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BACKGROUND: STI and HIV services and infection rates were affected during the COVID-19 pandemic, because of changes in access to health care and individual behavior. Understanding how individuals made decisions around prevention and sexual activities during different phases of the pandemic is useful to addressing the rising rates of STIs and HIV. SETTING: Federally-qualified health center focused on sexual and gender minority health, Chicago IL, 2021. METHODS: Patients with a history of PrEP use who were contacted by the PrEP retention team as part of standard care were invited to complete an online survey. A subset of survey participants were then contacted to complete one-on-one interviews. Participants were asked about two distinct periods: November 2020 to January 2021 and February to June 2021. RESULTS: From the 356 survey participants (mostly young, insured, and experienced with PrEP), more than half maintained their number of sex partners during the early pandemic and most also maintained PrEP use; during the later pandemic; most reported more or the same number of sex partners and almost all maintained PrEP use. From interviews, we identified diverse and changing experiences regarding sexual practices throughout the pandemic; whereas many participants changed PrEP use in accordance with sexual practices, many others maintained PrEP use as a habit. COVID-19 prevention was also a factor in sexual activities, particularly prevaccination. CONCLUSION: Many PrEP users try to align their HIV prevention with their sexual exposures and establish PrEP as a long-term habit. Removing financial and access barriers is important to improve PrEP use and STI testing.
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COVID-19 , Infecções por HIV , Profilaxia Pré-Exposição , Minorias Sexuais e de Gênero , Infecções Sexualmente Transmissíveis , Masculino , Humanos , Infecções por HIV/epidemiologia , Infecções por HIV/prevenção & controle , Pandemias/prevenção & controle , Homossexualidade Masculina , COVID-19/epidemiologia , COVID-19/prevenção & controle , Comportamento Sexual , Infecções Sexualmente Transmissíveis/prevenção & controle , Profilaxia Pré-Exposição/métodosRESUMO
Subsets of tumor-produced cell surface and secreted proteins can bind to IgG1 type antibodies and suppress their immune-effector activities. As they affect antibody and complement-mediated immunity, we call these proteins humoral immuno-oncology (HIO) factors. Antibody-drug conjugates (ADCs) use antibody targeting to bind cell surface antigens, internalize into the cell, then kill target cells upon liberation of the cytotoxic payload. Binding of the ADC antibody component by a HIO factor may potentially hamper ADC efficacy due to reduced internalization. To determine the potential effects of HIO factor ADC suppression, we evaluated the efficacy of a HIO-refractory, mesothelin-directed ADC (NAV-001) and a HIO-bound, mesothelin-directed ADC (SS1). The HIO factor MUC16/CA125 binding to SS1 ADC was shown to have a negative effect on internalization and tumor cell killing. The MUC16/CA125 refractory NAV-001 ADC was shown to have robust killing of MUC16/CA125 expressing and non-expressing tumor cells in vitro and in vivo at single, sub-mg/kg dosing. Moreover, NAV-001-PNU, which contains the PNU-159682 topoisomerase II inhibitor, demonstrated good stability in vitro and in vivo as well as robust bystander activity of resident cells while maintaining a tolerable safety profile in vivo. Single-dose NAV-001-PNU demonstrated robust tumor regression of a number of patient-derived xenografts from different tumor types regardless of MUC16/CA125 expression. These findings suggest that identification of HIO-refractory antibodies to be used in ADC format may improve therapeutic efficacy as observed by NAV-001 and warrants NAV-001-PNU's advancement to human clinical trials as a monotherapy to treat mesothelin-positive cancers.
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Antineoplásicos , Imunoconjugados , Humanos , Anticorpos , Antineoplásicos/farmacologia , Antígeno Ca-125/metabolismo , Linhagem Celular Tumoral , Imunoconjugados/farmacologia , Proteínas de Membrana/metabolismo , MesotelinaRESUMO
Mesothelin (MSLN) is a cell surface protein overexpressed in a number of cancer types. Several antibody- and cellular-based MSLN targeting agents have been tested in clinical trials where their therapeutic efficacy has been moderate at best. Previous studies using antibody and Chimeric Antigen Receptor-T cells (CAR-T) strategies have shown the importance of particular MSLN epitopes for optimal therapeutic response, while other studies have found that certain MSLN-positive tumors can produce proteins that can bind to subsets of IgG1-type antibodies and suppress their immune effector activities. In an attempt to develop an improved anti-MSLN targeting agent, we engineered a humanized divalent anti-MSLN/anti-CD3ε bispecific antibody that avoids suppressive factors, can target a MSLN epitope proximal to the tumor cell surface, and is capable of effectively binding, activating, and redirecting T cells to the surface of MSLN-positive tumor cells. NAV-003 has shown significantly improved tumor cell killing against lines producing immunosuppressive proteins in vitro and in vivo. Moreover, NAV-003 demonstrated good tolerability in mice and efficacy against patient-derived mesothelioma xenografts co-engrafted with human peripheral blood mononuclear cells. Together these data support the potential for NAV-003 clinical development and human proof-of-concept studies in patients with MSLN-expressing cancers.
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Leucócitos Mononucleares , Mesotelina , Humanos , Animais , Camundongos , Proteínas Ligadas por GPI , Epitopos , Linhagem Celular Tumoral , Modelos Animais de DoençasRESUMO
The Opacity Platform on the National Ignition Facility (NIF) has been developed to measure opacities at varying densities and temperatures relevant to the solar interior and thermal cooling rates in white dwarf stars. The typical temperatures reached at NIF range between 150 and 210 eV, which allow these measurements to be performed experimentally. The captured opacities are crucial to validating radiation-hydrodynamic models that are used in astrophysics. The NIF opacity platform has a unique new capability that allows in situ measurement of the sample expansion. The sample expansion data are used to better understand the plasma conditions in our experiments by inferring the sample density throughout the duration of the laser drive. We present the details of the density measurement technique, data analysis, and recent results for Fe and MgO.
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Suicides are preventable tragedies, if risk factors are tracked and mitigated. We had previously developed a new quantitative suicidality risk assessment instrument (Convergent Functional Information for Suicidality, CFI-S), which is in essence a simple polyphenic risk score, and deployed it in a busy urban hospital Emergency Department, in a naturalistic cohort of consecutive patients. We report a four years follow-up of that population (n = 482). Overall, the single administration of the CFI-S was significantly predictive of suicidality over the ensuing 4 years (occurrence- ROC AUC 80%, severity- Pearson correlation 0.44, imminence-Cox regression Hazard Ratio 1.33). The best predictive single phenes (phenotypic items) were feeling useless (not needed), a past history of suicidality, and social isolation. We next used machine learning approaches to enhance the predictive ability of CFI-S. We divided the population into a discovery cohort (n = 255) and testing cohort (n = 227), and developed a deep neural network algorithm that showed increased accuracy for predicting risk of future suicidality (increasing the ROC AUC from 80 to 90%), as well as a similarity network classifier for visualizing patient's risk. We propose that the widespread use of CFI-S for screening purposes, with or without machine learning enhancements, can boost suicidality prevention efforts. This study also identified as top risk factors for suicidality addressable social determinants. Supplementary Information: The online version contains supplementary material available at 10.1007/s44192-022-00016-z.
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BACKGROUND AND PURPOSE: Microstructural white matter abnormalities on DTI using Tract-Based Spatial Statistics at term-equivalent age are associated with cognitive and motor outcomes at 2 years of age or younger. However, neurodevelopmental tests administered at such early time points are insufficiently predictive of mild-moderate motor and cognitive impairment at school age. Our objective was to evaluate the microstructural antecedents of cognitive and motor outcomes at 3 years' corrected age in a cohort of very preterm infants. MATERIALS AND METHODS: We prospectively recruited 101 very preterm infants (<32 weeks' gestational age) and performed DTI at term-equivalent age. The Differential Ability Scales, 2nd ed, Verbal and Nonverbal subtests, and the Bayley Scales of Infant and Toddler Development, 3rd ed, Motor subtest, were administered at 3 years of age. We correlated DTI metrics from Tract-Based Spatial Statistics with the Bayley Scales of Infant and Toddler Development, 3rd ed, and the Differential Ability Scales, 2nd ed, scores with correction for multiple comparisons. RESULTS: Of the 101 subjects, 84 had high-quality DTI data, and of these, 69 returned for developmental testing (82%). Their mean (SD) gestational age was 28.4 (2.5) weeks, and birth weight was 1121.4 (394.1) g. DTI metrics were significantly associated with Nonverbal Ability in the corpus callosum, posterior thalamic radiations, fornix, and inferior longitudinal fasciculus and with Motor scores in the corpus callosum, internal and external capsules, posterior thalamic radiations, superior and inferior longitudinal fasciculi, cerebral peduncles, and corticospinal tracts. CONCLUSIONS: We identified widespread microstructural white matter abnormalities in very preterm infants at term that were significantly associated with cognitive and motor development at 3 years' corrected age.
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Imagem de Tensor de Difusão , Substância Branca , Encéfalo/diagnóstico por imagem , Pré-Escolar , Imagem de Difusão por Ressonância Magnética , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Recém-Nascido Prematuro , Substância Branca/diagnóstico por imagemRESUMO
The Opacity Platform on the National Ignition Facility (NIF) has been developed to measure iron opacities at varying densities and temperatures relevant to the solar interior and to verify recent experimental results obtained at the Sandia Z-machine, that diverge from theory. The first set of NIF experiments collected iron opacity data at â¼150 eV to 160 eV and an electron density of â¼7 × 1021 cm-3, with a goal to study temperatures up to â¼210 eV, with electron densities of up to â¼3 × 1022 cm-3. Among several techniques used to infer the temperature of the heated Fe sample, the absolutely calibrated DANTE-2 filtered diode array routinely provides measurements of the hohlraum conditions near the sample. However, the DANTE-2 temperatures are consistently low compared to pre-shot LASNEX simulations for a range of laser drive energies. We have re-evaluated the estimated uncertainty in the reported DANTE-2 temperatures and also the error generated by varying channel participation in the data analysis. An uncertainty of ±5% or better can be achieved with appropriate spectral coverage, channel participation, and metrology of the viewing slot.
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Virtual Reality (VR) offers the opportunity to display data, instrumentation, and experimental setups in three dimensions and gives the user the ability to interact with the objects. This technology moves visualization beyond two-dimensional projections on a flat screen with a fixed field of view in which a keyboard or another similar controller is needed to change the view. Advances in both hardware and software for VR make it possible for the non-expert to develop visualization tools for scientific applications both for viewing and for sharing data or diagnostic hardware between users in three dimensions. This manuscript describes application development using two VR software tools, Unity gaming engine and A-frame, for visualizing data and high energy physics targets.
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BACKGROUND: We sought to determine the mediating effects of magnetic resonance imaging (MRI) biomarkers at term gestation on the relationship between perinatal illness severity and neurodevelopment. METHODS: The Clinical Risk Index for Babies-second edition (CRIB-II) was correlated with indices of brain maturation or injury and neurodevelopment at 2-year follow-up in infants born less than 32 weeks gestation. Using a counterfactual mediation analysis, associations between CRIB-II, MRI biomarkers, and neurodevelopment were confirmed, followed by an assessment of the mediating effects of MRI biomarkers on the relationship between CRIB-II and neurodevelopment. RESULTS: CRIB-II correlated significantly with neurodevelopment and MRI biomarkers of brain injury or cortical maturation. Two MRI biomarkers, cortical surface area and global injury score, were associated with neurodevelopmental scores at follow-up and included in mediation analyses. CONCLUSION: Biomarkers of cortical maturation or brain injury at term-equivalent age mediated a substantial portion of the risks conveyed by perinatal illness severity on neurodevelopmental outcomes at 2 years corrected age.
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Lactente Extremamente Prematuro , Transtornos do Neurodesenvolvimento , Encéfalo/diagnóstico por imagem , Pré-Escolar , Idade Gestacional , Humanos , Lactente , Recém-Nascido , Imageamento por Ressonância Magnética , Transtornos do Neurodesenvolvimento/etiologiaRESUMO
A European consortium of 15 laboratories across nine nations have worked together under the EUROFusion Enabling Research grants for the past decade with three principle objectives. These are: (a) investigating obstacles to ignition on megaJoule-class laser facilities; (b) investigating novel alternative approaches to ignition, including basic studies for fast ignition (both electron and ion-driven), auxiliary heating, shock ignition, etc.; and (c) developing technologies that will be required in the future for a fusion reactor. A brief overview of these activities, presented here, along with new calculations relates the concept of auxiliary heating of inertial fusion targets, and provides possible future directions of research and development for the updated European Roadmap that is due at the end of 2020. This article is part of a discussion meeting issue 'Prospects for high gain inertial fusion energy (part 2)'.
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Rayleigh-Taylor instability growth is shown to be hydrodynamically scale invariant in convergent cylindrical implosions for targets that varied in radial dimension and implosion timescale by a factor of 3. The targets were driven directly by laser irradiation providing a short impulse, and instability growth at an embedded aluminum interface occurs as it converges radially inward by a factor of 2.25 and decelerates on a central foam core. Late-time growth factors of 14 are observed for a single-mode m=20 azimuthal perturbation at both scales, despite the differences in laser drive conditions between the experimental facilities, consistent with predictions from radiation-hydrodynamics simulations. This platform enables detailed investigations into the limits of hydrodynamic scaling in high-energy-density systems.
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A point-projection soft X-ray Opacity Spectrometer (OpSpec) has been implemented to measure X-ray spectra from â¼1 to 2 keV on the National Ignition Facility (NIF). Measurement of such soft X-rays with open-aperture point-projection detectors is challenging because only very thin filters may be used to shield the detector from the hostile environment. OpSpec diffracts X-rays from 540 to 2100 eV off a potassium (or rubidium) acid phthalate (KAP or RbAP) crystal onto either image plates or, most recently, X-ray films. A "sacrificial front filter" strategy is used to prevent crystal damage, while 2 or 3 rear filters protect the data. Since May 2017, OpSpec has been recording X-ray transmission data for iron-magnesium plasmas on the NIF, at "Anchor 1" plasma conditions (temperature â¼150 eV, density â¼7 × 1021 e -/cm3). Upgrades improved OpSpec's performance on 6 NIF shots in August and December 2017, with reduced backgrounds and 100% data return using filter stacks as thin as 2.9 µm (total). Photometric noise is beginning to meet requirements, and further work will reduce systematic errors.
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C1q-engagement with IgG and IgM type antibodies is the initiating step of classical complement-mediated immunity. The tumor shed antigen CA125 has been reported to have immunosuppressive effects on host tumor responses as well as commercially approved and experimental monoclonal antibody (mAb)-based therapeutic agents. To better understand this effect, molecular and cellular studies were carried out testing the ability of CA125 to perturb the classical complement pathway. Here, we show that patient-derived CA125 inhibits IgG1, IgG3, and IgM-mediated complement-dependent cytotoxicity (CDC) by perturbing antibody-Fc interaction with the C1q complement-initiating protein only in those mAbs that are directly bound by CA125. This mechanism was found to impact naturally generated IgM antibodies as well as experimental and clinically approved mAbs, such as farletuzumab and rituximab, respectively. These data support a role for CA125 in humoral immune suppression and as a potential mechanism by which tumors may possibly avoid host immune responses.
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Anticorpos Monoclonais/imunologia , Antígenos de Neoplasias/imunologia , Antígeno Ca-125/imunologia , Complemento C1q/imunologia , Neoplasias/imunologia , Animais , Anticorpos Monoclonais Humanizados/imunologia , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Células CHO , Ativação do Complemento/imunologia , Cricetulus , Humanos , Fragmentos Fc das Imunoglobulinas/imunologia , Imunoglobulina G/imunologia , Rituximab/imunologiaRESUMO
The tumor-shed antigen CA125 has recently been found to bind certain monoclonal antibodies (mAbs) and suppress immune-effector mediated killing through perturbation of the Fc domain with CD16a and CD32a Fc-γ activating receptors on immune-effector cells. Amatuximab is a mAb targeting mesothelin whose mechanism of action utilizes in part antibody-dependent cellular cytotoxicity (ADCC). It is being tested for its therapeutic activity in patients with mesothelioma in combination with first line standard-of-care. To determine if CA125 has immunosuppressive effects on amatuximab ADCC and associated clinical outcomes, post hoc subgroup analysis of patients from a Phase 2 study with primary diagnosed stage III/IV unresectable mesothelioma treated with amatuximab plus cisplatin and pemetrexed were conducted. Analysis found patients with baseline CA125 levels no greater than 57 U/m (â¼3X the upper limit of normal) had a 2 month improvement in progression free survival (HR = 0.43, p = 0.0062) and a 7 month improvement in overall survival (HR = 0.40, p = 0.0022) as compared to those with CA125 above 57 U/mL. In vitro studies found that CA125 was able to bind amatuximab and perturb ADCC activity via decreased Fc-γ-receptor engagement. These data suggest that clinical trial designs of antibody-based drugs in cancers producing CA125, including mesothelioma, should consider stratifying patients on baseline CA125 levels for mAbs that are experimentally determined to be bound by CA125.
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Anticorpos Monoclonais/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Antígeno Ca-125/metabolismo , Neoplasias Pulmonares/tratamento farmacológico , Proteínas de Membrana/metabolismo , Mesotelioma/tratamento farmacológico , Neoplasias Pleurais/tratamento farmacológico , Idoso , Anticorpos Monoclonais/uso terapêutico , Citotoxicidade Celular Dependente de Anticorpos/imunologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Antígeno Ca-125/sangue , Antígeno Ca-125/genética , Antígeno Ca-125/imunologia , Linhagem Celular Tumoral , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Ensaios Clínicos Fase II como Assunto , Feminino , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/imunologia , Proteínas Ligadas por GPI/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/mortalidade , Neoplasias Pulmonares/patologia , Masculino , Proteínas de Membrana/sangue , Proteínas de Membrana/genética , Proteínas de Membrana/imunologia , Mesotelina , Mesotelioma/sangue , Mesotelioma/mortalidade , Mesotelioma/patologia , Mesotelioma Maligno , Pessoa de Meia-Idade , Pemetrexede/farmacologia , Pemetrexede/uso terapêutico , Neoplasias Pleurais/sangue , Neoplasias Pleurais/mortalidade , Neoplasias Pleurais/patologia , Intervalo Livre de Progressão , RNA Interferente Pequeno/metabolismo , Receptores de IgG/imunologia , Receptores de IgG/metabolismoRESUMO
Energy-transport effects can alter the structure that develops as a supernova evolves into a supernova remnant. The Rayleigh-Taylor instability is thought to produce structure at the interface between the stellar ejecta and the circumstellar matter, based on simple models and hydrodynamic simulations. Here we report experimental results from the National Ignition Facility to explore how large energy fluxes, which are present in supernovae, affect this structure. We observed a reduction in Rayleigh-Taylor growth. In analyzing the comparison with supernova SN1993J, a Type II supernova, we found that the energy fluxes produced by heat conduction appear to be larger than the radiative energy fluxes, and large enough to have dramatic consequences. No reported astrophysical simulations have included radiation and heat conduction self-consistently in modeling supernova remnants and these dynamics should be noted in the understanding of young supernova remnants.
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BACKGROUND: Diagnosing pulmonary embolism in suspected patients is notoriously difficult as signs and symptoms are non-specific. Different diagnostic strategies have been developed, usually combining clinical probability assessment with D-dimer testing. However, their predictive performance differs across different healthcare settings, patient subgroups, and clinical presentation, which are currently not accounted for in the available diagnostic approaches. METHODS: This is a protocol for a large diagnostic individual patient data meta-analysis (IPDMA) of currently available diagnostic studies in the field of pulmonary embolism. We searched MEDLINE (search date January 1, 1995, till August 25, 2016) to retrieve all primary diagnostic studies that had evaluated diagnostic strategies for pulmonary embolism. Two authors independently screened titles, abstracts, and subsequently full-text articles for eligibility from 3145 individual studies. A total of 40 studies were deemed eligible for inclusion into our IPDMA set, and principal investigators from these studies were invited to participate in a meeting at the 2017 conference from the International Society on Thrombosis and Haemostasis. All authors agreed on data sharing and participation into this project. The process of data collection of available datasets as well as potential identification of additional new datasets based upon personal contacts and an updated search will be finalized early 2018. The aim is to evaluate diagnostic strategies across three research domains: (i) the optimal diagnostic approach for different healthcare settings, (ii) influence of comorbidity on the predictive performance of each diagnostic strategy, and (iii) optimize and tailor the efficiency and safety of ruling out PE across a broad spectrum of patients with a new, patient-tailored clinical decision model that combines clinical items with quantitative D-dimer testing. DISCUSSION: This pre-planned individual patient data meta-analysis aims to contribute in resolving remaining diagnostic challenges of time-efficient diagnosis of pulmonary embolism by tailoring available diagnostic strategies for different healthcare settings and comorbidity. SYSTEMATIC REVIEW REGISTRATION: Prospero trial registration: ID 89366.
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Direct drive implosions of plastic capsules have been performed at the National Ignition Facility to provide a broad-spectrum (500-2000 eV) X-ray continuum source for X-ray transmission spectroscopy. The source was developed for the high-temperature plasma opacity experimental platform. Initial experiments using 2.0 mm diameter polyalpha-methyl styrene capsules with â¼20 µm thickness have been performed. X-ray yields of up to â¼1 kJ/sr have been measured using the Dante multichannel diode array. The backlighter source size was measured to be â¼100 µm FWHM, with â¼350 ps pulse duration during the peak emission stage. Results are used to simulate transmission spectra for a hypothetical iron opacity sample at 150 eV, enabling the derivation of photometrics requirements for future opacity experiments.
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Farletuzumab is a humanized monoclonal antibody that binds to folate receptor alpha and elicits an anti-tumor response via immune effector activity. Recent studies from a global phase 3 trial in ovarian cancer patients treated with carboplatin/taxane plus farletuzumab found that the tumor-produced CA125 protein can suppress farletuzumab function via perturbing its engagement to the activating Fc-γ receptors CD32a (FCGR2A) and CD16a (FCGR3A). Previous reports have indicated that naturally occurring polymorphisms in both of these receptors may play a role in their ability to engage therapeutic antibodies and elicit an optimal immune response via antibody-dependent cellular cytotoxicity (ADCC). In light of the importance of farletuzumab ADCC function for optimal tumor cell killing, we evaluated the frequency of FCGR2A-131H/R and FCGR3A-158V/F polymorphisms in 461 consenting patients from this global clinical study and their association with clinical outcome to placebo versus farletuzumab treatment. Here, we show that farletuzumab has enhanced binding to FCGR3A-158V high-affinity receptor and has an enhanced clinical outcome in patients with low baseline CA125 levels and at least 1 high-affinity allele of FCGR2A or FCGR3A.