ABSTRACT
Electronic frequency mixers are fundamental building blocks of electronic systems. Harmonic frequency mixing in particular enables broadband electromagnetic signal analysis across octaves of spectrum using a single local oscillator. However, conventional harmonic frequency mixers do not operate beyond hundreds of gigahertz to a few terahertz. If extended to the petahertz scale in a compact and scalable form, harmonic mixers would enable field-resolved optical signal analysis spanning octaves of spectra in a monolithic device without the need for frequency conversion using nonlinear crystals. Here, we demonstrate lightwave-electronic harmonic frequency mixing beyond 0.350 PHz using plasmonic nanoantennas. We demonstrate that the mixing process enables complete, field-resolved detection of spectral content far outside that of the local oscillator, greatly extending the range of detectable frequencies compared to conventional heterodyning techniques. Our work has important implications for applications where optical signals of interest exhibit coherent femtosecond-scale dynamics spanning multiple harmonics.
ABSTRACT
Although genomic anomalies in glioblastoma (GBM) have been well studied for over a decade, its 5-year survival rate remains lower than 5%. We seek to expand the molecular landscape of high-grade glioma, composed of IDH-wildtype GBM and IDH-mutant grade 4 astrocytoma, by integrating proteomic, metabolomic, lipidomic, and post-translational modifications (PTMs) with genomic and transcriptomic measurements to uncover multi-scale regulatory interactions governing tumor development and evolution. Applying 14 proteogenomic and metabolomic platforms to 228 tumors (212 GBM and 16 grade 4 IDH-mutant astrocytoma), including 28 at recurrence, plus 18 normal brain samples and 14 brain metastases as comparators, reveals heterogeneous upstream alterations converging on common downstream events at the proteomic and metabolomic levels and changes in protein-protein interactions and glycosylation site occupancy at recurrence. Recurrent genetic alterations and phosphorylation events on PTPN11 map to important regulatory domains in three dimensions, suggesting a central role for PTPN11 signaling across high-grade gliomas.
Subject(s)
Brain Neoplasms , Glioma , Protein Tyrosine Phosphatase, Non-Receptor Type 11 , Signal Transduction , Humans , Brain Neoplasms/genetics , Brain Neoplasms/pathology , Brain Neoplasms/metabolism , Protein Tyrosine Phosphatase, Non-Receptor Type 11/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 11/metabolism , Glioma/genetics , Glioma/pathology , Glioma/metabolism , Mutation , Proteomics/methods , Protein Processing, Post-Translational , Gene Expression Regulation, Neoplastic , Glioblastoma/genetics , Glioblastoma/pathology , Glioblastoma/metabolism , Phosphorylation , Neoplasm Grading , Isocitrate Dehydrogenase/genetics , Isocitrate Dehydrogenase/metabolismABSTRACT
Growing clinical evidence shows that sulfonylurea therapy for patients with type 2 diabetic mellitus (T2DM) contributes to progressive worsening of their liver. The present study presents hepatotoxicity induced by gliclazide, a second-generation sulfonylurea, and alpha-lipoic acid (ALA) as a novel and promising drug for T2DM treatment. Normal human liver cells (HL-7702) were incubated with high-glucose DMEM in the presence or absence of gliclazide and ALA for 72 h, and cell viability and death were measured by flow cytometry. Next, Sprague-Dawley rats were subjected to 12 h of fasting, and fasting blood glucose was measured. The rats were randomized into four groups: HC (healthy control; n = 7), T2DM (diabetic rats without treatment; n = 9), GLC (diabetic rats with 15 mg/kg gliclazide treatment; n = 7) and GLC+ALA (diabetic rats with gliclazide and 60 mg/kg ALA treatment; n = 7). T2DM was induced by a bolus administration of 110 mg/kg nicotinamide and 55 mg/kg streptozotocin intraperitoneally. The experimental protocol lasted for 6 weeks after which the animals were sacrificed and pancreas, liver and blood samples were collected for biochemical, histological and molecular analyses. Compared to healthy control (HC) group, exposure of HL-7702 cells to high glucose induced significant cell death by 19 % (p < 0.001), which was exacerbated with gliclazide treatment by 29 % (p < 0.0001) but markedly reduced by 6 % to near HC value following ALA treatment. In vivo, GLC-treated rats had severe liver damage characterized by increased hepatocellular vacuolation, and significant expression of ED-1, iNOS and caspase-3 as well as markedly high levels of liver enzymes (aspartate aminotransferase, alanine aminotransferase and alkaline phosphatase compared to T2DM rats. Interestingly, ALA administration prevented these pathological changes and protected the diabetic liver to levels comparable to HC rats. ALA showed hepatoprotective effect against gliclazide-induced hepatotoxicity by suppressing inflammation and apoptosis while activating antioxidant pathway in the diabetic liver. Abbreviations: ALA, Alpha-lipoic acid; ALT, Alanine aminotransferase; ALP, Alkaline phosphatase; AMPK, Adenosine monophosphate-activated protein kinase; AST, Aspartate aminotransferase; ATP, Adenosine triphosphate; DMEM, Dulbecco's Modified Eagle Medium; EDTA, ethylenediaminetetraacetic acid; FBG, Fasting blood glucose; FBS, Fetal bovine serum; GLC, Gliclazide; GLUT4, Glucose transporter type 4; GSH, Glutathione; H&E, Hematoxylin/Eosin; HbA1c, Glycosylated haemoglobin A1c; HC, Healthy control; HG, Hyperglycemic group; HOMA-ß, Homeostasis model assessment of ß-cell function; IL-1ß, Interleukin-1ß; IL-6, Interleukin-6; iNOS, Inducible nitric oxide synthase; KATP, ATP-dependent potassium channels; MDA, Malondialdehyde; MPTP, Mitochondrial permeability transition pore; NO, Nitric oxide; P/S, Penicillin/streptomycin; PAS, Periodic acid-Schiff; RIA, Radioimmunoassay; ROS, Reactive oxygen species; SOD, Superoxide dismutase; T2DM, Type 2 diabetes mellitus; TBARS, Thiobarbituric acid reactive substances; TNF-α, Tumor necrosis factor-alpha.
Subject(s)
Diabetes Mellitus, Experimental , Diabetes Mellitus, Type 2 , Gliclazide , Rats, Sprague-Dawley , Thioctic Acid , Thioctic Acid/pharmacology , Thioctic Acid/therapeutic use , Animals , Gliclazide/pharmacology , Gliclazide/therapeutic use , Humans , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/chemically induced , Diabetes Mellitus, Type 2/drug therapy , Diabetes Mellitus, Type 2/chemically induced , Diabetes Mellitus, Type 2/metabolism , Rats , Male , Glucose/metabolism , Glucose/toxicity , Chemical and Drug Induced Liver Injury/prevention & control , Chemical and Drug Induced Liver Injury/pathology , Chemical and Drug Induced Liver Injury/metabolism , Chemical and Drug Induced Liver Injury/drug therapy , Chemical and Drug Induced Liver Injury/etiology , Liver/drug effects , Liver/pathology , Liver/metabolism , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Cell Line , Hepatocytes/drug effects , Hepatocytes/metabolism , Hepatocytes/pathology , Antioxidants/pharmacology , Antioxidants/therapeutic useABSTRACT
Rovibrational levels of low-lying electronic states of the gas-phase, diatomic molecules, PtH+ and PtH-, are computed on potential-energy functions obtained by using a hybrid spin-orbit configuration-interaction procedure. PtH- has a well-separated Σ0++1 ground state, while the first two electronic states of PtH+ (Σ0++1 and 3Δ3) are nearly degenerate. Combining the experimental photoelectron (PE) spectra of PtH- with theoretical photodetachment spectroscopy leads to an improved value for the electron affinity of PtH, EA(PtH) = (1.617 ± 0.015) eV. When PtH- is a product of photodissociation of PtHCO2-, its PE spectrum is broad because of rotational excitation. Temperature-dependent thermodynamic functions and thermochemistry of dissociation are computed from the theoretical energy levels. Previously published energetic quantities for PtH+ and PtH- are revised. The ground 1Σ+ term of PtH+ is not well described using single-reference theory.
ABSTRACT
Ultra-fast single-photon detectors with high current density and operating temperature can benefit space and ground applications, including quantum optical communication systems, lightweight cryogenics for space crafts, and medical use. Here we demonstrate magnesium diboride (MgB2) thin-film superconducting microwires capable of single-photon detection at 1.55 µm optical wavelength. We used helium ions to alter the properties of MgB2, resulting in microwire-based detectors exhibiting single-photon sensitivity across a broad temperature range of up to 20 K, and detection efficiency saturation for 1 µm wide microwires at 3.7 K. Linearity of detection rate vs incident power was preserved up to at least 100 Mcps. Despite the large active area of up to 400 × 400 µm2, the reset time was found to be as low as ~ 1 ns. Our research provides possibilities for breaking the operating temperature limit and maximum single-pixel count rate, expanding the detector area, and raises inquiries about the fundamental mechanisms of single-photon detection in high-critical-temperature superconductors.
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Acute myeloid leukemia is a poor-prognosis cancer commonly stratified by genetic aberrations, but these mutations are often heterogeneous and fail to consistently predict therapeutic response. Here, we combine transcriptomic, proteomic, and phosphoproteomic datasets with ex vivo drug sensitivity data to help understand the underlying pathophysiology of AML beyond mutations. We measure the proteome and phosphoproteome of 210 patients and combine them with genomic and transcriptomic measurements to identify four proteogenomic subtypes that complement existing genetic subtypes. We build a predictor to classify samples into subtypes and map them to a "landscape" that identifies specific drug response patterns. We then build a drug response prediction model to identify drugs that target distinct subtypes and validate our findings on cell lines representing various stages of quizartinib resistance. Our results show how multiomics data together with drug sensitivity data can inform therapy stratification and drug combinations in AML.
Subject(s)
Leukemia, Myeloid, Acute , Proteogenomics , Humans , Proteomics/methods , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/genetics , Leukemia, Myeloid, Acute/metabolism , Genomics/methods , MutationABSTRACT
OBJECTIVES: Determination of bone marrow cellularity is a key part of bone marrow examination because it provides a small window into a patient's current state of hematopoietic well-being. Traditionally, bone marrow cellularity is estimated semiquantitatively through microscopic examination of core biopsy specimens harvested from the iliac crest of the pelvic bone. Bone marrow cellularity is then designated as hypercellular, normocellular, or hypocellular based on the patient's age. This assessment can have significant clinical impact, but the variation in the age-adjusted normocellularity range is not sufficiently characterized because of a lack of study data, especially in older patients (those older than 70 years of age). This study further established the normal range of bone marrow cellularity, particularly in older adults. METHODS: In this study, 570 benign staging and healthy donor bone marrows from patients 1 year to 93 years of age were analyzed for cellularity. RESULTS: Linear regression modeling demonstrates that cellularity in adults declines approximately 3% per decade, including after the seventh decade of life. The 90% reference interval for normocellularity in United States is 30% to 75% for those aged 18 to 90 years. CONCLUSIONS: The findings revealed a more stable and slower rate of decline in cellularity with age in adults than the widely used linear model of "100% minus the patient age in decades." Normocellularity is better modeled based on age group. In those younger than 20 years of age, normocellularity ranges from 45% to 85% (mean [SD], 65% [20%]), as defined by Friebert et al in 1998. Based on our study finding of a little less than 3% decline per decade of age, the following is our recommendation for normocellularity range: For individuals 20 to 40 years of age, it ranges from 40% to 70% (mean [SD], 55% [15%]); for individuals 40 to 60 years of age, it ranges from 35% to 65% (mean [SD], 50% [15%]); and for individuals older than 60 years of age, it ranges from 30% to 60% (mean [SD], 45% [15%]). Interestingly, those older than 70 years of age do not show a significant decrease from those aged 60 to 69 years.
Subject(s)
Bone Marrow Cells , Bone Marrow , Humans , Aged , Young Adult , Adult , Infant , Bone Marrow/pathology , Bone Marrow Examination , Bone Marrow Cells/pathology , Biopsy, Large-Core Needle , Hyperplasia/pathologyABSTRACT
Microglia, the innate immune cells of the central nervous system, have been genetically implicated in multiple neurodegenerative diseases. We previously mapped the genetic regulation of gene expression and mRNA splicing in human microglia, identifying several loci where common genetic variants in microglia-specific regulatory elements explain disease risk loci identified by GWAS. However, identifying genetic effects on splicing has been challenging due to the use of short sequencing reads to identify causal isoforms. Here we present the isoform-centric microglia genomic atlas (isoMiGA) which leverages the power of long-read RNA-seq to identify 35,879 novel microglia isoforms. We show that the novel microglia isoforms are involved in stimulation response and brain region specificity. We then quantified the expression of both known and novel isoforms in a multi-ethnic meta-analysis of 555 human microglia short-read RNA-seq samples from 391 donors, the largest to date, and found associations with genetic risk loci in Alzheimer's disease and Parkinson's disease. We nominate several loci that may act through complex changes in isoform and splice site usage.
ABSTRACT
Microbial response to changing environmental factors influences the fate of soil organic carbon, and drought has been shown to affect microbial metabolism and respiration. We hypothesized that the access of microbes to different carbon pools in response to dry-rewet events occurs sequentially at different rates. We amended desiccated soils with 13C-labeled glucose and measured the rates of 12CO2 and 13CO2 respiration in real time after rewetting. Using these differentiated 12CO2 and 13CO2 respiration rate soils after rewetting, we were able to deduce when microbes are accessing different pools of carbon. Immediately upon rewetting, respiration of 12CO2 occurred first, with negligible 13CO2 respiration. Appreciable metabolism and respiration of the added 13C glucose did not occur until 15 min after rewetting. We conclude that, while all carbon pools are being accessed in the first 9 h after rewetting, the rate and timing at which new and existing carbon pools are being accessed varies. Within this study, using stable isotope-labeled substrates to discern which carbon pools are metabolized first uniquely illustrates how microorganisms access different carbon pools which has implications into understanding how carbon metabolism can further affect climate, carbon sequestration, and soil health.
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Barzykowski and Moulin's view on involuntary autobiographical memory focuses on automatic activation of representations and inhibitory control mechanisms. We discuss how and when a known neural mechanism - pattern completion - may result in involuntary autobiographical memories, the types of cues that may elicit this phenomenon and consider interactions with future-oriented cognition.
Subject(s)
Cues , Memory, Episodic , Humans , Mental Recall/physiology , CognitionABSTRACT
BACKGROUND: Physiological and biochemical processes across tissues of the body are regulated in response to the high demands of intense physical activity in several occupations, such as firefighting, law enforcement, military, and sports. A better understanding of such processes can ultimately help improve human performance and prevent illnesses in the work environment. METHODS: To study regulatory processes in intense physical activity simulating real-life conditions, we performed a multi-omics analysis of three biofluids (blood plasma, urine, and saliva) collected from 11 wildland firefighters before and after a 45 min, intense exercise regimen. Omics profiles post- versus pre-exercise were compared by Student's t-test followed by pathway analysis and comparison between the different omics modalities. RESULTS: Our multi-omics analysis identified and quantified 3835 proteins, 730 lipids and 182 metabolites combining the 3 different types of samples. The blood plasma analysis revealed signatures of tissue damage and acute repair response accompanied by enhanced carbon metabolism to meet energy demands. The urine analysis showed a strong, concomitant regulation of 6 out of 8 identified proteins from the renin-angiotensin system supporting increased excretion of catabolites, reabsorption of nutrients and maintenance of fluid balance. In saliva, we observed a decrease in 3 pro-inflammatory cytokines and an increase in 8 antimicrobial peptides. A systematic literature review identified 6 papers that support an altered susceptibility to respiratory infection. CONCLUSION: This study shows simultaneous regulatory signatures in biofluids indicative of homeostatic maintenance during intense physical activity with possible effects on increased infection susceptibility, suggesting that caution against respiratory diseases could benefit workers on highly physical demanding jobs.
Subject(s)
Exercise , Multiomics , Humans , Exercise/physiology , CytokinesABSTRACT
BACKGROUND: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and fibromyalgia have overlapping neurologic symptoms particularly disabling fatigue. This has given rise to the question whether they are distinct central nervous system (CNS) entities or is one an extension of the other. MATERIAL AND METHODS: To investigate this, we used unbiased quantitative mass spectrometry-based proteomics to examine the most proximal fluid to the brain, cerebrospinal fluid (CSF). This was to ascertain if the proteome profile of one was the same or different from the other. We examined two separate groups of ME/CFS, one with (n = 15) and one without (n = 15) fibromyalgia. RESULTS: We quantified a total of 2083 proteins using immunoaffinity depletion, tandem mass tag isobaric labelling and offline two-dimensional liquid chromatography coupled to tandem mass spectrometry, including 1789 that were quantified in all the CSF samples. ANOVA analysis did not yield any proteins with an adjusted p value <.05. CONCLUSION: This supports the notion that ME/CFS and fibromyalgia as currently defined are not distinct entities.Key messageME/CFS and fibromyalgia as currently defined are not distinct entities.Unbiased quantitative mass spectrometry-based proteomics can be used to discover cerebrospinal fluid proteins that are biomarkers for a condition such as we are studying.
Subject(s)
Fatigue Syndrome, Chronic , Fibromyalgia , Humans , Proteome , Fatigue Syndrome, Chronic/diagnosis , Fibromyalgia/diagnosis , Central Nervous System , BrainABSTRACT
OBJECTIVES: To assess objectively the course of the anterior cerebral artery (ACA) by measuring its distance to the tela choroidea in the midsagittal view, and to compare this distance in normal fetuses with that in those with agenesis of the corpus callosum (ACC), a condition known to be associated with an abnormal course of the ACA. METHODS: The tela-choroidea-to-anterior-cerebral-artery distance (TACAD) was measured in the midsagittal view of the brain on color Doppler, between the anterior border of the tela choroidea and the ACA at the level of the callosal genu. Reference ranges in relation to gestational age were established in a prospective, cross-sectional study of 253 normal healthy fetuses between 19 and 36 weeks of gestation. The study group included fetuses with complete ACC (n = 28) or partial ACC (n = 18). RESULTS: TACAD of normal fetuses showed an increase during the second half of pregnancy, with a mean value of 10.1 mm and 14.2 mm at 22 and 30 weeks of gestation, respectively. All (28/28) fetuses with complete ACC and 83% (15/18) of those with partial ACC had significantly shorter TACAD, with mean values of 3.9 mm and 6.6 mm, respectively. CONCLUSIONS: TACAD is a measurement that is simple to obtain during fetal color Doppler neurosonography, which enables quantification of the course of the ACA and pericallosal artery. TACAD is shorter in fetuses with complete or partial ACC than in normal fetuses and provides an objective, quantifiable value, rather than merely descriptive information. © 2023 The Authors. Ultrasound in Obstetrics & Gynecology published by John Wiley & Sons Ltd on behalf of International Society of Ultrasound in Obstetrics and Gynecology.
Subject(s)
Anterior Cerebral Artery , Corpus Callosum , Female , Pregnancy , Humans , Corpus Callosum/diagnostic imaging , Anterior Cerebral Artery/diagnostic imaging , Cross-Sectional Studies , Prospective Studies , Ultrasonography, Prenatal , Retrospective Studies , Agenesis of Corpus Callosum/diagnostic imaging , Fetus , Gestational AgeABSTRACT
BACKGROUND: TAVI is a widely accepted treatment for patients with severe aortic stenosis (AS). Despite the adoption of diverse therapies, opportunities remain to develop technologies tailored to provide optimal acute and potential long-term benefits, particularly around haemodynamics, flow and durability. AIMS: We aimed to evaluate the safety and feasibility of the DurAVR transcatheter heart valve (THV), a first-in-class biomimetic valve, in the treatment of patients with symptomatic severe AS. METHODS: This was a first-in-human (FIH), prospective, non-randomised, single-arm, single-centre study. Patients with severe, symptomatic AS of any surgical risk and who were eligible for the DurAVR THV prosthesis were recruited; they were assessed at baseline, 30 days, 6 months, and 1 year post-procedure for implant success, haemodynamic performance, and safety. RESULTS: Thirteen patients (73.9±6.4 years old, 77% female) were enrolled. The DurAVR THV was successfully implanted in 100% of cases with no device-related complications. One access site complication, one permanent pacemaker implantation, and one case of moderate aortic regurgitation occurred. Otherwise, no deaths, stroke, bleeding, reinterventions, or myocardial infarction were reported during any of the follow-up visits. Despite a mean annulus size of 22.95±1.09 mm, favourable haemodynamic results were observed at 30 days (effective orifice area [EOA] 2.00±0.17 cm2, and mean pressure gradient [MPG] 9.02±2.68 mmHg) and were sustained at 1 year (EOA 1.96±0.11 cm2, MPG 8.82±1.38 mmHg), resulting in zero patients with any degree of prosthesis-patient mismatch. Additionally, new valve performance measures derived from cardiovascular magnetic resonance displayed restoration of laminar flow, consistent with a predisease state, in conjunction with a mean coaptation length of 8.3±1.7 mm. CONCLUSIONS: Preliminary results from the FIH study with DurAVR THV demonstrate a good safety profile with promising haemodynamic performance sustained at 1 year and restoration of near-normal flow dynamics. Further clinical investigation is warranted to evaluate how DurAVR THV may play a role in addressing the challenge of lifetime management in AS patients.
Subject(s)
Aortic Valve Stenosis , Heart Valve Prosthesis , Transcatheter Aortic Valve Replacement , Humans , Female , Aged , Aged, 80 and over , Male , Aortic Valve/diagnostic imaging , Aortic Valve/surgery , Transcatheter Aortic Valve Replacement/adverse effects , Transcatheter Aortic Valve Replacement/methods , Aortic Valve Stenosis/surgery , Prospective Studies , Feasibility Studies , Biomimetics , Treatment Outcome , Prosthesis DesignABSTRACT
Among all RNA viruses, coronavirus RNA transcription is the most complex and involves a process termed "discontinuous transcription" that results in the production of a set of 3'-nested, co-terminal genomic and subgenomic RNAs during infection. While the expression of the classic canonical set of subgenomic RNAs depends on the recognition of a 6- to 7-nt transcription regulatory core sequence (TRS), here, we use deep sequence and metagenomics analysis strategies and show that the coronavirus transcriptome is even more vast and more complex than previously appreciated and involves the production of leader-containing transcripts that have canonical and noncanonical leader-body junctions. Moreover, by ribosome protection and proteomics analyses, we show that both positive- and negative-sense transcripts are translationally active. The data support the hypothesis that the coronavirus proteome is much vaster than previously noted in the literature.
ABSTRACT
Rovibrational levels of low-lying electronic states of the diatomic molecule PtH are computed using non-relativistic wavefunction methods and a relativistic core pseudopotential. Dynamical electron correlation is treated at the coupled-cluster with single and double excitations and a perturbative estimate of triple excitations level, with basis-set extrapolation. Spin-orbit coupling is treated by configuration interaction in a basis of multireference configuration interaction states. The results compare favorably with available experimental data, especially for low-lying electronic states. For the yet-unobserved first excited state, Ω = 1/2, we predict constants including Te = (2036 ± 300) cm-1 and ΔG1/2 = (2252.5 ± 8) cm-1. Temperature-dependent thermodynamic functions, and thermochemistry of dissociation, are computed from the spectroscopic data. The ideal-gas enthalpy of formation is ΔfH298.15o(PtH) = (449.1 ± 4.5) kJ mol-1 (uncertainties expanded by k = 2). The experimental data are reinterpreted, using a somewhat speculative procedure, to yield the bond length Re = (1.5199 ± 0.0006) Å.
ABSTRACT
Background: While hypertension is a modifiable risk factor of Alzheimer's disease and related dementias (ADRD), limited studies have been conducted on the effectiveness of antihypertensive medications (AHMs) in altering the progression from mild cognitive impairment (MCI) to ADRD; similarly, few studies have assessed drug-drug interactions of AHMs with drugs targeted to modify other risk factors of ADRD such as type II diabetes and hypercholesterolemia. Method: 128,683 unique hypertensive patients with MCI on US-based Optum claims data were identified. Diuretics, beta blockers (BBs), calcium channel blockers (CCBs), angiotensin-converting enzyme inhibitors (ACE inhibitors), and angiotensin II receptor antagonists (ARBs) were identified as five major AHM classes. Baseline characteristics were compared. Cox proportional hazards (PH) models were used to study the association between specific AHM exposure and the progression from MCI to ADRD while controlling for demographic variables, comorbidities, and the use of Statins and Metformin. To examine the association of AHM-Statin or AHM-Metformin interaction with ADRD progression, we also investigated models controlling for the aforementioned confounders, as well as drug-drug interactions. Result: The study included 100,678 patients who were taking at least one class of AHM and 28,005 who were not taking any AHMs during the study period. AHM users had a higher incidence of comorbidities (all P≤0.039) and consumption of Metformin and Statins (both P<0.001) compared to non-users. Users of each major AHM class showed significantly lower risk of developing ADRD compared to non-users of that specific drug class (adjusted hazard ratio (aHR): 0.96-0.98; all P≤0.048). Within patients on monotherapy (using only one AHM drug), no specific AHM class had significantly lower risk of ADRD diagnosis compared to other AHM drug classes (aHR: 0.97-1.11; all P≥0.053). Use of Diuretics or CCBs in combination with Metformin consumption (aHR: 0.89, 0.91, respectively) showed lower risk of MCI to ADRD progression than use without Metformin consumption (aHR: 0.97, 0.98, respectively), whereas use of any of the five major AHMs with Statin consumption (aHR: 0.91-0.94) all showed lower risk than without Statin consumption (aHR: 0.98-1.04). Conclusion: All five major AHM classes showed a protective effect against ADRD progression among hypertensive patients with MCI. Also, certain combinations of AHMs with Metformin or Statins showed a stronger protective effect compared to AHMs alone, and some drug-drug interactions of AHM-Metformin or AHM-Statin also showed protective effects against progression from MCI to ADRD.
ABSTRACT
Introduction Radiation safety training remains variable among gastroenterologists performing endoscopic retrograde cholangiopancreatography (ERCP). This study sought to ascribe dosimeter readings to various real-world ERCP scenarios to provide data supporting the 3 pillars of radiation safety: distance, time, and shielding. Methods An ERCP fluoroscopy unit was used to generate radiation scatter from 2 differently sized anthropomorphic phantoms. Radiation scatter was measured at various distances from the emitter, with and without a lead apron, and at various frame rates (measured in frames per second, fps) and degrees of fluoroscopy pedal actuation. An image quality phantom was used to assess resolution at various frame rates and air gaps. Results Increasing the distance resulted in a decrease in measured scatter (from 0.75 mR/h at 1.5 ft to 0.15 mR/h at 9 ft with the average phantom and from 50 mR/h at 1.5 ft to 3.06 mR/h at 9 ft with the large phantom). Depressing the fluoroscopy pedal less frequently, or decreasing the frame rate (ie, increasing the time per frame), resulted in a linear decrease in scatter (from 55 mR/h at 8 fps to 24.5 mR/h at 4 fps and 13.60 mR/h at 2 fps). Providing shielding through the presence of a 0.5-mm lead apron reduced scatter (from 4.10 to 0.11 mR/h with the average phantom; from 15.30 mR/h to 0.43 mR/h with the large phantom). However, decreasing the frame rate from 8 fps to 2 fps did not change the number of line pairs identified on the image phantom. A greater air gap increased the number of line pairs resolved. Conclusions Implementing the 3 pillars of radiation safety led to a quantifiable, clinically significant decrease in radiation scatter. The authors hope that these findings spark greater implementation of radiation safety measures among practitioners utilizing fluoroscopy.
Subject(s)
Cholangiopancreatography, Endoscopic Retrograde , Radiation Protection , Humans , Cholangiopancreatography, Endoscopic Retrograde/adverse effects , Radiation Dosage , Radiation Protection/methods , Fluoroscopy/adverse effects , Phantoms, ImagingABSTRACT
Children born preterm are at increased risk for autism spectrum disorder (ASD). There is limited knowledge about whether ASD phenotypes in children born preterm differ from children born at term. The objective of this study was to compare ASD core symptoms and associated characteristics among extremely preterm (EP) and term-born children with ASD. EP participants (n = 59) from the Extremely Low Gestational Age Newborn Study who met diagnostic criteria for ASD at approximately 10 years of age were matched with term-born participants from the Simons Simplex Collection on age, sex, spoken language level, and nonverbal IQ. Core ASD symptomatology was evaluated with the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Schedule (ADOS). Developmental milestones, anthropometrics, seizure disorder, and psychiatric symptoms were also investigated. The EP group had lower parent-reported symptom scores on ADI-R verbal communication, specifically stereotyped language, and restricted, repetitive behaviors. There were no between-group differences on ADI-R nonverbal communication and ADI-R reciprocal social interaction or with direct observation on the ADOS-2. The EP group was more likely to have delayed speech milestones and lower physical growth parameters. Results from female-only analyses were similar to those from whole-group analyses. In sum, behavioral presentation was similar between EP and IQ- and sex-matched term-born children assessed at age 10 years, with the exception of less severe retrospectively reported stereotyped behaviors, lower physical growth parameters, and increased delays in language milestones among EP-born children with ASD.