus prevents the developmental maturation of working memory capacity in mice. Moreover, copy number elevations of COMT or Tbx1 reduced the proliferation of adult neural stem/progenitor cells in a cell-autonomous manner in vitro and migration of their progenies in the hippocampus granular layer in vivo. Our data provide evidence for the novel hypothesis that copy number elevations of these 22q11.2 genes alter the developmental trajectory of working memory capacity via suboptimal adult neurogenesis in the hippocampus.

Advanced basal cell cancer: concise review of molecular characteristics and novel targeted and immune therapeutics.

Metastatic basal cell carcinoma is an ultra-rare manifestation of a common disease, appearing in 0.0028%-0.5% of basal cell carcinomas. Initial therapeutic efforts focused on cytotoxic chemotherapy administration. However, it is now known that the Hedgehog signaling pathway is crucial for basal cell proliferation and Hedgehog pathway mutations may lead to tumorigenesis; thus, small-molecule inhibitors of alterations in the components of this pathway, including smoothened (SMO) and GLI, have been the focus of recent therapeutic developments. Indeed, the European Medicines Agency and the Food and Drug Administration have approved the SMO inhibitors, vismodegib and sonidegib, with additional GLI inhibitors currently in clinical trials. Molecular profiling of these tumors has revealed other potential targets for therapy, including high tumor mutational burden and PD-L1 amplification, which predict response to immune checkpoint blockade (PD-1 and PD-L1 inhibitors). An illustrative patient with a giant, advanced, unresectable basal cell carcinoma who obtained an ongoing complete remission after treatment with a combination of an immune checkpoint inhibitor (due to the tumor's high mutational burden) and the Hedgehog inhibitor vismodegib is described. A fuller understanding of the genomic portfolio of these patients can assist in developing novel, rational therapeutic approaches that should continue to improve responses and outcomes.

Correction to: Stimulation of intestinal calcium absorption by orally administrated vitamin D3 compounds: a prospective open-label randomized trial in osteoporosis.

There were two errors in this article. 1. In the section "Ethical considerations", the registration number of the study was incorrectly given as UMIN000024492. The correct number is UMIN0000 20267. 2. The Acknowledgments paragraph was incomplete.

Stimulation of intestinal calcium absorption by orally administrated vitamin D3 compounds: a prospective open-label randomized trial in osteoporosis.

Intestinal fractional calcium absorption (FCA) was assessed before and after vitamin D3 treatment. Serum 1,25(OH)2D concentration was significantly increased by plain vitamin D3 and reduced by eldecalcitol. The 1α hydroxyl calcidiol and eldecalcitol treatments increased FCA, which may be induced through direct stimulation of vitamin D receptors in the intestine. INTRODUCTION: To assess the effects of vitamin D3 compounds on intestinal FCA and calcium-regulating hormones in post-menopausal osteoporosis, a randomized open-label prospective study was conducted. METHODS: Forty eligible patients were allocated randomly into four groups: eldecalcitol (ELD; 0.75 µg/day), 1α hydroxyl calcidiol (ALF; 1 µg/day), plain vitamin D3 (800 IU/day), and control. Before and after the 4-week treatment, intestinal FCA was estimated by using a double isotope method, and serum concentrations of calcium-regulating hormones and a bone turnover marker were measured. RESULTS: The baseline FCA value of the participants was 21.5 ± 7.9% (mean ± SD) and was significantly correlated with serum 1,25(OH)2D (calcitriol) concentration. After the treatment, the FCA significantly increased by 59.5% (95% CI, 41.6 to 77.4%) in the ELD group and by 45.9% (27.9 to 63.8%) in the ALF group, whereas no significant change in the plain vitamin D3 group was found. Unlike the baseline FCA, post-treatment FCA exhibited no significant correlation with serum calcitriol concentration. Parathyroid hormone levels were suppressed by ALF and plain vitamin D3 but were sustained in the ELD and control groups. Serum calcitriol tended to be suppressed by ELD, whereas plain vitamin D3 treatment increased both serum 25(OH)D and calcitriol concentrations. CONCLUSION: These findings suggest that oral administration of vitamin D3 analogues (ALF and ELD) stimulates FCA but plain vitamin D3 does not. Those effects of vitamin D3 compounds on FCA were independent of serum calcitriol concentration, suggesting that ALF and ELD may directly stimulate intestinal vitamin D receptors.

Gene therapy approaches in the non-human primate model of Parkinson's disease.

The field of gene therapy has recently witnessed a number of major conceptual changes. Besides the traditional thinking that comprises the use of viral vectors for the delivery of a given therapeutic gene, a number of original approaches have been recently envisaged, focused on using vectors carrying genes to further modify basal ganglia circuits of interest. It is expected that these approaches will ultimately induce a therapeutic potential being sustained by gene-induced changes in brain circuits. Among others, at present, it is technically feasible to use viral vectors to (1) achieve a controlled release of neurotrophic factors, (2) conduct either a transient or permanent silencing of any given basal ganglia circuit of interest, (3) perform an in vivo cellular reprogramming by promoting the conversion of resident cells into dopaminergic-like neurons, and (4) improving levodopa efficacy over time by targeting aromatic L-amino acid decarboxylase. Furthermore, extensive research efforts based on viral vectors are currently ongoing in an attempt to better replicate the dopaminergic neurodegeneration phenomena inherent to the progressive intraneuronal aggregation of alpha-synuclein. Finally, a number of incoming strategies will soon emerge over the horizon, these being sustained by the underlying goal of promoting alpha-synuclein clearance, such as, for instance, gene therapy initiatives based on increasing the activity of glucocerebrosidase. To provide adequate proof-of-concept on safety and efficacy and to push forward true translational initiatives based on these different types of gene therapies before entering into clinical trials, the use of non-human primate models undoubtedly plays an instrumental role.

Dynamic behaviour of the soft palate during nasal positive pressure ventilation under anaesthesia and paralysis: comparison between patients with and without obstructive sleep-disordered breathing.

BACKGROUND: Difficult mask ventilation is common and is known to be associated with sleep-disordered breathing (SDB). It is our hypothesis that the incidence of expiratory retropalatal (RP) airway closure (primary outcome) during nasal positive pressure ventilation (PPV) is more frequent in patients with SDB (apnea hypopnea index ≥5 h-1) than non-SDB subjects. METHODS: The severity of SDB was assessed before surgery using a portable sleep monitor. In anaesthetized and paralysed patients with (n=11) and without SDB (n=9), we observed the behaviour of the RP airway endoscopically during nasal PPV with the mouth closed and determined the dynamic RP closing pressure, which was defined as the highest airway pressure above which the RP airway closure was reversed. The static RP closing pressure was obtained during cessation of mechanical ventilation in patients with dynamic RP closure during nasal PPV. RESULTS: The expiratory RP airway closure accompanied by expiratory flow limitation occurred more frequently in SDB patients (9/11, 82%) than in non-SDB subjects (2/9, 22%; exact logistic regression analysis: P=0.022, odds ratio 3.6, 95% confidence interval 1.1-15.4). Receiver operating characteristic curve analyses indicated AHI >10h-1 and presence of habitual snoring as clinically useful predictors for the occurrence of RP closure during PPV. Dynamic RP closing pressure was greater than the static RP closing pressure by approximately 4-5 cm H2O. CONCLUSIONS: Valve-like dynamic RP closure that limits expiratory flow during nasal PPV occurs more frequently in SDB patients.

Evaluation of the molecular lipid organization in millimeter-sized stratum corneum by synchrotron X-ray diffraction.

BACKGROUND: The aim of this study was to investigate whether the lamellar and lateral structure of intercellular lipid of stratum corneum (SC) can be evaluated from millimeter-sized SC (MSC) by X-ray diffraction. MATERIALS AND METHODS: A 12 mm × 12 mm SC sheet from hairless mouse was divided into 16 pieces measuring 3 mm × 3 mm square. From another sheet, 4 pieces of ultramillimeter-sized SC (USC:1.5 mm × 1.5 mm square) were prepared. Small and wide-angle X-ray diffraction (SAXD and WAXD) measurements were performed on each piece. For MSC and USC, changes in the lamellar and lateral structure after the application of d-limonene were measured. RESULTS: The intensity of SAXD peaks due to the lamellar phase of long periodicity phase (LPP) and WAXD peaks due to the lateral hydrocarbon chain-packing structures varied in MSC and USC pieces, although over the 12 mm × 12 mm SC sheet. These results indicated that the intercellular lipid components and their proportion appeared nearly uniform. Application of d-limonene on MSC and USC piece with strong peaks in SAXD and the WAXD resulted in the disappearance of peaks due to the lamellar phase of LPP and decrease in peak intensity for the lateral hydrocarbon chain-packing structures. These changes are consistent with normal-sized sample results. CONCLUSION: We found that the selection of a sample piece with strong diffraction peaks due to the lamellar and lateral structure enabled evaluation of the SC structure in small-sized samples by X-ray diffraction.

Risk of new-onset diabetes mellitus during treatment with low-dose statins in Japan: A retrospective cohort study.

WHAT IS KNOWN AND OBJECTIVE: The risk of new-onset diabetes mellitus (NODM) in Japanese patients using low-dose hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) has not been previously examined. The aim of this study was to assess the risk of NODM associated with use of high- and low-potency statins in Japanese patients taking low-dose statins. METHODS: A retrospective cohort study of 2554 Japanese patients who started treatment with a statin was conducted. Only patients taking the same dose of the same statin were enrolled, and patients were separated into high- and low-potency statin groups. The outcome was incidence of NODM during statin treatment. RESULTS: The incidence rate of NODM in the cohort was 7.4% (n = 190). Kaplan-Meier survival curves showed a significantly higher rate of NODM in patients taking high-potency statins compared with those taking low-potency statins (P < .001, log-rank test). Baseline fasting plasma glucose levels, use of high-potency statins, male gender and combination treatment with calcium channel blockers, immunosuppressants or steroids were identified as factors that significantly increased the risk for NODM using Cox proportional hazard regression analysis. WHAT IS NEW AND CONCLUSION: The use of high-potency statins at a low standard daily dose significantly increased the risk of NODM in Japanese patients compared with low-potency statins. Furthermore, clinicians should also be careful when prescribing statins in combination with steroids or immunosuppressants due to the increased risk of NODM.