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The 20S proteasome is a multimeric protease complex that is essential for proteostasis in the cell. Small molecule proteasome inhibitors are approved drugs for various cancers and are advancing clinically as antiparasitics. Although tools and technologies to study the 20S proteasome have advanced, only one probe is commercially available to image proteasome activity. This probe consists of a fluorescently labeled, peptidyl vinyl sulfone that binds to one or more of the catalytic proteasome subunits. Here, we synthesized two, active site-directed epoxyketone probes, LJL-1 and LJL-2, that were based on the peptidyl backbones of the anticancer drugs, carfilzomib and bortezomib, respectively. Each probe was conjugated, via click chemistry, to a bifunctional group comprising 5-carboxytetramethylrhodamine (TAMRA) and biotin to, respectively, visualize and enrich the 20S proteasome from protein extracts of two eukaryotic pathogens, Leishmania donovani and Trichomonas vaginalis. Depending on species, each probe generated a different subunit-binding profile by sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE), and the biotin tag enabled the enrichment of the bound subunits which were then formally identified by proteomics. Species differences in the order of electrophoretic migration by the ß subunits were also noted. Finally, both probes reacted specifically with the 20S subunits in contrast to the commercial vinyl sulfone probe that cross reacted with cysteine proteases. LJL-1 and LJL-2 should find general utility in the identification and characterization of pathogen proteasomes, and serve as reagents to evaluate the specificity and mechanism of binding of new antiparasitic proteasome inhibitors.
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Interictal high-frequency oscillation (HFO) is a promising biomarker of the epileptogenic zone (EZ). However, objective definitions to distinguish between pathological and physiological HFOs have remained elusive, impeding HFOs' clinical applications. We employed self-supervised deep generative variational autoencoders to learn such discriminative HFO features directly from their morphologies in a data-driven manner. We studied a large retrospective cohort of 185 patients who underwent intracranial monitoring and analyzed 686,410 candidate HFO events collected from 18,265 brain contacts across diverse brain regions. The model automatically clustered HFOs into distinct morphological groups in the latent space. One cluster consisted of putative morphologically defined pathological HFOs (mpHFOs): HFOs in that cluster were observed to be associated with spikes and exhibited high signal intensity both in the HFO band (>80 Hz) at detection and in the sub-HFO band (10-80 Hz) surrounding the detection and were primarily localized in the seizure onset zone (SOZ). Moreover, resection of brain regions based on a higher prevalence of interictal mpHFOs better predicted postoperative seizure outcomes than current clinical standards based on SOZ removal. Our self-supervised, explainable, deep generative model distills pathological HFOs and thus potentially helps delineate the EZ purely from interictal intracranial EEG data.
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Schistosomiasis is a neglected disease of poverty that affects over 200 million people worldwide and relies on a single drug for therapy. The cathepsin B1 cysteine protease (SmCB1) of Schistosoma mansoni has been investigated as a potential target. Here, a structure-based pharmacophore virtual screening (VS) approach was used on a data set of approved drugs to identify potential antischistosomal agents targeting SmCB1. Pharmacophore (PHP) models underwent validation through receiver operating characteristics curves achieving values >0.8. The data highlighted riboflavin (RBF) as a compound of particular interest. A 1 µs molecular dynamics simulation demonstrated that RBF altered the conformation of SmCB1, causing the protease's binding site to close around RBF while maintaining the protease's overall integrity. RBF inhibited the activity of SmCB1 at low micromolar values and killed the parasite in vitro. Finally, in a murine model of S. mansoni infection, oral administration of 100 mg/kg RBF for 7 days significantly decreased worm burdens by â¼20% and had a major impact on intestinal and fecal egg burdens, which were decreased by â¼80%.
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BACKGROUND: Cancer patients with diabetes are at increased risk for cardiovascular diseases due to common risk factors and well-documented drug-associated cardiotoxicity. Sodium-glucose cotransporter-2 (SGLT2) inhibitors have shown cardiovascular benefits in patients with diabetes, but their effects on cancer patients remain unclear. This study aimed to evaluate the cardiovascular outcomes associated with SGLT2 inhibitor therapy in patients with concomitant diabetes and cancer. METHODS: We conducted a systematic review and meta-analysis of cohort studies comparing cardiovascular outcomes between cancer patients with diabetes receiving SGLT2 inhibitors and those not receiving SGLT2 inhibitors. PubMed, Embase, and the Cochrane Library were searched from inception to February 29, 2024. The primary outcome was all-cause mortality, and the secondary outcomes were heart failure hospitalization, and adverse events. Random-effect models were used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Subgroup and sensitivity analyses were conducted to identify potential sources of heterogeneity and explore the effect of SGLT2 inhibitors on mitigating cardiotoxicity. RESULTS: Nine cohort studies involving 82,654 patients were included. SGLT2 inhibitor use was associated with a significantly lower risk of all-cause mortality (RR 0.46, 95% CI 0.31-0.68, P < 0.0001; I2 = 98%) and heart failure hospitalization (RR 0.49, 95% CI 0.30-0.81, P = 0.006; I2 = 21%) compared to non-use. The mortality benefit remained significant in patients receiving anthracycline chemotherapy (RR 0.50, 95% CI 0.28-0.89, P = 0.02; I2 = 71%). SGLT2 inhibitor use was also associated with a lower risk of sepsis (RR 0.32, 95% CI 0.23-0.44, P < 0.00001; I2 = 0%) and no increased risk of diabetic ketoacidosis (RR 0.66, 95% CI 0.20-2.16, P = 0.49; I2 = 0%). CONCLUSIONS: SGLT2 inhibitor therapy is associated with lower risks of all-cause mortality and heart failure hospitalization in patients with concomitant diabetes and cancer. These findings suggest that SGLT2 inhibitors may offer cardiovascular benefits in this high-risk population. Randomized controlled trials are needed to validate these findings and evaluate the safety and efficacy of SGLT2 inhibitors in specific cancer types and treatment regimens.
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Objective. This study aims to develop and validate an end-to-end software platform, PyHFO, that streamlines the application of deep learning (DL) methodologies in detecting neurophysiological biomarkers for epileptogenic zones from EEG recordings.Approach. We introduced PyHFO, which enables time-efficient high-frequency oscillation (HFO) detection algorithms like short-term energy and Montreal Neurological Institute and Hospital detectors. It incorporates DL models for artifact and HFO with spike classification, designed to operate efficiently on standard computer hardware.Main results. The validation of PyHFO was conducted on three separate datasets: the first comprised solely of grid/strip electrodes, the second a combination of grid/strip and depth electrodes, and the third derived from rodent studies, which sampled the neocortex and hippocampus using depth electrodes. PyHFO demonstrated an ability to handle datasets efficiently, with optimization techniques enabling it to achieve speeds up to 50 times faster than traditional HFO detection applications. Users have the flexibility to employ our pre-trained DL model or use their EEG data for custom model training.Significance. PyHFO successfully bridges the computational challenge faced in applying DL techniques to EEG data analysis in epilepsy studies, presenting a feasible solution for both clinical and research settings. By offering a user-friendly and computationally efficient platform, PyHFO paves the way for broader adoption of advanced EEG data analysis tools in clinical practice and fosters potential for large-scale research collaborations.
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Aprendizaje Profundo , Electroencefalografía , Electroencefalografía/métodos , Electroencefalografía/instrumentación , Animales , Ratas , Algoritmos , Epilepsia/fisiopatología , Epilepsia/diagnóstico , Programas Informáticos , Humanos , Hipocampo/fisiologíaRESUMEN
BACKGROUND: The healing process after a myocardial infarction (MI) in humans involves complex events that replace damaged tissue with a fibrotic scar. The affected cardiac tissue may lose its function permanently. In contrast, zebrafish display a remarkable capacity for scar-free heart regeneration. Previous studies have revealed that syndecan-4 (SDC4) regulates inflammatory response and fibroblast activity following cardiac injury in higher vertebrates. However, whether and how Sdc4 regulates heart regeneration in highly regenerative zebrafish remains unknown. METHODS AND RESULTS: This study showed that sdc4 expression was differentially regulated during zebrafish heart regeneration by transcriptional analysis. Specifically, sdc4 expression increased rapidly and transiently in the early regeneration phase upon ventricular cryoinjury. Moreover, the knockdown of sdc4 led to a significant reduction in extracellular matrix protein deposition, immune cell accumulation, and cell proliferation at the lesion site. The expression of tgfb1a and col1a1a, as well as the protein expression of Fibronectin, were all down-regulated under sdc4 knockdown. In addition, we verified that sdc4 expression was required for cardiac repair in zebrafish via in vivo electrocardiogram analysis. Loss of sdc4 expression caused an apparent pathological Q wave and ST elevation, which are signs of human MI patients. CONCLUSIONS: Our findings support that Sdc4 is required to mediate pleiotropic repair responses in the early stage of zebrafish heart regeneration.
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Corazón , Regeneración , Sindecano-4 , Pez Cebra , Animales , Pez Cebra/genética , Pez Cebra/metabolismo , Sindecano-4/genética , Sindecano-4/metabolismo , Regeneración/genética , Corazón/fisiología , Corazón/fisiopatología , Proteínas de Pez Cebra/genética , Proteínas de Pez Cebra/metabolismo , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Proliferación Celular/genética , Miocardio/metabolismo , Miocardio/patología , Técnicas de Silenciamiento del GenRESUMEN
Schistosomiasis, or bilharzia, is a neglected tropical disease caused by Schistosoma spp. blood flukes that infects over 200 million people worldwide. Just one partially effective drug is available, and new drugs and drug targets would be welcome. The 20S proteasome is a validated drug target for many parasitic infections, including those caused by Plasmodium and Leishmania. We previously showed that anticancer proteasome inhibitors that act through the Schistosoma mansoni 20S proteasome (Sm20S) kill the parasite in vitro. To advance these initial findings, we employed Multiplex Substrate Profiling by Mass Spectrometry (MSP-MS) to define the substrate cleavage specificities of the three catalytic ß subunits of purified Sm20S. The profiles in turn were used to design and synthesize subunit-specific optimized substrates that performed two to eight fold better than the equivalent substrates used to measure the activity of the constitutive human proteasome (c20S). These specific substrates also eliminated the need to purify Sm20S from parasite extracts - a single step enrichment was sufficient to accurately measure substrate hydrolysis and its inhibition with proteasome inhibitors. Finally, we show that the substrate and inhibition profiles for the 20S proteasome from the three medically important schistosome species are similar, suggesting that data arising from an inhibitor development campaign that focuses on Sm20S can be extrapolated to the other two targets with consequent time and cost savings.
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Studies have shown that depending on the substitution pattern, microtubule (MT)-targeting 1,2,4-triazolo[1,5-a]pyrimidines (TPDs) can produce different cellular responses in mammalian cells that may be due to these compounds interacting with distinct binding sites within the MT structure. Selected TPDs are also potently bioactive against the causative agent of human African trypanosomiasis, Trypanosoma brucei, both inâ vitro and inâ vivo. So far, however, there has been no direct evidence of tubulin engagement by these TPDs in T. brucei. Therefore, to enable further investigation of anti-trypanosomal TPDs, a TPD derivative amenable to photoaffinity labeling (PAL) was designed, synthesized, and evaluated in PAL experiments using HEK293 cells and T. brucei. The data arising confirmed specific labeling of T. brucei tubulin. In addition, proteomic data revealed differences in the labeling profiles of tubulin between HEK293 and T. brucei, suggesting structural differences between the TPD binding site(s) in mammalian and trypanosomal tubulin.
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Tripanocidas , Trypanosoma brucei brucei , Tripanosomiasis Africana , Animales , Humanos , Tubulina (Proteína)/metabolismo , Células HEK293 , Proteómica , Tripanosomiasis Africana/tratamiento farmacológico , Trypanosoma brucei brucei/metabolismo , Pirimidinas/química , Tripanocidas/química , Mamíferos/metabolismoRESUMEN
Herbicide and pesticide exposure [e.g., agent orange (AO)] is associated with an increased risk of multiple myeloma (MM) due to the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). However, it is unclear whether TCDD/AO exposure (AO exposure hereafter) increases the risk of progression of monoclonal gammopathy of undetermined significance (MGUS) to MM. We sought to evaluate the association in a nationwide study of US Veterans. A natural language processing algorithm was used to confirm MGUS and progression to MM. We included Veterans who were diagnosed with MGUS from 10/1/1999 to 12/31/2021 and served during the Vietnam War Era from 1/9/1962 to 5/7/1975. AO exposure was stratified according to three TCDD exposure levels: high (1/9/1962-11/30/1965), medium (12/1/1965-12/31/1970), or low (1/1/1971-5/7/1975). The association between AO exposure and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. The analytic cohort included 10,847 Veterans with MGUS, of whom 26.3% had AO exposure and 7.4% progressed to MM over a median follow-up of 5.2 years. In multivariable analysis, high exposure was associated with an increased progression rate (multivariable-adjusted hazard ratio 1.48; 95% confidence interval 1.02-2.16), compared to Veterans with no exposure. This information is critical to inform progression risk in patients diagnosed with MGUS and prior AO exposure. It is also applicable to MGUS patients with occupational TCDD exposure from herbicides and pesticides.
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Herbicidas , Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Dibenzodioxinas Policloradas , Veteranos , Humanos , Mieloma Múltiple/inducido químicamente , Mieloma Múltiple/epidemiología , Gammopatía Monoclonal de Relevancia Indeterminada/inducido químicamente , Gammopatía Monoclonal de Relevancia Indeterminada/epidemiología , Agente Naranja , Vietnam , Herbicidas/efectos adversos , Dibenzodioxinas Policloradas/toxicidadRESUMEN
Initial results of the phase I trial of talquetamab, a bispecific antibody targeting GPRC5D and CD3, were reported in December of 2022 for the treatment of relapsed or refractory multiple myeloma in the fourth line or later setting. It demonstrated a similar efficacy profile and durability of response to teclistamab, the first bispecific antibody therapy to be approved in multiple myeloma. Additionally, it has less infections than teclistamab but demonstrates unique class-specific side effects including skin, oral, and nail-related adverse events. Despite this, it is still a highly efficacious and well-tolerated therapy that will add to the armamentarium of therapeutics against heavily pretreated multiple myeloma.
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Anticuerpos Biespecíficos , Mieloma Múltiple , Neoplasias de Células Plasmáticas , Humanos , Mieloma Múltiple/tratamiento farmacológico , Anticuerpos Biespecíficos/uso terapéutico , PielRESUMEN
ABSTRACT: Idecabtagene vicleucel (ide-cel) was the first chimeric antigen receptor T-cell therapy to gain US Food and Drug Administration approval for patients with relapsed/refractory multiple myeloma (RRMM). The clinical outcomes of standard of care (SOC) ide-cel in racially and ethnically diverse populations have been understudied. This study pooled data from 207 patients with RRMM (28% patients of racial and ethnic minority groups) treated with SOC ide-cel across 11 institutions to examine racial and ethnic differences in the incidence of toxicities and adverse events, response to ide-cel, and survival. This study included 22 (11%) Hispanic, 36 (17%) non-Hispanic Black, and 149 (72%) non-Hispanic White patients with RRMM. Compared with Hispanic and non-Hispanic White patients, non-Hispanic Black patients had higher median levels of C-reactive protein (1.0, 0.8, and 3.5 mg/dL, respectively; P = .02) and baseline ferritin (362.0 vs 307.0 vs 680.5, respectively; P = .08) and were more likely to develop cytokine release syndrome (77%, 85%, and 97%, respectively; P = .04). Although best overall response rate was lower among Hispanic patients (59%) than among non-Hispanic Black (86%) and White patients (86%; P = .01), there were no racial and ethnic differences in progression-free or overall survival. We provide, to our knowledge, the first and largest investigation of clinical outcomes of SOC ide-cel by race and ethnicity. Despite differences in safety and response to ide-cel, our findings encourage the use of ide-cel in all patients with RRMM. These findings should be confirmed in larger samples of diverse patients with RRMM, with longer follow-up time.
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Mieloma Múltiple , Neoplasias de Células Plasmáticas , Estados Unidos , Humanos , Mieloma Múltiple/terapia , Inmunoterapia Adoptiva/efectos adversos , Etnicidad , Grupos MinoritariosRESUMEN
BACKGROUND: Beam modifying accessories for proton therapy often need to be placed in close proximity of the patient for optimal dosimetry. However, proton treatment units are larger in size and as a result the planned treatment geometry may not be achievable due to collisions with the patient. A framework that can accurately simulate proton treatment geometry is desired. PURPOSE: A quantitative framework was developed to model patient-specific proton treatment geometry, minimize air gap, and avoid collisions. METHODS: The patient's external contour is converted into the International Electrotechnique Commission (IEC) gantry coordinates following the patient's orientation and each beam's gantry and table angles. All snout components are modeled by three-dimensional (3D) geometric shapes such as columns, cuboids, and frustums. Beam-specific parameters such as isocenter coordinates, snout type and extension are used to determine if any point on the external contour protrudes into the various snout components. A 3D graphical user interface is also provided to the planner to visualize the treatment geometry. In case of a collision, the framework's analytic algorithm quantifies the maximum protrusion of the external contour into the snout components. Without a collision, the framework quantifies the minimum distance of the external contour from the snout components and renders a warning if such distance is less than 5 cm. RESULTS: Three different snout designs are modeled. Examples of potential collision and its aversion by snout retraction are demonstrated. Different patient orientations, including a sitting treatment position, as well as treatment plans with multiple isocenters, are successfully modeled in the framework. Finally, the dosimetric advantage of reduced air gap enabled by this framework is demonstrated by comparing plans with standard and reduced air gaps. CONCLUSION: Implementation of this framework reduces incidence of collisions in the treatment room. In addition, it enables the planners to minimize the air gap and achieve better plan dosimetry.
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Terapia de Protones , Humanos , Protones , Algoritmos , Planificación de la Radioterapia Asistida por Computador/métodos , Dosificación RadioterapéuticaRESUMEN
PURPOSE: To develop and validate natural language processing (NLP)-assisted machine learning (ML)-based classification models to confirm diagnoses of monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) from electronic health records (EHRs) in the Veterans Health Administration (VHA). MATERIALS AND METHODS: We developed precompiled lexicons and classification rules as features for the following ML classifiers: logistic regression, random forest, and support vector machines (SVMs). These features were trained on 36,044 EHR documents from a random sample of 400 patients with at least one International Classification of Disease code for MGUS diagnosis from 1999 to 2021. The best-performing feature combination was calibrated in the validation set (17,826 documents/200 patients) and evaluated in the testing set (9,250 documents/100 patients). Model performance in diagnosis confirmation was compared with manual chart review results (gold standard) using recall, precision, accuracy, and F1 score. For patients correctly labeled as disease-positive, the difference between model-identified diagnosis dates and the gold standard was also computed. RESULTS: In the testing set, the NLP-assisted classification model using SVMs achieved best performance in both MGUS and MM confirmation with recall/precision/accuracy/F1 of 98.8%/93.3%/93.0%/96.0% for MGUS and 100.0%/92.3%/99.0%/96.0% for MM. Dates of diagnoses matched (±45 days) with those of gold standard in 73.0% of model-confirmed MGUS and 84.6% of model-confirmed MM. CONCLUSION: An NLP-assisted classification model can reliably confirm MGUS and MM diagnoses and dates and extract laboratory results using automated interpretation of EHR data. This algorithm has the potential to be adapted to other disease areas in VHA EHR system.
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Gammopatía Monoclonal de Relevancia Indeterminada , Mieloma Múltiple , Veteranos , Humanos , Gammopatía Monoclonal de Relevancia Indeterminada/diagnóstico , Procesamiento de Lenguaje Natural , Registros Electrónicos de Salud , Mieloma Múltiple/diagnósticoRESUMEN
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors have demonstrated to reduce cardiovascular risk in patients with type 2 diabetes mellitus (T2DM) in large trials independent of glycemic control. The mechanisms of this cardioprotective property remain uncertain. Evidence suggests positive hemodynamic changes and favorable cardiac remodeling contributing to the clinical outcomes but results were conflicting. We aim to investigate the potential impact on hemodynamic parameters, cardiac structure and functions. This prospective observational study included T2DM patients receiving canagliflozin 100 mg per day in addition to their antidiabetic treatment. We analyzed hemodynamic parameters assessed by echocardiographic measurements and impedance cardiography (ICG) to evaluate systolic and diastolic functions from baseline to 24 weeks after treatment. A total of 47 patients (25 males and 22 females) averaging 64.6 ± 10.9 years had a significant reduction in HbA1c, body weight, and systolic blood pressure. Hematocrit increased significantly, while NT-proBNP remained unchanged. E/e', left atrium (LA) volume, and LA stiffness were reduced, while left ventricle (LV) global longitudinal strain (GLS) and LA strain rates increased at 24 weeks by conventional and speckle tracking echocardiography. LV mass and ejection fraction showed no differences. ICG suggested significant improvement in hemodynamic parameters with increased stroke volume index and cardiac output index and decreased systemic vascular resistance index at 12 and 24 weeks. Canagliflozin improved hemodynamic parameters and had a favorable impact on LA and LV reverse remodeling. These changes may explain the beneficial effect on cardiovascular outcomes in large clinical trials.
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Diabetes Mellitus Tipo 2 , Femenino , Humanos , Masculino , Canagliflozina/farmacología , Canagliflozina/uso terapéutico , Atrios Cardíacos , Hemodinámica , Volumen Sistólico , Función Ventricular Izquierda , Remodelación Ventricular , Persona de Mediana Edad , AncianoRESUMEN
Background: Herbicide and pesticide exposure (e.g., agent orange [AO]) is associated with an increased risk of multiple myeloma (MM) due to the contaminant, 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). Monoclonal gammopathy of undetermined significance (MGUS) is the precursor state to MM; however, not all patients with MGUS progress to MM. It is unclear whether AO exposure increases the risk of progression of MGUS to MM. Purpose: We aimed to determine the association between AO exposure and progression to MM in a nation-wide study of U.S. Veterans with MGUS. Patients and Methods: This is a population-based cohort study of Vietnam Era Veterans diagnosed with MGUS. A natural language processing (NLP) algorithm was used to confirm MGUS and progression to MM. The association between AO and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. Veterans who served during the Vietnam War Era from 1/9/1962-5/7/1975 and were diagnosed with MGUS between 10/1/1999-12/31/2021 were included. We excluded patients with missing BMI values, progression within 1 year after MGUS diagnosis date, non-IgG or IgA MGUS, or birth years outside of the range of the AO exposed group, and race other than Black and White. AO exposure and service during 1/9/1962-;5/7/1975 and stratified according to TCDD exposure levels by three time periods: 1/9/1962-11/30/1965 (high), 12/1/1965-12/31/1970 (medium), or 1/1/1971-5/7/1975 (low). The association between AO and progression was analyzed using multivariable Fine-Gray subdistribution hazard model with death as a competing event. Results: We identified 10,847 Veterans with MGUS, of whom 7,996 had AO exposure. Overall, 7.4% of MGUS patients progressed to MM over a median follow-up of 5.2 years. In multivariable analysis, AO exposure from 1/9/1962-11/30/1965, high TCDD exposure, was associated with an increased risk of progression (adjusted hazard ratio 1.48; 95% confidence interval 1.02-2.16), compared to Veterans with no exposure. Conclusions: In patients with MGUS, the high Agent Orange exposure time period is associated with a 48% increased risk of progression to multiple myeloma. This suggests that patients with MGUS and prior Agent Orange exposure or occupational exposure to TCDD (eg. Agricultural workers) may require thorough screening for plasma cell dyscrasias.
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Background: Coronavirus disease 2019 (COVID-19) had caused huge impacts worldwide. Polymerase chain reaction (PCR) is the mainstay diagnostic modality. In most hospitals in Taiwan, samples for PCR are collected at emergency department (ER) or outdoor clinics to avoid virus spread inside hospitals. Home rapid antigen test (RAT) is a feasible, low-cost, and convenient tool with moderate sensitivity and high specificity, which can be performed at home to reduce hospital visits. Due to comparably low severity of omicron variant and high vaccine coverage (~80% residents fully vaccinated with AstraZeneca, Moderna, or Pfizer BioNTech COVID-19 vaccines as of March 2022), the policy was shifted from containment to co-existing with COVID-19 in Taiwan. Virus spread rapidly in the community after the ease of social restrictive measurements. To acquire a confirmed diagnosis, PCR testing was requested for people with suspected COVID-19 infection. As a consequence, people with respiratory symptoms or contact history surged into hospitals for PCR testing, thus, the medical capacity was challenged. The diagnostic policy was altered from PCR to RAT, but the impact of diagnostic policy change remains unclear. Objectives: We conducted this study to investigate the number of COVID-19 cases, PCR testing, hospitalizations, mortalities, and hospital visits during the epidemic and evaluate the impact of diagnostic policy change on hospital visits. Methods: The diagnostic policy change was implemented in late May 2022. We used nationwide and hospital-based data of COVID-19 cases, PCR testing, hospitalizations, mortalities, and hospital visits before and after policy change as of 31 Jul 2022. Results: During the omicron epidemic, significant and synchronous increase of COVID-19 patients, PCR testing, hospital visits were observed. COVID-19 cases increased exponentially since April 2022 and the COVID-19 patients peaked in June (1,943, 55,571, and 61,511 average daily new cases in April, May, and June, respectively). The PCR testing peaked in May (85,788 daily tests) with high positive rate (81%). The policy of RAT as confirmatory diagnosis was implemented on 26 May 2022 and a substantial decline of PCR testing numbers occurred (85,788 and 83,113 daily tests in May and June). People hospitalized for COVID-19 peaked in June (821.8 patients per day) and decreased in July (549.5 patients). The mortality cases also peaked in June (147 cases/day). This trend was also validated by the hospital-based data with a significant decrease of emergency department visits (11,397 visits in May while 8,126 visits in June) and PCR testing (21,314 in May and 6,158 in June). The proportion of people purely for PCR testing also decreased (10-26 vs. 5-14%, before and after policy change, respectively). Conclusions: The impact of diagnostic policy change was a complicated issue and our study demonstrated the huge impact of diagnostic policy on health seeking behavior. The PCR testing numbers and emergency department visits had substantial decrease after diagnostic policy change, and the plateau of epidemic peak eased gradually in ~1 month later. Widespread RAT application may contribute to the decreased hospital visits and preserve medical capacity. Our study provides some evidences for policy maker's reference.
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COVID-19 , Humanos , COVID-19/diagnóstico , COVID-19/epidemiología , SARS-CoV-2 , Vacunas contra la COVID-19 , Reacción en Cadena de la Polimerasa , Prueba de COVID-19RESUMEN
Posttransplant lymphoproliferative disease (PTLD) is a potentially life-threatening complication of hematopoietic cell transplantation. With improvements in Epstein-Barr virus (EBV) monitoring and supportive care, PTLD incidence has decreased throughout the history of bone marrow transplantation. It is rare to develop PTLD after the first year following transplant, across all donor categories. In this case, we hope to elucidate details that may have predisposed to this unusual presentation. We present the case of a 55-year-old gentleman with acute myeloid leukemia who underwent a haploidentical transplant for consolidation and presented with fatigue, lethargy and presumed septic shock nearly 7 years after transplant.
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Tubulin and microtubules (MTs) are potential protein targets to treat parasitic infections and our previous studies have shown that the triazolopyrimidine (TPD) class of MT-active compounds hold promise as antitrypanosomal agents. MT-targeting TPDs include structurally related but functionally diverse congeners that interact with mammalian tubulin at either one or two distinct interfacial binding sites; namely, the seventh and vinca sites, which are found within or between α,ß-tubulin heterodimers, respectively. Evaluation of the activity of 123 TPD congeners against cultured Trypanosoma brucei enabled a robust quantitative structure-activity relationship (QSAR) model and the prioritization of two congeners for inâ vivo pharmacokinetics (PK), tolerability and efficacy studies. Treatment of T.â brucei-infected mice with tolerable doses of TPDs significantly decreased blood parasitemia within 24â h. Further, two once-weekly doses at 10â mg/kg of a candidate TPD significantly extended the survival of infected mice relative to infected animals treated with vehicle. Further optimization of dosing and/or the dosing schedule of these CNS-active TPDs may provide alternative treatments for human African trypanosomiasis.
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Tripanocidas , Trypanosoma brucei brucei , Tripanosomiasis Africana , Humanos , Ratones , Animales , Tripanosomiasis Africana/tratamiento farmacológico , Tubulina (Proteína)/metabolismo , Pirimidinas/farmacología , Pirimidinas/uso terapéutico , Pirimidinas/química , Microtúbulos/metabolismo , Relación Estructura-Actividad , Trypanosoma brucei brucei/metabolismo , Tripanocidas/farmacología , Tripanocidas/uso terapéutico , Tripanocidas/química , Mamíferos/metabolismoRESUMEN
Serine hydrolases have important roles in signaling and human metabolism, yet little is known about their functions in gut commensal bacteria. Using bioinformatics and chemoproteomics, we identify serine hydrolases in the gut commensal Bacteroides thetaiotaomicron that are specific to the Bacteroidetes phylum. Two are predicted homologs of the human dipeptidyl peptidase 4 (hDPP4), a key enzyme that regulates insulin signaling. Our functional studies reveal that BT4193 is a true homolog of hDPP4 that can be inhibited by FDA-approved type 2 diabetes medications targeting hDPP4, while the other is a misannotated proline-specific triaminopeptidase. We demonstrate that BT4193 is important for envelope integrity and that loss of BT4193 reduces B. thetaiotaomicron fitness during in vitro growth within a diverse community. However, neither function is dependent on BT4193 proteolytic activity, suggesting a scaffolding or signaling function for this bacterial protease.