Entinostat in patients with relapsed or refractory abdominal neuroendocrine tumors.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare neoplasms with an increasing annual incidence and prevalence. Many are metastatic at presentation or recur following surgical resection and require systemic therapy, for which somatostatin analogs such as octreotide or lanreotide comprise typical first-line therapies. Nonetheless, treatment options remain limited. Epigenetic processes such as histone modifications have been implicated in malignant transformation and progression. In this study, we evaluated the anti-proliferative effects of a histone deacetylase (HDAC) inhibitor, entinostat, which was computationally predicted to show anti-cancer activity, as confirmed in in vitro and in vivo models of GEP-NETs. METHODS: This was a phase II study to evaluate the efficacy and safety of entinostat in patients with relapsed or refractory abdominal NETs. The primary objective was to estimate the objective response rate to entinostat. Additionally, with each patient as his/her own control we estimated the rates of tumor growth prior to enrollment on study and while receiving entinostat. Patients received 5 mg entinostat weekly until disease progression or intolerable toxicity. The dose could be changed to 10 mg biweekly for patients who did not experience grade ≥ 2 treatment-related adverse events (AEs) in cycle 1, but was primarily administered at the starting 5 mg weekly dose. RESULTS: The study enrolled only 5 patients due to early termination by the drug sponsor. The first patient that enrolled had advanced disease and died within days of enrollment before follow-up imaging due to a grade 5 AE unrelated to study treatment and was considered non-evaluable. Best RECIST response for the remaining 4 patients was stable disease (SD) with time on study of 154+, 243, 574, and 741 days. With each patient as his/her own control, rates of tumor growth on entinostat were markedly reduced with rates 20%, 33%, 54%, and 68% of the rates prior to enrollment on study. Toxicities possibly or definitely related to entinostat included grade 2/3 neutrophil count decrease [2/4 (50%)/ 2/4 (50%)], grade 3 hypophosphatemia [1/4, (25%)], grade 1/2 fatigue [1/4 (25%)/ 2/4 (50%)], and other self-limiting grade 1/2 AEs. CONCLUSION: In the treatment of relapsed or refractory abdominal NETs, entinostat 5 mg weekly led to prolonged SD and reduced the rate of tumor growth by 32% to 80% with an acceptable safety profile (ClinicalTrials.gov Identifier: NCT03211988).

Analysis of data from the PALOMA-3 trial confirms the efficacy of palbociclib and offers alternatives for novel assessment of clinical trials.

PURPOSE: There remains a need for novel therapies for patients with metastatic breast cancer (MBC). We explore the use of a novel biomarker of survival that could potentially expedite the testing of novel therapies. METHODS: We applied a tumor regression-growth model to radiographic measurement data from 393 women with MBC enrolled in PALOMA-3 examining efficacy of palbociclib in disease that had progressed on previous endocrine therapy. 261 and 132 women were randomized to fulvestrant plus palbociclib or placebo, respectively. We estimated rates of regression (d) and growth (g) of the sensitive and resistant fractions of tumors, respectively. We compared the median g of both arms. We examined the relationship between g and progression-free and overall survival (OS). RESULTS: As in other tumors, g is a biomarker of OS. In PALOMA-3, we found significant differences in g among patients with tumors sensitive to endocrine therapy but not amongst resistant tumors, emulating clinical trial results. Subgroup analysis found favorable g values in visceral metastases treated with palbociclib. Palbociclib efficacy demonstrated by slower g values was evident early in the trial, twelve weeks after the first 28 patients had been enrolled. CONCLUSION: Values of g, estimated using data collected while a patient is enrolled in a clinical trial is an excellent biomarker of OS. Our results correlate with the survival outcomes of PALOMA-3 and argue strongly for using g as a clinical trial endpoint to help inform go/no-go decisions, improve trial efficiency, and deliver novel therapies to patients sooner.

Tumor Growth Rate Informs Treatment Efficacy in Metastatic Pancreatic Adenocarcinoma: Application of a Growth and Regression Model to Pivotal Trial and Real-World Data.

BACKGROUND: Methods for screening agents earlier in development and strategies for conducting smaller randomized controlled trials (RCTs) are needed. METHODS: We retrospectively applied a tumor growth model to estimate the rates of growth of pancreatic cancer using radiographic tumor measurements or serum CA 19-9 values from 3033 patients with stages III-IV PDAC who were enrolled in 8 clinical trials or were included in 2 large real-world data sets. RESULTS: g correlated inversely with OS and was consistently lower in the experimental arms than in the control arms of RCTs. At the individual patient level, g was significantly faster for lesions metastatic to the liver relative to those localized to the pancreas. Regardless of regimen, g increased toward the end of therapy, often by over 3-fold. CONCLUSIONS: Growth rates of PDAC can be determined using radiographic tumor measurement and CA 19-9 values. g is inversely associated with OS and can differentiate therapies within the same trial and across trials. g can also be used to characterize changes in the behavior of an individual's PDAC, such as differences in the growth rate of lesions based on metastatic site, and the emergence of chemoresistance. We provide examples of how g can be used to benchmark phase II and III clinical data to a virtual reference arm to inform go/no go decisions and consider novel trial designs to optimize and accelerate drug development.

REM sleep behavior disorder correlates with constipation in de novo Chinese Parkinson's disease patients.

BACKGROUND: Constipation, rapid eye movement sleep behavior disorder (RBD) and hyposmia are common prodromal symptoms of Parkinson's disease (PD), and they may represent two distinct types of disease origin, from the body or the brain. Our study aimed to compare the clinical characteristics of de novo PD patients with and without constipation and identify which prodromal symptoms were associated with constipation. METHODS: A total of 111 de novo, drug-naïve Chinese PD patients were consecutively enrolled from Jan 2017 to Sept 2021. Patients were classified into PD with and without constipation based on item 5 of the Scales for Outcomes in Parkinson's disease-Autonomic Dysfunction (SCOPA-AUT). The demographic data, motor, and non-motor symptoms were compared between the two groups. The associated factors of constipation were analyzed by the multivariate logistic regression analysis. RESULTS: In total, 44.1% (n = 49) of de novo PD patients had constipation. PD patients with constipation were older (p = 0.028), had higher proportions of Hoehn and Yahr (H-Y) stage [Formula: see text] 2 (p = 0.002), clinical possible RBD (cpRBD) (p = 0.002) and depression (p = 0.023), as well as marginal increase of hyposmia (p = 0.058) and freezing of gait (p = 0.069). After adjusting for H-Y stage and other confounding factors, cpRBD (OR = 3.508, p = 0.009), rather than hyposmia or depression, was closely related to constipation in de novo Chinese PD patients. CONCLUSIONS: RBD is closely associated with constipation in de novo Chinese PD patients. Our results support the theory that prodromal symptoms that represent the same pathological origin are closely related to each other.

TMEM147 is a novel biomarker for diagnosis and prognosis of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the most common type of liver malignancy with high incidence and poor prognosis. Transmembrane protein 147 (TMEM147) has been implicated in the development of colon cancer. However, the role of TMEM147 in HCC remains unclear. In this study, data of 371 HCC tissues, 50 adjacent nontumor tissues, and 110 normal liver tissues were retrieved from the TCGA and GTEx databases. TMEM147 expression was found to be increased in HCC tissues. High expression of TMEM147 was related to poor prognosis, and TMEM147 was confirmed to be an independent prognostic factor for HCC patients. A receiver operating characteristics (ROC) analysis was performed and showed that the diagnostic efficacy of TMEM147 was significantly higher than that of AFP (0.908 versus 0.746, p < 0.001). Furthermore, TMEM147 promoted tumor immune infiltration, and macrophages were the immune cells that predominantly expressed TMEM147 in HCC. Further analysis revealed that TMEM147 mainly impacted the ribosome pathway, and CTCF, MLLT1, TGIF2, ZNF146, and ZNF580 were predicted to be the upstream transcription factors for TMEM147 in HCC. These results suggest that TMEM147 serves as a promising biomarker for diagnosis and prognosis and may potentially become a therapeutic target for HCC.

Leverage knowledge graph and GCN for fine-grained-level clickbait detection.

Clickbait is the use of an enticing title as bait to deceive users to click. However, the corresponding content is often disappointing, infuriating or even deceitful. This practice has brought serious damage to our social trust, especially to online media, which is one of the most important channels for information acquisition in our daily life. Currently, clickbait is spreading on the internet and causing serious damage to society. However, research on clickbait detection has not yet been well performed. Almost all existing research treats clickbait detection as a binary classification task and only uses the title as the input. This shallow usage of information and detection technology not only suffers from low performance in real detection (e.g., it is easy to bypass) but is also difficult to use in further research (e.g., potential empirical studies). In this work, we proposed a novel clickbait detection model that incorporated a knowledge graph, a graph convolutional network and a graph attention network to conduct fine-grained-level clickbait detection. According to experiments using a real dataset, our novel proposed model outperformed classical and state-of-the-art baselines. In addition, certain explainability can also be achieved in our model through the graph attention network. Our fine-grained-level results can provide a measurement foundation for future empirical study. To the best of our knowledge, this is the first attempt to incorporate a knowledge graph and deep learning technique to detect clickbait and achieve explainability.

Cascade Transcription Amplification of RNA Aptamer for Ultrasensitive MicroRNA Detection.

MicroRNAs (miRNAs) play a critical role in multifarious biological processes and being deemed to be important biomarkers for clinical cancer diagnosis, prognosis, and therapy. Thus, assays for sensitive and accurate quantification of miRNAs are highly demanded. Herein, we have constructed a RNA aptamer involved cascade transcription amplification method (termed RACTA), enabling label-free, ultrasensitive, and specific detection of miRNA. Target miRNA-initiated strand-displacement amplification would allow for the production of plenty of ssDNA that triggers the subsequent transcriptional amplification of spinach RNA aptamers. Consequently, transcribed tremendous spinach aptamers activated fluorophore DFHBI (( Z)-4-(3,5-difluoro-4-hydroxybenzylidene)-1,2-dimethyl-1 H-imidazol-5(4 H)-one) for miRNA quantitative analysis. RACTA outperforms conventional strand displacement amplification (SDA) at both background and amplification rate due to the light-up mechanism of DFHBI dye-Spinach aptamer and cascade signal amplification of RACTA. Thus, the signal-to-noise ratio of RACTA was increased by about 20-fold compared to that of SDA. This RACTA assay could confer a highly sensitive detection of miRNA with a detection limit of 5.12 × 10-18 M and excellent specificity enabling differentiation between miRNAs and homologous families. Besides, this assay has been successfully demonstrated for quantification of miRNAs in different cell lines. Therefore, the proposed method holds great potential for miRNA biomarker based early diagnosis and prognosis monitoring.

ROLE OF MAGNETIC RESONANCE IMAGING IN THE ASSESSMENT OF ACTIVE THYROID-ASSOCIATED OPHTHALMOPATHY PATIENTS WITH LONG DISEASE DURATION.

Objective: In thyroid-associated ophthalmopathy (TAO), long disease duration is negatively correlated with the response to immunosuppression treatment. The current treatment decision-making process does not involve magnetic resonance imaging (MRI); thus, we investigated the predictive value of MRI parameters for the immunosuppressive response in active moderate to severe TAO patients with different disease durations. Methods: We retrospectively analyzed the baseline MRI parameters of active TAO patients treated with guideline-recommended weekly glucocorticoid therapy in our center. Data were stratified by the quartile of disease duration. The signal intensity ratio (SIR) of T2-weighted images was used to describe the activity of extraocular muscles (EOMs). Results: Compared to the lowest quartile of disease duration, SIR values of EOMs were significantly lower in quartile 3 (Q3) and quartile 4 (Q4). Meanwhile, the clinical activity score (CAS) curve did not change in parallel and was not correlated with the SIR curve. In the highest quartile of disease duration, nonresponders had significantly lower SIR values of the most inflamed muscle (P = .03) and the medial rectus (P = .004) than did the responders, while no such significance was observed in patients within the lower 3 quartiles. A multivariable predictive model (including CAS, TAO duration, and SIR value) was established in each quartile. The fit of the model was better than CAS with regard to prognostic prediction and showed a high positive predictive value (Model 1: 86.67%; Model 2: 92.86%) and negative predictive value (Model 1: 88.89%; Model 2: 90%) in the top quartile. Conclusion: The anterior manifestation assessed by CAS is not always consistent with retro-orbital activity in long-term TAO patients. CAS is sufficient to reflect disease activity in short-term TAO patients. The supplementation of CAS with orbital MRI would be valuable in selecting appropriate active patients with a long disease duration. Abbreviations: AUC = area under the curve; CAS = clinical activity score; EOM = extraocular muscle; FT3 = free triiodothyronine; FT4 = free thyroxine; GC = glucocorticoid; ivGC = intravenous glucocorticoids; MRI = magnetic resonance imaging; NPV = negative predictive value; PPV = positive predictive value; SIR = signal intensity ratio; TAO = thyroid-associated ophthalmopathy; TRAb = thyroid-stimulating hormone receptor antibody; TSH = thyroid-stimulating hormone.

Amplified Tandem Spinach-Based Aptamer Transcription Enables Low Background miRNA Detection.

MicroRNAs (miRNAs) play key roles in regulating gene expression and cell functions, which are recognized as potential biomarkers for many human diseases. Sensitive, specific, and reliable detection of miRNA is highly demanded for clinical diagnosis and therapy. Herein, we describe a label-free and low-background fluorescent assay, termed amplified tandem Spinach-based aptamer transcription assay (AmptSpi assay) for highly sensitive miRNA detection by polymeric rolling circle amplicon mediated multiple transcription. Target miRNA is recognized by padlock probe to form polymeric rolling circle amplicon. Then the following transcription process rapidly produces large amounts of repeats of RNA Spinach aptamers, lightened up by the addition of fluorescent dye DFHBI for miRNA quantitative analysis, achieving label-free and nearly zero-background. Besides, the assay could also confer high selectivity to distinguish miRNA among the miRNA family members with 1- or 2-nucleotide (nt) difference. This method was capable of completing detection in human serum sample or cell extracts in hours, indicating great potential in the early diagnosis of diseases.

Serum and thyroid tissue level of let-7b and their correlation with TRAb in Graves' disease.

BACKGROUND: Abnormal microRNAs (miRNAs) were reported to be involved in the mechanism of Graves' disease (GD). Dysregulated miRNAs may be overlapping in different cells and can be secreted to circulation. We chose miRNAs which were previously reported to be differentially expressed in peripheral blood mononuclear cells (PBMCs) in patients with GD with different disease stage, detected the expression of those miRNAs in serum, corroborated the findings in thyroid tissue, and validated the target gene in vitro to investigate the possible role of circulating miRNAs in GD. METHODS: A total of 54 individuals with untreated GD, 12 individuals with GD in remission and 14 disease-free controls were enrolled. The expression of miR-142-3p, miR-154-3p, miR-431-3p, miR-590-5p, and let-7b was detected in the serum. Ten thyroid tissue samples from patients with GD and six disease-free thyroid samples were used for further validation. The potential target genes were identified and validated in vitro. RESULTS: miR-142-3p, miR-154-3p, miR-431-3p, miR-590-5p, and let-7b were present in serum and two of them (miR-142-3p and let-7b) were significantly increased in serum of patients with untreated GD (for serum miR-142-3p, P = 0.033, for serum let-7b, P = 0.026) and gradually decreased to normal levels in patients with GD in remission. Correlation analysis showed that let-7b level was strongly correlated with TRAb level (r = 0.305, P = 0.001). let-7b directly inhibited promyelocytic leukemia zinc finger (PLZF) expression and increased the expression of TSHR in thyroid cells in vitro. Furthermore, let-7b levels in GD thyroid tissue were found to be inversely correlated with PLZF levels (r = - 0.849, P = 0.033). Decreased PLZF and increased TSHR was validated in thyroid tissue in patients with GD. CONCLUSIONS: The present study confirmed that a portion of miRNAs in PBMCs were also presented and differentially expressed in serum and thyroid tissue. Upregulated in all these three compartments, let-7b may be used as a disease biomarker and therapeutic targets in patients with GD. Circulating let-7b had a strong correlation with disease severity and let-7b may participate in the production of TRAb via targeting PLZF in patients with GD.

Interference voltage measurement and analysis of cardiac implants exposed to electric fields at extremely low frequency.

Objective.The possibility of interference by electromagnetic fields in the workplaces with cardiac implants is a concern for both individuals and employers. This article presents an analysis of the interference to which cardiac implants are subjected under high-intensity electric field at the power frequency.Approach.Evaluations of interference were conducted by studying the induced voltages at the device input in the real case study and the substitute study, and establishing an association between them with the equivalence factorF. A funnel-shaped phantom, designed forin vitrotesting and representing the electrical characteristics of the locations where cardiac implants are installed, was used in the substitute study. A measuring system was implemented to measure the induced voltage at the device input under high intensity electric fields.Main results.The induced voltages obtained in the experimental measurements align with the findings of the numerical study in the phantom. By applying the equivalence factors derived between the real case study and the substitute study (2.39 for unipolar sensing; 3.64 for bipolar sensing), the induced voltages on the cardiac implants can be determined for the real case using the substitute experimental set-up.Significance.The interference voltages on the cardiac implants under electric field exposures at low frequency were experimentally measured with detailed description. The findings provide evidence for an analysis method to systematically study the electromagnetic interference on the cardiac implants at low frequency.

The Synergistic Effect Study of Lipopolysaccharide (LPS) and A53T-α-Synuclein: Intranasal LPS Exposure on the A53T-α-Synuclein Transgenic Mouse Model of Parkinson's Disease.

Aging and interactions between genetic and environmental factors are believed to be involved the chronic development of Parkinson's disease (PD). Among PD patients, abnormally aggregated α-synuclein is a major component of the Lewy body. Generally, the intranasal route is believed to be a gate way to the brain, and it assists environmental neurotoxins in entering the brain and is related to anosmia during early PD. The current study applies the chronic intranasal application of lipopolysaccharides (LPS) in 4-, 8-, 12- and 16-month-old A53T-α-synuclein (A53T-α-Syn) transgenic C57BL/6 mice at 2-day intervals for a 2-month period, for evaluating the behavioral, pathological, and biochemical changes and microglial activation in these animals. According to our results, after intranasal administration of LPS, A53T-α-Syn mice showed severe progressive anosmia, hypokinesia, selective dopaminergic (DAergic) neuronal losses, decreased striatal dopamine (DA) level, and enhanced α-synuclein accumulation within the substantia nigra (SN) in an age-dependent way. In addition, we found obvious NF-кB activation, Nurr1 inhibition, IL-1ß, and TNF-α generation within the microglia of the SN. Conversely, the wild-type (WT) mice showed mild, whereas A53T-α-Syn mice had moderate PD-like changes among the old mice. This study demonstrated the synergistic effect of intranasal LPS and α-synuclein burden on PD development. Its underlying mechanism may be associated with Nurr1 inhibition within microglia and the amplification of CNS neuroinflammation. The mice with multiple factors, including aging, neuroinflammation, and α-synuclein mutation, have played a significant role in enhancing our understanding of how inflammation and α-synuclein mutation contribute to the neurodegeneration observed in PD.

Combined influence of the nanoplastics and polycyclic aromatic hydrocarbons exposure on microbial community in seawater environment.

Nanoplastics (NPs) and polycyclic aromatic hydrocarbons (PAHs) are recognized as persistent organic pollutant (POPs) with demonstrated physiological toxicity. When present in aquatic environments, the two pollutants could combine with each other, resulting in cumulative toxicity to organisms. However, the combined impact of NPs and PAHs on microorganisms in seawater is not well understood. In this study, we conducted an exposure experiment to investigate the individual and synergistic effects of NPs and PAHs on the composition, biodiversity, co-occurrence networks of microbial communities in seawater. Exposure of individuals to PAHs led to a reduction in microbial community richness, but an increase in the relative abundance of species linked to PAHs degradation. These PAHs-degradation bacteria acting as keystone species, maintained a microbial network complexity similar to that of the control treatment. Exposure to individual NPs resulted in a reduction in the complexity of microbial networks. Furthermore, when PAHs and NPs were simultaneously present, the toxic effect of NPs hindered the presence of keystone species involved in PAHs degradation, subsequently limiting the degradation of PAHs by marine microorganisms, resulting in a decrease in community diversity and symbiotic network complexity. This situation potentially poses a heightened threat to the ecological stability of marine ecosystems. Our work strengthened the understanding of the combined impact of NPs and PAHs on microorganisms in seawater.

Vestibular-evoked myogenic potential abnormalities in Parkinson's disease with freezing of gait.

BACKGROUND: Vestibular dysfunction is closely associated with the pathophysiology of Parkinson's disease (PD) accompanied by freezing of gait (FOG); however, evidence supporting this clinical association is lacking. Vestibular-evoked myogenic potentials (VEMPs) have been widely acknowledged as a crucial electrophysiological parameter in the clinical evaluation of vestibular function. OBJECTIVE: The present study investigated the possible correlation of FOG occurrence with VEMP observations in patients diagnosed with PD. METHODS: Altogether, 95 idiopathic PD patients were recruited into the present cross-sectional study. All patients underwent motor and non-motor assessments using serial scales. In addition, the electrophysiological vestibular evaluation was conducted, which included cervical (cVEMP) and ocular VEMP (oVEMP) assessments. Furthermore, the correlations of bilateral c/oVEMP absence with clinical phenotypes, especially FOG, among the PD patients were analyzed. RESULTS: Among the 95 patients with PD, 44 (46.3%) had bilateral oVEMP absence and 23 (24.2%) had bilateral cVEMP absence, respectively. The proportions of patients with bilateral oVEMP absence (77.8% vs 30.9%, p = 0.004) and bilateral cVEMP absence (44.4% vs 19.5%, p = 0.035) were higher in the patient group exhibiting FOG than in the group without FOG. Following the adjustment of confounding variables, bilateral oVEMP absence (OR = 8.544, p = 0.007), rather than bilateral cVEMP absence, was shown to independently predict FOG occurrence in patients with PD. CONCLUSION: The close correlation between bilateral oVEMP absence and FOG in PD patients sheds new light on the possible role of central vestibular/upper brainstem dysfunction in FOG development in patients with PD.

Assessment of PSA responses and changes in the rate of tumor growth (g-rate) with immune checkpoint inhibitors in US Veterans with prostate cancer.

We examined data from US Veterans with prostate cancer (PC) to assess disease response to immune checkpoint inhibitors (ICI) as monotherapy or combined with abiraterone or enzalutamide to assess ICI efficacy in the real-world. We queried the VA corporate data warehouse (CDW) to identify Veterans with a diagnosis of PC who received ICI for any malignancy and had ≥1 PSA measurement while receiving ICI. To evaluate ICI monotherapy, we restricted analysis to Veterans who had not received LHRH agonists/antagonists, PC-directed medical therapy, or radiation/extirpative surgery of the bladder/prostate within and preceding the duration of ICI administration. For ICI combination analysis, we identified Veterans who received abiraterone or enzalutamide for PC while on ICI. We calculated rates of tumor (PSA) growth (g-rates), comparing them to a 1:2 matched reference cohort. We identified 787 Veterans with PC and ≥1 PSA measurement while receiving an ICI. Median duration of ICI therapy was 155 days. 223 Veterans received ICI monotherapy, with only 17(8%) having a reduction in PSA (median decline = 43%). 12 (5%) had PSA declines >30% (PSA30) which included 6 (3%) who had PSA reductions greater than 50% (PSA50). Median g-rates for ICI plus abiraterone (n = 20) or enzalutamide (n = 31) were 0.000689/d-1 and 0.002819/d-1, respectively, and were statistically insignificant compared to g-rates of matched cohorts receiving abiraterone (g = 0.000925/d-1, P = 0.73) or enzalutamide (g = 0.001929/d-1, P = 0.58) alone. Our data align with clinical trial data in PC, demonstrating limited benefit from ICI monotherapy and predicting no survival benefit from simultaneous abiraterone or enzalutamide with an ICI using g-rate.

Using deep learning for the automated identification of cone and rod photoreceptors from adaptive optics imaging of the human retina.

Adaptive optics imaging has enabled the enhanced in vivo retinal visualization of individual cone and rod photoreceptors. Effective analysis of such high-resolution, feature rich images requires automated, robust algorithms. This paper describes RC-UPerNet, a novel deep learning algorithm, for identifying both types of photoreceptors, and was evaluated on images from central and peripheral retina extending out to 30° from the fovea in the nasal and temporal directions. Precision, recall and Dice scores were 0.928, 0.917 and 0.922 respectively for cones, and 0.876, 0.867 and 0.870 for rods. Scores agree well with human graders and are better than previously reported AI-based approaches.

Interference thresholds for active implantable cardiovascular devices in occupational low-frequency electric and magnetic fields: a numerical and in vitro study.

In light of concerns regarding the occupational safety and health of workers wearing active implantable medical devices (AIMDs), this study aims to investigate the potential risks of electromagnetic interference (EMI) between AIMDs and low-frequency 50/60 Hz electromagnetic fields (EMFs) in the workplace. A total of 58 AIMDs, consisting of pacemakers (PMs) and implantable cardiac defibrillators (ICDs) of different brands, models, and configurations were tested to determine the immunity thresholds for high-voltage electric fields (EFs) and magnetic fields (MFs) at 50/60 Hz. The EFs and MFs at the levels in workplaces are reproduced by setups using Helmholtz coils and aluminum plates, respectively, to ensure that the EM/MF exposures are controllable and reproducible. The EMI thresholds were recorded by observing the occurrences of PM or ICD dysfunctions. In addition, numerical studies on anatomical models were carried out using CST® software. The results indicate that the recorded thresholds all exceed the EF and MF public exposure limits given in the ICNIRP 2010 guidelines. No dysfunction was observed among four ICDs tested under MF exposure up to 2750 µT at 50 Hz and 2480 µT at 60 Hz. However, among the 43 PMs and 11 ICDs tested under EF exposures, potential hazards may occur below the occupational exposure level proposed in the ICNIRP guidelines.

Plasma miR-153 and miR-223 Levels as Potential Biomarkers in Parkinson's Disease.

Background: Small molecule RNAs (miRNAs) could induce downregulation of α-synuclein (SNCA) expression by binding the 3' untranslated region of SNCA, thus playing an important role in the pathogenesis of Parkinson's disease (PD). Recent studies suggest that SNCA-related miRNAs in saliva are promising PD biomarkers. Research on those miRNAs in plasma is rare in patients with PD. Objective: To detect the plasma expression levels of three SNCA related miRNAs (miR-7, miR-153, and miR-223) in PD, and to explore their diagnostic value and associations with clinical phenotype. Methods: MiR-7, miR-153, and miR-223 levels were detected in the plasma of 75 PD patients and 73 normal controls (NCs) via real-time quantitative polymerase chain reaction. The receiver operating characteristic (ROC) curves were delineated to evaluate their diagnostic value in PD. In addition, their associations with demographic, key motor, and non-motor symptoms were explored by serial scales. Results: The expression levels of plasma miR-153 and miR-223 were significantly decreased in patients with PD relative to NCs. The area under the ROC curve separating PD from NCs was 63.1% for miR-153 and 86.2% for miR-223, respectively. The plasma miR-153 level in de novo PD was lower than that in treated patients (p = 0.006), its level increased gradually with disease duration (r = 0.358, p = 0.002) and Unified Parkinson's Disease Rating Scale Part III score (r = 0.264, p = 0.022). Plasma miR-223 level was decreased in patients with clinical possible rapid eye movement sleep behavior disorder (cpRBD) compared with those without cpRBD (p < 0.001), and its level was negatively associated with RBDSQ score (r = -0.334, p = 0.003). Multiple linear regression analysis revealed that disease duration (p = 0.049) was the independently associated factor of miR-153 level; whereas, RBDSQ (p = 0.009) was related to miR-223 level in PD. Conclusion: Plasma miR-153 and miR-223 levels could be potential biomarkers of PD.

Oculomotor impairments in de novo Parkinson's disease.

Objective: Reliable electrophysiological indicators are urgently needed in the precise evaluation of Parkinson's disease (PD). It is still elusive whether oculomotor performance is impaired or has clinical value in early PD. This study aims to explore oculomotor performance in newly diagnosed, drug-naïve PD and its correlation with clinical phenotype. Methods: Seventy-five patients with de novo PD, 75 patients with essential tremor (ET), and 46 gender-and age-matched healthy controls (HCs) were included in this cross-sectional study. All subjects underwent oculomotor test via videonystagmography. Visually guided saccade latency, saccadic accuracy and gain in smooth pursuit eye movement (SPEM) at three frequencies of the horizontal axis were compared among the three groups. Patients with PD also received detailed motor and non-motor evaluation by serial scales. The association between key oculomotor parameters and clinical phenotypes were explored in PD patients. Results: Both de novo PD and ET patients showed prolonged saccadic latency and decreased saccadic accuracy relative to HCs. SPEM gain in PD was uniformly reduced at each frequency. SPEM gain at 0.4 Hz was also decreased in ET compared with HCs. However, there was no significant difference of oculomotor parameters between de novo PD and ET patients. Furthermore, prolonged saccadic latency was correlated with long disease duration, whereas decreased SPEM gain was associated with severe motor symptoms in de novo PD patients. Conclusion: Ocular movements are impaired in de novo, drug naïve PD patients; these changes could be indicators for disease progression in PD.

Influence of Cancer on COVID-19 Incidence, Outcomes, and Vaccine Effectiveness: A Prospective Cohort Study of U.S. Veterans.

PURPOSE: Coronavirus disease 2019 (COVID-19) has been a constant health threat since its emergence. Amongst risk factors proposed, a diagnosis of cancer has been worrisome. We report the impact of cancer and other risk factors in US Veterans receiving care at Veterans Administration (VA) Hospitals, their adjusted odds ratio (aOR) for infection and death, and report on the impact of vaccines on the incidence and severity of COVID-19 infections in Veterans without/with cancer. METHODS: We conducted a cohort study of US Veterans without/with cancer by mining VA COVID-19 Shared Data Resource (CSDR) data using the VA Informatics and Computing Infrastructure (VINCI). Our observation period includes index dates from 14DEC2020 to 25JAN2022, encompassing both the delta and omicron waves in the US. RESULTS: We identified 915,928 Veterans, 24% of whom were African Americans who had undergone COVID testing-688,541 were and 227,387 were not vaccinated. 157,072 had a cancer diagnosis in the preceding two years. Age emerged as the major risk factor, with gender, BMI, and (Elixhauser) comorbidity contributing less. Among veterans with solid tumors other than lung cancer, risks of infection and death within 60 days were comparable to Veterans without cancer. However, those with hematologic malignancies fared worse. Vaccination was highly effective across all cancer cohorts; the respective rates of infection and death after infection were 8% and 5% among the vaccinated compared to 47% and 10% in the unvaccinated. Amongst vaccinated, increased risk of infection was noted in both, Veterans with hematologic malignancy treated with chemotherapy (HR, 2.993, P < 0.0001) or targeted therapies (HR, 1.781, P < 0.0001), and in solid tumors treated with either chemotherapy (HR 2.328, 95%CI 2.075-2.611, P < 0.0001) or targeted therapies (HR 1.328, P < 0.0001) when compared to those not on treatment. CONCLUSIONS: Risk for COVID-19 infection and death from infection vary based on cancer type and therapies administered. Importantly and encouragingly, the duration of protection from infection following vaccination in Veterans with a diagnosis of cancer was remarkably like those without a cancer diagnosis. Veterans with hematologic malignancies are especially vulnerable, with lower vaccine effectiveness (VE).