Background
The impact of hypoglycaemic episode (HE) on the risk of ventricular arrhythmia (VA) and sudden cardiac arrest (SCA) remains unclear. We hypothesized that HE increases the risk of both VA ...and SCA and that glucose‐lowering agents causing HE also increase the risk of VA/SCA in patients with type 2 diabetes (T2D).
Methods
Patients aged 20 years or older with newly diagnosed T2D were identified using the Taiwan National Health Insurance Database. HE was defined as the presentation of hypoglycaemic coma or specified/unspecified hypoglycaemia. The control group consisted of T2D patients without HE. The primary outcome was the occurrence of VA (including ventricular tachycardia and fibrillation) and SCA during the defined follow‐up periods. A multivariate Cox hazards regression model was used to evaluate the hazard ratio (HR) for VA or SCA.
Results
A total of 54 303 patients were screened, with 1037 patients with HE assigned to the HE group and 4148 frequency‐matched patients without HE constituting the control group. During a mean follow‐up period of 3.3 ± 2.5 years, 29 VA/SCA events occurred. Compared with the control group, HE group had a higher incidence of VA/SCA (adjusted HR: 2.42, P = .04). Patients who had used insulin for glycaemic control showed an increased risk of VA/SCA compared with patients who did not receive insulin (adjusted HR: 3.05, P = .01).
Conclusions
The HEs in patients with T2D increased the risk of VA/SCA, compared with those who did not experience HEs. Use of insulin also independently increased the risk of VA/SCA.
Abstract Objective To compare the responsiveness of the Rasch-calibrated 37-item Fugl-Meyer motor Scale with that of the 12-item Fugl-Meyer motor scale at both an individual and a group level. Design ...Repeated-measurements design. Setting Medical center. Participants Patients (N=301) 14 days after stroke. Interventions Not applicable. Main Outcome Measures 50-item Fugl-Meyer motor scale, 37-item Fugl-Meyer motor scale, and 12-item Fugl-Meyer motor scale. Results The patients were assessed with the original 50-item Fugl-Meyer motor scale 4 times, at 14, 30, 90, and 180 days after stroke onset. The patients' responses were used for estimating the Rasch scores of the 37-item Fugl-Meyer motor scale and 12-item Fugl-Meyer motor scale. The effect size, standardized response mean, and paired t test were used to compare the group-based responsiveness of the 3 forms (50-item Fugl-Meyer motor scale, 37-item Fugl-Meyer motor scale, 12-item Fugl-Meyer motor scale). Individual-level responsiveness was compared based on the significance of change between the 37-item Fugl-Meyer motor scale and 12-item Fugl-Meyer motor scale. Because up to 13 items of the 50-item Fugl-Meyer motor scale did not meet the Rasch model's assumptions, the significance of change of the 50-item Fugl-Meyer motor scale was not calculated. At the group level, the FM-37 and FM-12 Fugl-Meyer motor scale had sufficient and similar responsiveness. At the individual level, the FM-37 Fugl-Meyer motor scale detected more patients with significant improvement than the FM-12 Fugl-Meyer motor scale. The SC values and category distribution of the FM-37 Fugl-Meyer motor scale were significantly better than those of the FM-12 Fugl-Meyer motor scale ( P <.001). Conclusions Although the group-level responsiveness of the 12-item Fugl-Meyer motor scale was sufficient and very similar to that of the 37-item Fugl-Meyer motor scale, the 37-item Fugl-Meyer motor scale had better individual-level responsiveness. The 37-item Fugl-Meyer motor scale is suggested as an outcome measure for both clinicians and researchers.
Immediate monitoring of the conditions of the grinding wheel during the grinding process is important because it directly affects the surface accuracy of the workpiece. Because the variation in ...machining sound during the grinding process is very important for the field operator to judge whether the grinding wheel is worn or not, this study applies artificial intelligence technology to attempt to learn the experiences of auditory recognition of experienced operators. Therefore, we propose an intelligent system based on machining sound and deep learning to recognize the grinding wheel condition. This study uses a microphone embedded in the grinding machine to collect audio signals during the grinding process, and extracts the most discriminated feature from spectrum analysis. The features will be input the designed CNNs architecture to create a training model based on deep learning for distinguishing different conditions of the grinding wheel. Experimental results show that the proposed system can achieve an accuracy of 97.44%, a precision of 98.26% and a recall of 96.59% from 820 testing samples.
Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) are the two most common immune checkpoints targeted in triple-negative breast cancer (BC). Refining patient selection for immunotherapy ...is non-trivial and finding an appropriate digital pathology framework for spatial analysis of theranostic biomarkers for PD-1/PD-L1 inhibitors remains an unmet clinical need.
We describe a novel computer-assisted tool for three-dimensional (3D) imaging of PD-L1 expression in immunofluorescence-stained and optically cleared BC specimens (n = 20). The proposed 3D framework appeared to be feasible and showed a high overall agreement with traditional, clinical-grade two-dimensional (2D) staining techniques. Additionally, the results obtained for automated immune cell detection and analysis of PD-L1 expression were satisfactory.
The spatial distribution of PD-L1 expression was heterogeneous across various BC tissue layers in the 3D space. Notably, there were six cases (30%) wherein PD-L1 expression levels along different layers crossed the 1% threshold for admitting patients to PD-1/PD-L1 inhibitors. The average PD-L1 expression in 3D space was different from that of traditional immunohistochemistry (IHC) in eight cases (40%). Pending further standardization and optimization, we expect that our technology will become a valuable addition for assessing PD-L1 expression in patients with BC.
Via a single round of immunofluorescence imaging, our approach may provide a considerable improvement in patient stratification for cancer immunotherapy as compared with standard techniques.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
We design an open-loop active flow control for separated flows around a plunging circular cylinder based on resolvent analysis. The cylinder is plunging at a Strouhal number of 0.36 and a Reynolds ...number of 500. A linear time-periodic system for control is obtained by linearizing the non-inertial incompressible vorticity equation in the cylinder-fixed frame about a time-averaged base flow. Using the Lyapunouv–Floquet transformation, the linear time-periodic system is transformed into a similar linear time-invariant system, whose resolvent is analysed to obtain an optimal actuating Strouhal number of 0.1464 for the transformed linear system. Simulations show that the active control with tangential actuations is capable of reducing the lift fluctuation by up to 25.7 % when the flow is actuated near the predicted harmonic and subharmonic frequencies.
To demonstrate the feasibility of presymptomatic diagnosis of spinal muscular atrophy (SMA) through newborn screening (NBS).
We performed a screening trial to assess all newborns who underwent ...routine newborn metabolic screening at the National Taiwan University Hospital newborn screening center between November 2014 and September 2016. A real-time polymerase chain reaction (RT-PCR) genotyping assay for the SMN1/SMN2 intron 7 c.888+100A/G polymorphism was performed to detect homozygous SMN1 deletion using dried blood spot (DBS) samples. Then the exon 7 c.840C>T mutation and SMN2 copy number were determined by both droplet digital PCR (ddPCR) using the original screening DBS and multiplex ligation-dependent probe amplification (MLPA) using a whole blood sample.
Of the 120 267 newborns, 15 tested positive according to the RT-PCR assay. The DBS ddPCR assay excluded 8 false-positives, and the other 7 patients were confirmed by the MLPA assay. Inclusion of the second-tier DBS ddPCR screening assay resulted in a positive prediction value of 100%. The incidence of SMA was 1 in 17 181 (95% CI, 1 in 8323 to 1 in 35 468). Two of the 3 patients with 2 copies of SMN2 and all 4 patients with 3 or 4 copies of SMN2 were asymptomatic at the time of diagnosis. Five of the 8 false-positives were caused by intragenic recombination between SMN1 and SMN2.
Newborn screening can detect patients affected by SMA before symptom onset and enable early therapeutic intervention. A combination of a RT-PCR and a second-tier ddPCR can accurately diagnose SMA from DBS samples with no false-positives.
ClinicalTrials.gov NCT02123186.
The development of a portfolio of COVID-19 vaccines to vaccinate the global population remains an urgent public health imperative
. Here we demonstrate the capacity of a subunit vaccine, comprising ...the SARS-CoV-2 spike protein receptor-binding domain displayed on an I53-50 protein nanoparticle scaffold (hereafter designated RBD-NP), to stimulate robust and durable neutralizing-antibody responses and protection against SARS-CoV-2 in rhesus macaques. We evaluated five adjuvants including Essai O/W 1849101, a squalene-in-water emulsion; AS03, an α-tocopherol-containing oil-in-water emulsion; AS37, a Toll-like receptor 7 (TLR7) agonist adsorbed to alum; CpG1018-alum, a TLR9 agonist formulated in alum; and alum. RBD-NP immunization with AS03, CpG1018-alum, AS37 or alum induced substantial neutralizing-antibody and CD4 T cell responses, and conferred protection against SARS-CoV-2 infection in the pharynges, nares and bronchoalveolar lavage. The neutralizing-antibody response to live virus was maintained up to 180 days after vaccination with RBD-NP in AS03 (RBD-NP-AS03), and correlated with protection from infection. RBD-NP immunization cross-neutralized the B.1.1.7 SARS-CoV-2 variant efficiently but showed a reduced response against the B.1.351 variant. RBD-NP-AS03 produced a 4.5-fold reduction in neutralization of B.1.351 whereas the group immunized with RBD-NP-AS37 produced a 16-fold reduction in neutralization of B.1.351, suggesting differences in the breadth of the neutralizing-antibody response induced by these adjuvants. Furthermore, RBD-NP-AS03 was as immunogenic as a prefusion-stabilized spike immunogen (HexaPro) with AS03 adjuvant. These data highlight the efficacy of the adjuvanted RBD-NP vaccine in promoting protective immunity against SARS-CoV-2 and have led to phase I/II clinical trials of this vaccine (NCT04742738 and NCT04750343).
The treatment of recurrent or metastatic head and neck squamous-cell carcinoma (R/M HNSCC) remains challenging. Preclinical studies revealed that B cell depletion could modulate the microenvironment ...and overcome chemoresistance. We conducted a phase I study to evaluate the feasibility and safety of B cell depletion using the anti-CD20 antibody rituximab to treat HNSCC.
Ten patients were enrolled in two protocols. The first four patients treated using protocol 1 received rituximab 1000 mg on days -14 and -7, followed by gemcitabine/cisplatin every 3 weeks, and rituximab was administered every 6 months thereafter. Because of disease hyperprogression, protocol 1 was amended to protocol 2, which consisted of the concomitant administration of rituximab 375 mg/m
and gemcitabine/cisplatin every 3 weeks. Another six patients were enrolled and treated using protocol 2.
Three patients treated using protocol 1 exhibited rapid disease progression, and the remaining patient could not undergo evaluation after rituximab treatment. Conversely, no unpredicted harm was observed in the six patients treated using protocol 2. Among these patients, one achieved complete response, and two had partial responses. The disease-free durations in these patients were 7.0, 6.2, and 7.1 months, respectively. Immune cell analysis revealed a higher ratio of cytotoxic T cells to regulatory T cells in responders than in non-responders.
B cell depletion using rituximab alone in patients with HNSCC can cause hyperprogressive disease. Contrarily, the co-administration of rituximab and cisplatin/gemcitabine was feasible and safe.
ClinicalTrials.gov Identifier: NCT04361409 , 24 April 2020, retrospectively registered.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The p53 gene is an important tumour suppressor gene. Mutant p53 genes account for about half of all lung cancer cases. There is increasing evidence for the anti-tumour effects of statins via ...inhibition of the mevalonate pathway. We retrospectively investigated the correlation between statin use and lung cancer prognosis using the Taiwanese National Health Insurance Research Database, mainly focusing on early-stage lung cancer. This study reports the protective effects of statin use in early-stage lung cancer patients regardless of chemotherapy. Statin treatments reduced the 5-year mortality (odds ratio, 0.43; P < 0.001) in this population-based study. Significantly higher levels of cellular apoptosis, inhibited cell growth, and regulated lipid raft content were observed in mutant p53 lung cancer cells treated with simvastatin. Further, simvastatin increased the caspase-dependent apoptotic pathway, promotes mutant p53 protein degradation, and decreased motile activity in lung cancer cells with p53 missense mutations. These data suggest that statin use in selected lung cancer patients may have clinical benefits.
Aging, cancer, and longevity have been linked to intracellular Ca2+ signaling and nociceptive transient receptor potential (TRP) channels. We found that TRP canonical 7 (TRPC7) is a nociceptive ...mechanoreceptor and that TRPC7 channels specifically mediate the initiation of ultraviolet B (UVB)‐induced skin aging and tumor development due to p53 gene family mutations. Within 30 min after UVB irradiation, TRPC7 mediated UVB‐induced Ca2+ influx and the subsequent production of reactive oxygen species in skin cells. Notably, this function was unique to TRPC7 and was not observed for other TRP channels. In TRPC7 knockout mice, we did not observe the significant UVB‐associated pathology seen in wild‐type mice, including epidermal thickening, abnormal keratinocyte differentiation, and DNA damage response activation. TRPC7 knockout mice also had significantly fewer UVB‐induced cancerous tumors than did wild‐type mice, and UVB‐induced p53 gene family mutations were prevented in TRPC7 knockout mice. These results indicate that TRPC7 activity is pivotal in the initiation of UVB‐induced skin aging and tumorigenesis and that the reduction in TRPC7 activity suppresses the UVB‐induced aging process and tumor development. Our findings support that TRPC7 is a potential tumor initiator gene and that it causes cell aging and genomic instability, followed by a change in the activity of proto‐oncogenes and tumor suppressor genes to promote tumorigenesis.
Schematic representation of the role of TRPC7 as a potential tumor initiator gene in ultraviolet B (UVB)‐induced aging and cancer progression. UVB‐activated TRPC7 initiates skin aging via intracellular Ca2+ elevation, resulting in oxidative stress, DNA damage response activation, abnormal differentiation, and senescence inflammation response activation; this pathology is repaired with the activation of p53 to maintain tissue homeostasis. When homeostasis is no longer maintained and the aging process is activated, carcinogens promote cancer progression. TRPC7 initiates tumorigenesis by causing genomic instability, thereby changing the activity of proto‐oncogenes and tumor suppressor genes.
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