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The preassociation of reactants in a photoinitiated redox reaction through the use of noncovalent interactions can have a significant impact on excited state reactivity. As these noncovalent interactions render some stabilization to the associated species, they impact the kinetics and thermodynamics of photoinitiated electron transfer. Reported herein is a novel iridium(III) photocatalyst, equipped with an anion-sensitive, amide-substituted bipyridine ligand, and its reactivity with the halides (X = I-, Br-, Cl-) in acetonitrile and dichloromethane. A noteworthy periodic trend was observed, where the size and electron affinity dramatically altered the observed photoredox behavior. The binding affinity for the halides increased with decreasing ionic radius (Keq â¼103 to >106) in a polar medium but association was stoichiometric for each halide in a nonpolar medium. Evidence for the static quenching of iodide and bromide is presented while dynamic quenching was observed with all halides. These results highlight how the photophysics of halide adducts and the thermodynamics of intra-ionic photo-oxidation are impacted as a consequence of preassociation of a quencher through hydrogen bonding.
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BACKGROUND: Evaluation and hospitalization rates after a transient ischemic attack (TIA)-like presentation vary widely in clinical practice. This study aimed to examine variations in care settings at initial TIA diagnosis in the United States. METHODS: We retrospectively analyzed an adult cohort with a first TIA principal diagnosis between January 1, 2015, and December 31, 2019, from TriNetX Diamond Network. Care settings at TIA diagnosis were defined as hospital care (including inpatient services and observation unit care without admission) and outpatient care (including any outpatient or emergency department visits). We estimated the distribution of care settings at TIA diagnosis and examined the associations of the hospital care setting with baseline age, sex, race, ethnicity, region, and stroke history. RESULTS: Among the 554,315 included patients, 38.8% received hospital care at their initial TIA diagnosis. A higher percentage of hospital care was observed in the age group of 50-64 years (40.3%), Black (46.0%), Hispanic (41.2%), South (40.9%), and Midwest (43.0%) Regions, and with a history of stroke (39.6%). Multivariable logistic regression consistently showed patients who were aged 50-64 years (Odds Ratio=1.09, 95% CI: [1.07, 1.11]), Black (1.28, [1.24, 1.32]), Hispanic (1.13, [1.09, 1.18]), from South (1.20, [1.18, 1.22]) and Midwest Region (1.33, [1.30, 1.35]), and had a history of stroke (1.02, [1.00, 1.04]) to more likely receive hospital care. CONCLUSIONS: Although there are TIA care disparities based on demographics, most patients with initial TIA received acute care in outpatient settings. It is imperative to ensure primary providers can risk-stratify TIA patients and provide rapid and proper management.
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BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone or as a bivalent preparation with the prototype vaccine (NVX-CoV2373) to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or the bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated a superior neutralizing antibody response to BA.1 vs NVX-CoV2373 (n = 274) at day 14 (geometric mean titer ratio, 1.6; 95% CI, 1.33-2.03). Seroresponse rates were 73.4% (91/124; 95% CI, 64.7-80.9) for NVX-CoV2515 vs 50.9% (59/116; 95% CI, 41.4-60.3) for NVX-CoV2373. All formulations were similarly well tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant as compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov (NCT05372588).
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , Inmunogenicidad Vacunal , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/efectos adversos , Adulto , SARS-CoV-2/inmunología , SARS-CoV-2/genética , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Glicoproteína de la Espiga del Coronavirus/genética , Masculino , Femenino , COVID-19/prevención & control , COVID-19/inmunología , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Adulto Joven , Persona de Mediana Edad , Adolescente , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Vacunas Sintéticas/efectos adversosRESUMEN
Introduction: Recently, we reported that post COVID-19 condition patients also have Transient Receptor Potential Melastatin 3 (TRPM3) ion channel dysfunction, a potential biomarker reported in natural killer (NK) cells from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) patients. As there is no universal treatment for post COVID-19 condition, knowledge of ME/CFS may provide advances to investigate therapeutic targets. Naltrexone hydrochloride (NTX) has been demonstrated to be beneficial as a pharmacological intervention for ME/CFS patients and experimental investigations have shown NTX restored TRPM3 function in NK cells. This research aimed to: i) validate impaired TRPM3 ion channel function in post COVID-19 condition patients compared with ME/CFS; and ii) investigate NTX effects on TRPM3 ion channel activity in post COVID-19 condition patients. Methods: Whole-cell patch-clamp was performed to characterize TRPM3 ion channel activity in freshly isolated NK cells of post COVID-19 condition (N = 9; 40.56 ± 11.26 years), ME/CFS (N = 9; 39.33 ± 9.80 years) and healthy controls (HC) (N = 9; 45.22 ± 9.67 years). NTX effects were assessed on post COVID-19 condition (N = 9; 40.56 ± 11.26 years) and HC (N = 7; 45.43 ± 10.50 years) where NK cells were incubated for 24 hours in two protocols: treated with 200 µM NTX, or non-treated; TRPM3 channel function was assessed with patch-clamp protocol. Results: This investigation confirmed impaired TRPM3 ion channel function in NK cells from post COVID-19 condition and ME/CFS patients. Importantly, PregS-induced TRPM3 currents were significantly restored in NTX-treated NK cells from post COVID-19 condition compared with HC. Furthermore, the sensitivity of NK cells to ononetin was not significantly different between post COVID-19 condition and HC after treatment with NTX. Discussion: Our findings provide further evidence identifying similarities of TRPM3 ion channel dysfunction between ME/CFS and post COVID-19 condition patients. This study also reports, for the first time, TRPM3 ion channel activity was restored in NK cells isolated from post COVID-19 condition patients after in vitro treatment with NTX. The TRPM3 restoration consequently may re-establish TRPM3-dependent calcium (Ca2+) influx. This investigation proposes NTX as a potential therapeutic intervention and TRPM3 as a treatment biomarker for post COVID-19 condition.
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COVID-19 , Canales Catiónicos TRPM , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , COVID-19/inmunología , Tratamiento Farmacológico de COVID-19 , Síndrome de Fatiga Crónica/tratamiento farmacológico , Síndrome de Fatiga Crónica/inmunología , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Naltrexona/farmacología , Naltrexona/uso terapéutico , Técnicas de Placa-Clamp , SARS-CoV-2/fisiología , Canales Catiónicos TRPM/metabolismoRESUMEN
With the rapid development of Quantum Machine Learning, quantum neural networks (QNN) have experienced great advancement in the past few years, harnessing the advantages of quantum computing to significantly speed up classical machine learning tasks. Despite their increasing popularity, the quantum neural network is quite counter-intuitive and difficult to understand, due to their unique quantum-specific layers (e.g., data encoding and measurement) in their architecture. It prevents QNN users and researchers from effectively understanding its inner workings and exploring the model training status. To fill the research gap, we propose VIOLET, a novel visual analytics approach to improve the explainability of quantum neural networks. Guided by the design requirements distilled from the interviews with domain experts and the literature survey, we developed three visualization views: the Encoder View unveils the process of converting classical input data into quantum states, the Ansatz View reveals the temporal evolution of quantum states in the training process, and the Feature View displays the features a QNN has learned after the training process. Two novel visual designs, i.e., satellite chart and augmented heatmap, are proposed to visually explain the variational parameters and quantum circuit measurements respectively. We evaluate VIOLET through two case studies and in-depth interviews with 12 domain experts. The results demonstrate the effectiveness and usability of VIOLET in helping QNN users and developers intuitively understand and explore quantum neural networks.
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Primary ciliary dyskinesia (PCD), a disorder of the motile cilia, is now recognised as an underdiagnosed cause of bronchiectasis. Accurate PCD diagnosis comprises clinical assessment, analysis of cilia and the identification of biallelic variants in one of 50 known PCD-related genes, including HYDIN. HYDIN-related PCD is underdiagnosed due to the presence of a pseudogene, HYDIN2, with 98% sequence homology to HYDIN. This presents a significant challenge for Short-Read Next Generation Sequencing (SR-NGS) and analysis, and many diagnostic PCD gene panels do not include HYDIN. We have used a combined approach of SR-NGS with bioinformatic masking of HYDIN2, and state-of-the-art long-read Nanopore sequencing (LR_NGS), together with analysis of respiratory cilia including transmission electron microscopy and immunofluorescence to address the underdiagnosis of HYDIN as a cause of PCD. Bioinformatic masking of HYDIN2 after SR-NGS facilitated the detection of biallelic HYDIN variants in 15 of 437 families, but compromised the detection of copy number variants. Supplementing testing with LR-NGS detected HYDIN deletions in 2 families, where SR-NGS had detected a single heterozygous HYDIN variant. LR-NGS was also able to confirm true homozygosity in 2 families when parental testing was not possible. Utilising a combined genomic diagnostic approach, biallelic HYDIN variants were detected in 17 families from 242 genetically confirmed PCD cases, comprising 7% of our PCD cohort. This represents the largest reported HYDIN cohort to date and highlights previous underdiagnosis of HYDIN-associated PCD. Moreover this provides further evidence for the utility of LR-NGS in diagnostic testing, particularly for regions of high genomic complexity.
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BACKGROUND: SARS-CoV-2 variants evade immunity despite vaccination with prototype COVID-19 vaccines or previous infection. The 2019nCoV-311 (part 2) study is evaluating immune responses after two booster doses of a vaccine containing the omicron BA.5 subvariant spike protein in adults previously vaccinated with a prototype mRNA vaccine. This interim analysis reports on day 28 immunogenicity and safety outcomes after one booster dose. METHODS: In this phase 3, randomised, observer-blinded study conducted at 35 sites in Australia, medically stable, previously COVID-19-vaccinated (mRNA-based; ≥three doses) adults aged 18 years or older were enrolled and randomly allocated (1:1:1; via an interactive web response system) to receive two doses of bivalent (NVX-CoV2373 + NVX-CoV2540; bivalent group), authorised prototype (NVX-CoV2373; prototype group), or BA.5 (NVX-CoV2540; BA.5 group) vaccine. Only blinded personnel performed study assessments or had participant contact to collect data after study vaccination. Participants received vaccines containing 5 µg SARS-CoV-2 recombinant spike protein and 50 µg Matrix-M adjuvant, administered via a 0·5 mL intramuscular injection (2·5 µg of NVX-CoV2373 plus 2·5 µg of NVX-CoV2540 for the bivalent vaccine, prepared on-site as a 1:1 mixture). The coprimary endpoints include day 28 neutralising antibody geometric mean titre (GMT) ratios (GMTRs) to omicron BA.5 and the ancestral strain, and seroresponse rates to BA.5, in the bivalent and prototype groups. These endpoints were calculated in the per-protocol analysis set, which was defined as participants who had received a vaccine dose, had baseline and day 28 immunogenicity data, and were PCR-negative for SARS-CoV-2, with no major protocol deviations. The primary objective was to determine the primary outcome (antibody responses), which consisted of three comparisons: superiority of the bivalent versus prototype vaccine for neutralising antibody GMT to BA.5 (ie, lower bound of the GMTR 95% CI >1·0); non-inferiority of neutralising antibody seroresponse rate to BA.5 (ie, lower bound of the seroresponse rate 95% CI >-5%); and non-inferiority of neutralising antibody GMT to the ancestral strain (ie, lower bound of GMTR 95% CI >0·67). This trial was registered at ClinicalTrials.gov, number NCT05372588. FINDINGS: Between March 22, 2023 and May 2, 2023, 837 participants were screened for eligibility and 766 were randomly allocated to receive the BA.5 (n=255), prototype (n=252), or bivalent (n=259) vaccine. After accounting for exclusions due to participants being baseline SARS-CoV-2-positive, having previous infection, or protocol deviations, the per-protocol analysis set included 694 participants (236 in BA.5 group, 227 in prototype group, and 231 in bivalent group). In this interim analysis (maximum follow-up 35 days after the first dose), the bivalent group, compared with the prototype group, had superior neutralising antibody responses to BA.5 (GMT 1017·8 [95% CI 891·0-1162·6] vs 515·1 [450·4-589·0]; GMTR 2·0 [1·69-2·33]) and a non-inferior seroresponse rate to BA.5 at day 28 (39·8% [33·5-46·5] vs 12·3% [8·4-17·3]; difference 27·5% [19·8-35·0]). The bivalent group also had non-inferior neutralising antibody responses to the ancestral strain (GMTR 1·0 [0·84-1·20]), compared with the prototype group. All vaccines were similarly well tolerated. INTERPRETATION: All three coprimary endpoints were met in part 2 of the ongoing 2019nCoV-311 study. These data support the development of monovalent and/or bivalent vaccines for the most currently circulating variants, to optimise protection. With no new safety findings, further investigation of omicron-based subvariant vaccines is supported by the evidence. FUNDING: Novavax.
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Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra la COVID-19 , COVID-19 , Inmunización Secundaria , Inmunogenicidad Vacunal , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , Vacunas contra la COVID-19/inmunología , Vacunas contra la COVID-19/administración & dosificación , Glicoproteína de la Espiga del Coronavirus/inmunología , Masculino , COVID-19/prevención & control , COVID-19/inmunología , SARS-CoV-2/inmunología , Femenino , Inmunización Secundaria/métodos , Persona de Mediana Edad , Adulto , Anticuerpos Antivirales/sangre , Anticuerpos Neutralizantes/sangre , Anticuerpos Neutralizantes/inmunología , Vacunas Sintéticas/inmunología , Vacunas Sintéticas/administración & dosificación , Anciano , Australia , Adulto JovenRESUMEN
Most cells tightly control the length of their cilia. The regulation likely involves intraflagellar transport (IFT), a bidirectional motility of multi-subunit particles organized into trains that deliver building blocks into the organelle. In Chlamydomonas, the anterograde IFT motor kinesin-2 consists of the motor subunits FLA8 and FLA10 and the nonmotor subunit KAP. KAP dissociates from IFT at the ciliary tip and diffuses back to the cell body. This observation led to the diffusion-as-a-ruler model of ciliary length control, which postulates that KAP is progressively sequestered into elongating cilia because its return to the cell body will require increasingly more time, limiting motor availability at the ciliary base, train assembly, building block supply, and ciliary growth. Here, we show that Chlamydomonas FLA8 also returns to the cell body by diffusion. However, more than 95% of KAP and FLA8 are present in the cell body and, at a given time, just ~1% of the motor participates in IFT. After repeated photobleaching of both cilia, IFT of fluorescent kinesin subunits continued indicating that kinesin-2 cycles from the large cell-body pool through the cilia and back. Furthermore, growing and full-length cilia contained similar amounts of kinesin-2 subunits and the size of the motor pool at the base changed only slightly with ciliary length. These observations are incompatible with the diffusion-as-a-ruler model, but rather support an "on-demand model," in which the cargo load of the trains is regulated to assemble cilia of the desired length.
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OBJECTIVES: Routine screening for chronic kidney disease (CKD) could enable timely interventions to slow down disease progression, but currently there are no clinical guidelines for screening. We aim to evaluate the cost-effectiveness of screening for CKD using a novel analytical tool based on a cumulative sum statistic of estimated glomerular filtration rate (CUSUMGFR). METHODS: We developed a microsimulation model that captured CKD disease progression, major complications, patients' awareness, and treatment adherence for a nationally representative synthetic cohort of age ≥ 30 years in the United States. In addition to the status quo with no screening, we considered four CUSUMGFR-based universal screening policies by frequency (annual or biennial) and starting age (30 or 60 years), and two targeted annual screening policies for patients with hypertension and diabetes, respectively. For each policy, we evaluated the total discounted disability-adjusted life years (DALYs) and direct health costs over a lifetime horizon and estimated the incremental cost-effectiveness ratio (ICER). We further performed one-way and probabilistic sensitivity analyses to assess the impact of parameter uncertainty. RESULTS: Compared with the status quo, all the CUSUMGFR-based screening policies were cost-effective under the willingness-to-pay (WTP) range of $50,000 -$100,000, with the estimated incremental cost-effectiveness ratios (ICERs) ranging from $15,614/DALYs averted to $54,373/DALYs averted. Universal annual screening with starting age of 30 was the non-dominated policy on the cost-effectiveness frontier under the WTP of approximately $25,000. Adding more recent treatment option of sodium-glucose cotransporter-2 (SGLT2) inhibitors to the treatment regimen was found to be cost-saving. Among the most influential model parameters, variation in the CKD progression rate, adherence, and testing cost resulted in the highest variability in model outcomes. CONCLUSIONS: CUSUMGFR-based screening policies for CKD are highly cost-effective in identifying patients at risk of end stage kidney disease in early stages of CKD. Given its simple requirement of a basic blood test, the CUSUMGFR-based screening can be easily incorporated into clinical workflow for disease monitoring and prevention.
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Insuficiencia Renal Crónica , Humanos , Estados Unidos , Adulto , Persona de Mediana Edad , Análisis Costo-Beneficio , Insuficiencia Renal Crónica/complicaciones , Tasa de Filtración Glomerular , Tamizaje Masivo/métodos , Progresión de la Enfermedad , Años de Vida Ajustados por Calidad de VidaRESUMEN
The objective of this study was to evaluate the safety, tolerability, pharmacokinetics (PK), and immunogenicity of VIR-2482 in healthy adult subjects. A phase 1, first-in-human, randomized, double-blind, placebo-controlled dose-escalation study was conducted. One hundred participants were allocated to four cohorts (60 mg, 300 mg, 1,200 mg, and 1,800 mg). In each cohort, participants were randomized in a 4:1 ratio (active:placebo) to receive either VIR-2482 or volume-matched placebo by gluteal intramuscular injection. Participants remained at the investigative site under observation for 48 h, and adverse events (AEs) were collected for 56 days. PK and immunogenicity were measured up to 52 weeks post-dose. VIR-2482 was well tolerated at all doses studied. The overall incidence of AEs was comparable between VIR-2482 (68.8%) and placebo (85.0%). Nineteen VIR-2482 (23.8%) and six placebo (30.0%) recipients had Grade 1 or 2 AEs that were considered to be related to the study intervention. There were no treatment-related serious AEs. Injection-site reactions (ISRs) were reported in six (7.5%) VIR-2482 recipients, while no such reactions were reported among the placebo recipients. All ISRs were Grade 1, and there was no relationship with the dose. Median VIR-2482 serum elimination half-life ranged from 56.7 to 70.6 days across cohorts. The serum area under the curve and Cmax were dose-proportional. Nasopharyngeal VIR-2482 concentrations were approximately 2%-5% of serum levels and were less than dose-proportional. The incidence of immunogenicity across all cohorts was 1.3%. Overall, the safety, tolerability, and pharmacokinetic profile of VIR-2482 at doses up to 1,800 mg supported its further investigation as a long-acting antibody for the prevention of influenza A illness. This study has been registered at ClinicalTrials.gov under identifier NCT04033406.
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Anticuerpos Monoclonales , Gripe Humana , Adulto , Humanos , Anticuerpos Monoclonales/efectos adversos , Gripe Humana/tratamiento farmacológico , Gripe Humana/prevención & control , Voluntarios Sanos , Método Doble CiegoRESUMEN
Grating magneto-optical traps are an enabling quantum technology for portable metrological devices with ultracold atoms. However, beam diffraction efficiency and angle are affected by wavelength, creating a single-optic design challenge for laser cooling in two stages at two distinct wavelengths - as commonly used for loading, e.g., Sr or Yb atoms into optical lattice or tweezer clocks. Here, we optically characterize a wide variety of binary gratings at different wavelengths to find a simple empirical fit to experimental grating diffraction efficiency data in terms of dimensionless etch depth and period for various duty cycles. The model avoids complex 3D light-grating surface calculations, yet still yields results accurate to a few percent across a broad range of parameters. Gratings optimized for two (or more) wavelengths can now be designed in an informed manner suitable for a wide class of atomic species enabling advanced quantum technologies.
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Quantum computing offers significant speedup compared to classical computing, which has led to a growing interest among users in learning and applying quantum computing across various applications. However, quantum circuits, which are fundamental for implementing quantum algorithms, can be challenging for users to understand due to their underlying logic, such as the temporal evolution of quantum states and the effect of quantum amplitudes on the probability of basis quantum states. To fill this research gap, we propose QuantumEyes, an interactive visual analytics system to enhance the interpretability of quantum circuits through both global and local levels. For the global-level analysis, we present three coupled visualizations to delineate the changes of quantum states and the underlying reasons: a Probability Summary View to overview the probability evolution of quantum states; a State Evolution View to enable an in-depth analysis of the influence of quantum gates on the quantum states; a Gate Explanation View to show the individual qubit states and facilitate a better understanding of the effect of quantum gates. For the local-level analysis, we design a novel geometrical visualization dandelion chart to explicitly reveal how the quantum amplitudes affect the probability of the quantum state. We thoroughly evaluated QuantumEyes as well as the novel dandelion chart integrated into it through two case studies on different types of quantum algorithms and in-depth expert interviews with 12 domain experts. The results demonstrate the effectiveness and usability of our approach in enhancing the interpretability of quantum circuits.
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BACKGROUND: Mutations present in emerging SARS-CoV-2 variants permit evasion of neutralization with prototype vaccines. A novel Omicron BA.1 subvariant-specific vaccine (NVX-CoV2515) was tested alone, or as a bivalent preparation in combination with the prototype vaccine (NVX-CoV2373), to assess antibody responses to SARS-CoV-2. METHODS: Participants aged 18 to 64 years immunized with 3 doses of prototype mRNA vaccines were randomized 1:1:1 to receive a single dose of NVX-CoV2515, NVX-CoV2373, or bivalent mixture in a phase 3 study investigating heterologous boosting with SARS-CoV-2 recombinant spike protein vaccines. Immunogenicity was measured 14 and 28 days after vaccination for the SARS-CoV-2 Omicron BA.1 sublineage and ancestral strain. Safety profiles of vaccines were assessed. RESULTS: Of participants who received trial vaccine (N = 829), those administered NVX-CoV2515 (n = 286) demonstrated superior neutralizing antibody response to BA.1 versus NVX-CoV2373 (n = 274) at Day 14 (geometric mean titer ratio [95% CI]: 1.6 [1.33, 2.03]). Seroresponse rates [n/N; 95% CI] were 73.4% [91/124; 64.7, 80.9] for NVX-CoV2515 versus 50.9% [59/116; 41.4, 60.3] for NVX-CoV2373. All formulations were similarly well-tolerated. CONCLUSIONS: NVX-CoV2515 elicited a superior neutralizing antibody response against the Omicron BA.1 subvariant compared with NVX-CoV2373 when administered as a fourth dose. Safety data were consistent with the established safety profile of NVX-CoV2373.
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Magnetic field imaging is a valuable resource for signal source localization and characterization. This work reports an optically pumped magnetometer (OPM) based on the free-induction-decay (FID) protocol, that implements microfabricated cesium (Cs) vapor cell technology to visualize the magnetic field distributions resulting from various magnetic sources placed close to the cell. The slow diffusion of Cs atoms in the presence of a nitrogen (N2) buffer gas enables spatially independent measurements to be made within the same vapor cell by translating a 175â µm diameter probe beam over the sensing area. For example, the OPM was used to record temporal and spatial information to reconstruct magnetic field distributions in one and two dimensions. The optimal magnetometer sensitivity was estimated to be 0.43 pT/H z within a Nyquist limited bandwidth of 500â Hz. Furthermore, the sensor's dynamic range exceeds the Earth's field of approximately 50â µT, which provides a framework for magnetic field imaging in unshielded environments.
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BACKGROUND: We previously demonstrated the safety and immunogenicity of an MF59-adjuvanted COVID-19 vaccine based on the SARS-CoV-2 spike glycoprotein stabilised in a pre-fusion conformation by a molecular clamp using HIV-1 glycoprotein 41 sequences. Here, we describe 12-month results in adults aged 18-55 years and ≥56 years. METHODS: Phase 1, double-blind, placebo-controlled trial conducted in Australia (July 2020-December 2021; ClinicalTrials.govNCT04495933; active, not recruiting). Healthy adults (Part 1: 18-55 years; Part 2: ≥56 years) received two doses of placebo, 5 µg, 15 µg, or 45 µg vaccine, or one 45 µg dose of vaccine followed by placebo (Part 1 only), 28 days apart (n = 216; 24 per group). Safety, humoral immunogenicity (including against virus variants), and cellular immunogenicity were assessed to day 394 (12 months after second dose). Effects of subsequent COVID-19 vaccination on humoral responses were examined. FINDINGS: All two-dose vaccine regimens were well tolerated and elicited strong antigen-specific and neutralising humoral responses, and CD4+ T-cell responses, by day 43 in younger and older adults, although cellular responses were lower in older adults. Humoral responses waned by day 209 but were boosted in those receiving authorised vaccines. Neutralising activity against Delta and Omicron variants was present but lower than against the Wuhan strain. Cross-reactivity in HIV diagnostic tests declined over time but remained detectable in most participants. INTERPRETATION: The SARS-CoV-2 molecular clamp vaccine is well tolerated and evokes robust immune responses in adults of all ages. Although the HIV glycoprotein 41-based molecular clamp is not being progressed, the clamp concept represents a viable platform for vaccine development. FUNDING: This study was funded by the Coalition for Epidemic Preparedness Innovations, the National Health and Medical Research Council of Australia, and the Queensland Government.
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COVID-19 , Infecciones por VIH , Vacunas , Humanos , Anciano , SARS-CoV-2 , Vacunas contra la COVID-19/efectos adversos , COVID-19/prevención & control , Glicoproteína de la Espiga del Coronavirus , Adyuvantes Inmunológicos , Infecciones por VIH/prevención & control , Glicoproteínas , Método Doble Ciego , Anticuerpos Antivirales , Anticuerpos NeutralizantesRESUMEN
We report the electron transfer (ET) self-exchange rate constants (k11) for a pair of CuII/I complexes utilizing dpaR (dpa = dipicolylaniline, R = OMe, SMe) ligands assessed by NMR line broadening experiments. These ligands afford copper complexes that are conformationally dynamic in one oxidation state. With R = OMe, the CuI complex is dynamic, while with R = SMe, the CuII complex is dynamic. Both complexes exhibit unexpectedly large k11 values of 2.48(6) × 105 and 2.21(9) × 106 M-1 s-1 for [CuCl(dpaOMe)]+/0 and [CuCl(dpaSMe)]+/0, respectively. Among the fastest reported molecular copper coordination complexes to date, that of [CuCl(dpaSMe)]+/0 exceeds all others by an order of magnitude and compares only with those observed in type 1 blue copper proteins. The dynamicity of these complexes establishes pre-steady-state conformational equilibria that minimize the inner-sphere reorganization energies to 0.71 and 0.62 eV for R = OMe and SMe, respectively. In contrast to the emphasis on rigidity in the formulation of entatic states applied to blue copper proteins, the success of these two systems highlights the relevance of conformational dynamicity in mediating rapid ET.
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BACKGROUND: Australia, like many high-income countries, is experiencing a resurgence of infectious syphilis in pregnancy and congenital syphilis. Evaluations of public health notifications and clinical records suggest that healthcare systems may not be providing optimal care to women and their neonates. This study aims to explore the barriers to optimal management of syphilis in pregnancy and congenital syphilis to identify key areas for improvement. METHODS: Between 2021 and 2022, 34 healthcare workers (HCW) practicing in south-east Queensland (SEQ) Australia were recruited to complete semi-structured interviews regarding their perceptions towards management of syphilis in pregnancy and congenital syphilis. Interviews were analysed thematically. RESULTS: Thematic analysis identified four themes related to the management of syphilis in pregnancy. These included poor communication between disciplines, services, and teams from delivery through to management and post-delivery, lack of formal internal and external referral pathways, unclear and often complex maternal and congenital syphilis management procedures, and limited HCW knowledge of infectious syphilis in pregnancy and congenital syphilis. CONCLUSION: As congenital syphilis numbers continue to rise in SEQ, it is imperative that healthcare systems and HCWs identify and address gaps in the provision of health care.
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Complicaciones Infecciosas del Embarazo , Sífilis Congénita , Sífilis , Embarazo , Recién Nacido , Femenino , Humanos , Sífilis/diagnóstico , Sífilis/epidemiología , Sífilis Congénita/epidemiología , Complicaciones Infecciosas del Embarazo/epidemiología , Complicaciones Infecciosas del Embarazo/terapia , Queensland/epidemiología , AustraliaRESUMEN
Background: In a parallel-group, international, phase 3 study (ClinicalTrials.govNCT04762680), we evaluated prototype (D614) and Beta (B.1.351) variant recombinant spike protein booster vaccines with AS03-adjuvant (CoV2 preS dTM-AS03). Methods: Adults, previously primed with mRNA (BNT162b2, mRNA-1273), adenovirus-vectored (Ad26.CoV2.S, ChAdOx1nCoV-19) or protein (CoV2 preS dTM-AS03 [monovalent D614; MV(D614)]) vaccines were enrolled between 29 July 2021 and 22 February 2022. Participants were stratified by age (18-55 and ≥ 56 years) and received one of the following CoV2 preS dTM-AS03 booster formulations: MV(D614) (n = 1285), MV(B.1.351) (n = 707) or bivalent D614 + B.1.351 (BiV; n = 625). Unvaccinated adults who tested negative on a SARS-CoV-2 rapid diagnostic test (control group, n = 479) received two primary doses, 21 days apart, of MV(D614). Anti-D614G and anti-B.1.351 antibodies were evaluated using validated pseudovirus (lentivirus) neutralization (PsVN) assay 14 days post-booster (day [D]15) in 18-55-year-old BNT162b2-primed participants and compared with those pre-booster (D1) and on D36 in 18-55-year-old controls (primary immunogenicity endpoints). PsVN titers to Omicron BA.1, BA.2 and BA.4/5 subvariants were also evaluated. Safety was evaluated over a 12-month follow-up period. Planned interim analyses are presented up to 14 days post-last vaccination for immunogenicity and over a median duration of 5 months for safety. Findings: All three boosters elicited robust anti-D614G or -B.1.351 PsVN responses for mRNA, adenovirus-vectored and protein vaccine-primed groups. Among BNT162b2-primed adults (18-55 years), geometric means of the individual post-booster versus pre-booster titer ratio (95% confidence interval [CI]) were: for MV (D614), 23.37 (18.58-29.38) (anti-D614G); for MV(B.1.351), 35.41 (26.71-46.95) (anti-B.1.351); and for BiV, 14.39 (11.39-18.28) (anti-D614G) and 34.18 (25.84-45.22 (anti-B.1.351). GMT ratios (98.3% CI) versus post-primary vaccination GMTs in controls, were: for MV(D614) booster, 2.16 (1.69; 2.75) [anti-D614G]; for MV(B.1.351), 1.96 (1.54; 2.50) [anti-B.1.351]; and for BiV, 2.34 (1.84; 2.96) [anti-D614G] and 1.39 (1.09; 1.77) [anti-B.1.351]. All booster formulations elicited cross-neutralizing antibodies against Omicron BA.2 (across priming vaccine subgroups), Omicron BA.1 (BNT162b2-primed participants) and Omicron BA.4/5 (BNT162b2-primed participants and MV D614-primed participants). Similar patterns in antibody responses were observed for participants aged ≥56 years. Reactogenicity tended to be transient and mild-to-moderate severity in all booster groups. No safety concerns were identified. Interpretation: CoV2 preS dTM-AS03 boosters demonstrated acceptable safety and elicited robust neutralizing antibodies against multiple variants, regardless of priming vaccine. Funding: Sanofi and Biomedical Advanced Research and Development Authority (BARDA).
RESUMEN
The geometries of copper coordination complexes are intricately related to their electron transfer capabilities, but the role of dynamics in these processes are not fully understood. We have previously reported CuCl(dpaOMe), a complex exhibiting conformational fluxionality in its CuI state and rigidity upon oxidation to CuII. Here, we report the synthesis and characterization of [CuCl(dpaSMe)]+/0, a complex exhibiting relative rigidity in its CuI state and structural dynamics upon oxidation to CuII. The dynamics of [CuCl(dpaSMe)]+ were characterized via X-ray diffraction, cyclic voltammetry, and EPR spectroscopy, where temperature-dependent interconversion between trigonal bipyramidal and square pyramidal geometries is observed. Coupling these solid and solution-state characterization data enabled assignment of the coordination geometries involved. Factors impacting these dynamics and their potential implications for electron transfer are discussed.
RESUMEN
Background: Several US states have introduced legislation to support the legitimate medical use of opioids while limiting misuse and diversion. One concern which has been addressed through legislation is preventing individuals from seeking opioid prescriptions concurrently from multiple providers. However, the impact of this legislation on the incidence of patients receiving concurrent prescriptions remains relatively unexplored. This study examines this phenomenon based on claims data from Medicaid enrollees and the enactment of legislation in Indiana. Methods: Indiana Medicaid claims data over the period of January 2014 to December 2019 were used to determine the changes in the percentage of individuals receiving opioid prescriptions from multiple providers within a 30-day period, that is, concurrent opioid prescription (COP) individuals. Indiana Medicaid enrollees with a diagnosis of opioid use disorder (OUD) receiving opioid prescriptions, that is, the OUD-group, were identified and separated from the enrollees without a diagnosis but receiving opioid prescriptions, that is, the non-OUD group. The mean percentages of COP individuals (with or without an OUD diagnosis) within the subset of individuals that received opioid prescriptions were compared before and after the passage of Indiana Public Law 194. Results: There were 5336 who met the criteria of COP individuals, and 2050 of those were in the OUD-group. In either group, there was a significant difference in the change in percentages (slope) before and after Indiana Public Law 194 passed. In addition, there was a significant decrease in the mean percentage of COP individuals in the non-OUD group, while the difference was not significant in the OUD group. Conclusion: Our study suggests that Indiana Public Law 194 had a positive impact on curbing COP. This study is limited by the level of details available from claims data and suggests additional studies to evaluate prescription use and prescribing practices are warranted.