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Objective: Wearable ultrasound is emerging as a new paradigm of real-time imaging in freely moving humans and has wide applications from cardiovascular health monitoring to human gesture recognition. However, current wearable ultrasound devices have typically employed pulse-echo imaging which requires high excitation voltages and sampling rates, posing safety risks, and requiring specialized hardware. Our objective was to develop and evaluate a wearable ultrasound system based on time delay spectrometry (TDS) that utilizes low-voltage excitation and significantly simplified instrumentation. Methods: We developed a TDS-based ultrasound system that utilizes continuous, frequency-modulated sweeps at low excitation voltages. By mixing the transmit and receive signals, the system digitizes the ultrasound signal at audio frequency (kHz) sampling rates. Wearable ultrasound transducers were developed, and the system was characterized in terms of imaging performance, acoustic output, thermal characteristics, and applications in musculoskeletal imaging. Results: The prototype TDS system is capable of imaging up to 6 cm of depth with signal-to-noise ratio of up to 42 dB at a spatial resolution of 0.33 mm. Acoustic and thermal radiation measurements were within clinically safe limits for continuous ultrasound imaging. We demonstrated the ability to use a 4-channel wearable system for dynamic imaging of muscle activity. Conclusion: We developed a wearable ultrasound imaging system using TDS to mitigate challenges with pulse echo-based wearable ultrasound imaging systems. Our device is capable of high-resolution, dynamic imaging of deep-seated tissue structures and is safe for long-term use. Significance: This work paves the way for low-voltage wearable ultrasound imaging devices with significantly reduced hardware complexity.

We report biogenic synthesis of ZnO nanoparticles using phytochemical-enriched medicinal plant Azadirachta indicawith the viewpoint of augmenting therapeutic potential of the resultant AIZnO bionanocomposites (AIZnO-NC). As-synthesized samples were subjected to comprehensive physico-chemical characterization to get insights into the structure, size, morphology, and possibility of stabilization/surface functionalization of nano-ZnO by organic moieties of plant origin. The antimicrobial activity of the typical AIZnO-NC was tested by agar-well diffusion method against Gram-negative (K. pneumoniae, E. coli, P. aeruginosa) and Gram-positive (S. aureus) bacteria. Although the antimicrobial potential of the AIZnO-NC was found to be effective against all the tested human pathogens, it is particularly notable in the case of S. aureus, the notorious opportunistic bacteria responsible for drug-resistant skin and wound infections. The MIC value was recorded as 0.23 ± 0.05, 0.26 ± 0.05, 0.43 ± 0.10, and 0.16 ± 0.05 mg/ml against K. pneumoniae, E. coli, P. aeruginosa, and S. aureus, respectively. Besides, growth curve study revealed that the growth of S. aureuswas completely inhibited at 0.16 ± 0.05 mg/ml of AIZnO-NC. Cytotoxicity checked against HeLa cells by using different concentrations of AIZnO-NC displayed acceptably safe cytotoxicity for AIZnO bionanocomposites. In terms of favorable biocompatibility, antimicrobial activity, and less cytotoxicity, biogenic AIZnO-NC appears to be a promising candidate in skin-care applications.

A series of small-molecule YEATS4 binders have been discovered as part of an ongoing research effort to generate high-quality probe molecules for emerging and/or challenging epigenetic targets. Analogues such as 4dand 4edemonstrate excellent potency and selectivity for YEATS4 binding versus YEATS1,2,3 and exhibit good physical properties and in vitro safety profiles. A new X-ray crystal structure confirms direct binding of this chemical series to YEATS4 at the lysine acetylation recognition site of the YEATS domain. Multiple analogues engage YEATS4 with nanomolar potency in a whole-cell nanoluciferase bioluminescent resonance energy transfer assay. Rodent pharmacokinetic studies demonstrate the competency of several analogues as in vivo-capable binders.

Sickle cell disease (SCD) is a genetic disorder caused by a single point mutation (β6 Glu → Val) on the β-chain of adult hemoglobin (HbA) that results in sickled hemoglobin (HbS). In the deoxygenated state, polymerization of HbS leads to sickling of red blood cells (RBC). Several downstream consequences of polymerization and RBC sickling include vaso-occlusion, hemolytic anemia, and stroke. We report the design of a noncovalent modulator of HbS, clinical candidate PF-07059013 (23). The seminal hit molecule was discovered by virtual screening and confirmed through a series of biochemical and biophysical studies. After a significant optimization effort, we arrived at 23, a compound that specifically binds to Hb with nanomolar affinity and displays strong partitioning into RBCs. In a 2-week multiple dose study using Townes SCD mice, 23showed a 37.8% (±9.0%) reduction in sickling compared to vehicle treated mice. 23(PF-07059013) has advanced to phase 1 clinical trials.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD–foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD–foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD ‘down’, one-RBD ‘up’ state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+and IFNγ+CD8+T cell responses. Prime–boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2–18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1–3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).

Cholestatic jaundice in the first few weeks of life may herald potentially life-threatening pathology. It is therefore incumbent upon the pediatric practitioner to have a high index of suspicion for severe disease when investigating jaundice in a young infant. This article outlines the epidemiology, pathophysiology, differential diagnosis, and diagnostic workup for both the most common and the most severe causes of cholestasis in the neonatal period.

This paper presents an adaptive synthetic-focusing scheme that, when applied to photoacoustic (PA) data acquired using an annular array, improves focusing across a greater imaging depth and enhances spatial resolution. The imaging system was based on a 40-MHz, 5-element, annular-array transducer with a focal length of 12 mm and an 800-µm diameter hole through its central element to facilitate coaxial delivery of 532-nm laser. The transducer was raster-scanned to facilitate 3D acquisition of co-registered ultrasound and PA image data. Three synthetic-focusing schemes were compared for obtaining PA A-lines for each scan location: delay-and-sum (DAS), DAS weighted with a coherence factor (DAS + CF), and DAS weighted with a sign-coherence factor (DAS + SCF). Bench-top experiments that used an 80-µm hair were performed to assess the enhancement provided by the two coherence-based schemes. Both coherence-based schemes increased the signal-to-noise ratio by approximately 10 dB. When processed using the DAS-only scheme, the lateral dimension of the hair in a PA image with 20 dB dynamic range was between 300 µm and 1 mm for imaging depth ranging from 8 to 20 mm. In comparison, the DAS + CF scheme resulted in a lateral dimension of 200 to 450 µm over the same range. The DAS + SCF synthetic focusing further improved the smallest-resolvable dimension, which was between 150 and 400 µm over the same range of imaging depth. When used on PA data obtained from a 12-day-old mouse embryo, the DAS + SCF processing improved visualization of neurovasculature.

Highly versatile: The Ruppert–Prakash reagent (Me3SiCF3) can be an efficient source of difluorocarbene. By varying the nonmetallic initiator that is used (F−at lower temperatures and I−at higher temperatures), a range of structurally diverse alkenes and alkynes can be converted into the corresponding gem‐difluorinated cyclopropanes and cyclopropenes in good yields (see scheme).

Sehr vielseitig: Das Ruppert‐Prakash‐Reagens (Me3SiCF3) kann eine effiziente Quelle für Difluorcarben sein. Durch Variation des verwendeten, nichtmetallischen Initiators (F−bei tiefen Temperaturen und I−bei hohen Temperaturen) wurden verschiedene Alkene und Alkine mit guter Ausbeute in ihre entsprechenden gem‐difluorierten Cyclopropane bzw. Cyclopropene umgesetzt (siehe Schema).

Studying long-term stroke outcomes including body functioning (neurologic and neuropsychological impairments) and activity limitations and participation is essential for long-term evidence-based rehabilitation and service planning, resource allocation, and improving health outcomes in stroke. However, reliable data to address these issues is lacking.

Understanding the extent of long-term neuropsychological deficits poststroke and their contribution to functional outcomes is essential for evidence-based rehabilitation and resource planning, and could improve stroke outcomes. However, most existing neuropsychological stroke data are not population-based, examine limited outcomes, and have short-term follow-up.

Metabolic syndrome (MetS) involves a combination of factors that increases the risk of cardiovascular disease. With no immediate physical symptoms or medical problems associated with this disorder, the diagnosis of MetS is a challenging one. The most widely recognized metabolic criteria (lipid profile, blood pressure, and glucose level) are commonly performed during a hospitalization. The waist circumference (WC) measurement, not a routine component of admission, is not available. Incomplete criteria affect the ability to diagnose MetS and prescribe risk reduction therapy. This study evaluated the efficacy of incorporating WC measurements in screening inpatients for MetS.

Objective:To establish the feasibility of conducting a home-based progressive resistance exercise programme to improve calf muscle pump function in community-based patients with venous leg ulcers.Method:Participants were randomised to receive a 12-week progressive resistance exercise programme using heel raises in addition to compression. The control was usual care in addition to compression. Randomisation was stratifi ed by ulcer duration and ulcer size. Air plethysmography was used to determine changes in calf muscle pump function from baseline. Changes in ulcer parameters were measured using the SilhouetteMobile device.Results:Forty participants were randomised. There were significantly greater improvements in ejection fraction of the calf muscle in the exercise group compared with the control (usual care) group (mean difference 18.5%, 95% CI 0.03 to 36.6%, p<0.05). Other parameters improved in the exercise group but the mean differences were not significant. Adherence with prescribed exercises was 81% and there was no significant difference in the numbers reporting adverse events. There were also no significant differences in ulcer healing parameters (change in area, percentage change in area, number healed at 12 weeks, time to healing).Conclusion:A community-based randomised trial of progressive resistance exercise is feasible. The prescribed exercises appeared to increase ejection fraction, but the effect of exercise on ulcer healing requires further investigation.Declaration of interest:The study was funded by the Health Research Council of New Zealand. ARANZ Medical provided access to a SilhouetteMobile device.

The high prevalence of cardiovascular disease and its associated mortality rates mandate that risk reduction strategies be addressed in high-risk populations, including those diagnosed with atherosclerotic vascular disease, heart failure, and diabetes mellitus. Hospital-based systems that can identify and guide management of these high-risk populations can be effective adjuncts to patient care.

Objective The principal limitations of percutaneous techniques to replace the aortic valve are detailed visualization and durable prostheses. We report the feasibility of using real-time magnetic resonance imaging (MRI) to provide precise anatomic detail and visual feedback to implant a proven bioprosthesis.Methods Twelve domestic pigs were anesthetized, and, through a minimally invasive approach using real-time MRI guidance, underwent aortic valve replacement. This was accomplished on the beating heart by using a commercially available bioprosthesis. MRI was used to precisely identify the anatomic landmarks of the aortic annulus, coronary artery ostia, and the mitral valve leaflets. Additional intraoperative perfusion, flow velocity, and functional imaging were used to confirm adequacy of placement and function of the valve.Results Under real-time MRI, multiple oblique planes were prescribed to delineate the anatomy of the native aortic valve and left ventricular outflow track. Enhanced by the use of an active marker wire, this imaging allowed correct placement and orientation of the valve. Through a transapical approach, a series of bioprosthetic aortic valves (21 to 25 mm) were inserted. The time to implantation after the placement of the trocar to deployment of the valve was less than 90 seconds. The average procedure duration was less than 40 minutesConclusions Real-time MRI provides excellent anatomic detail and intraoperative assessment that permits placement of durable valve prostheses on the beating heart without the limitations of percutaneous approaches.

Objective The principal limitations of percutaneous techniques to replace the aortic valve are detailed visualization and durable prostheses. We report the feasibility of using real-time magnetic resonance imaging (MRI) to provide precise anatomic detail and visual feedback to implant a proven bioprosthesis.Methods Twelve domestic pigs were anesthetized, and, through a minimally invasive approach using real-time MRI guidance, underwent aortic valve replacement. This was accomplished on the beating heart by using a commercially available bioprosthesis. MRI was used to precisely identify the anatomic landmarks of the aortic annulus, coronary artery ostia, and the mitral valve leaflets. Additional intraoperative perfusion, flow velocity, and functional imaging were used to confirm adequacy of placement and function of the valve.Results Under real-time MRI, multiple oblique planes were prescribed to delineate the anatomy of the native aortic valve and left ventricular outflow track. Enhanced by the use of an active marker wire, this imaging allowed correct placement and orientation of the valve. Through a transapical approach, a series of bioprosthetic aortic valves (21 to 25 mm) were inserted. The time to implantation after the placement of the trocar to deployment of the valve was less than 90 seconds. The average procedure duration was less than 40 minutesConclusions Real-time MRI provides excellent anatomic detail and intraoperative assessment that permits placement of durable valve prostheses on the beating heart without the limitations of percutaneous approaches.

Uniform nanowires of silver and gold inside the channels of MCM-41 were prepared by controlled reduction of their respective metal salts with sodium borohydride (NaBH4). Presence of nanowires of silver and gold in MCM-41 were confirmed by high angle X-ray diffraction (XRD) data (peaks between 2ϑ= 30 − 60°) and transmission electron microscopy (TEM) confirmed the diameter of the nanowires. Diameter of nanowires is found to be ∼ 2.8 nm which is coincident with channel diameter of MCM-41. Optical properties of these heterostructured materials Ag-MCM-41 and Au-MCM-41 reveals the presence of surface plasmon absorption peaks of silver and gold respectively, and the shift in the absorption bands are associated to agglomeration of clusters inside the channels. Room temperature photoluminescence spectra exhibits interesting optical properties as observed for direct band gap semiconductors. Non-linear optical properties (NLO) corresponding to second harmonic generation (SHG) values were also recorded for self supported films of these heterostructured materials. Enhanced optical non-linearity was found to be arising from a corresponding increase of local field near the surface plasmon resonance. Further enhancement in SHG was found with poling due to an induction of orientation order.

Introduction: Cohort studies have contributed important scientific knowledge regarding the determinants of chronic diseases. Despite the need for etiologic investigations, this design has been infrequently used in injury prevention research. Objectives: To describe the baseline findings of the New Zealand Blood Donors' Health Study, a large prospective study designed to investigate relationships between lifestyle, psychosocial factors, and serious injury due to road crashes, falls, self harm, assault, work, sport, and recreation. Methods: Participants were recruited from fixed and mobile collection sites of a voluntary non-profit blood donor program. Baseline exposure data (for example risk taking behaviors, alcohol and marijuana use, sleep habits, and depression) were collected using a self administered questionnaire. Outcome data regarding serious injury will be collected prospectively through computerized record linkage of participants' unique identifiers to national morbidity and mortality databases. Results: In total, 22 389 participants enrolled in the study (81% response rate). The diverse study population included 36% aged 16-24 years, 20% rural residents, and large variability in exposures of interest. For example, in the 12 months before recruitment, 21% had driven a motor vehicle when they considered themselves over the legal limit for alcohol, and 11% had been convicted of traffic violations (excluding parking infringements). Twelve per cent had seriously considered attempting suicide sometime in their life. Conclusions: This is the first, large scale cohort study investigating determinants of serious injury in New Zealand and among the largest worldwide. Preliminary findings from prospective analyses that can inform injury prevention policy are expected within five years.

We have recently described an automated approach for homology modeling using restrained molecular dynamics and simulated annealing procedures (Li et al, Protein Sci., 6:956–970,1997). We have employed this approach for constructing a homology model of the putative RNA‐binding domain of the human RNA‐binding protein with multiple splice sites (RBP‐MS). The regions of RBP‐MS which are homologous to the template protein snRNP U1A were constrained by “homology distance constraints,” while the conformation of the non‐homologous regions were defined only by a potential energy function. A full energy function without explicit solvent was employed to ensure that the calculated structures have good conformational energies and are physically reasonable. The effects of misalignment of the unknown and the template sequences were also explored in order to determine the feasibility of this homology modeling method for distinguishing possible sequence alignments based on considerations of the resulting conformational energies of modeled structures. Differences in the alignments of the unknown and the template sequences result in significant differences in the conformational energies of the calculated homology models. These results suggest that conformational energies and residual constraint violations in these homology‐constrained simulated annealing calculations can be used as criteria to distinguish between correct and incorrect sequence alignments and chain folds. Proteins 33:558–566, 1998. © 1998 Wiley‐Liss, Inc.

We have recently described an automated approach for homology modeling using restrained molecular dynamics and simulated annealing procedures (Li et al, Protein Sci., 6:956–970,1997). We have employed this approach for constructing a homology model of the putative RNA-binding domain of the human RNA-binding protein with multiple splice sites (RBP-MS). The regions of RBP-MS which are homologous to the template protein snRNP U1A were constrained by “homology distance constraints,” while the conformation of the non-homologous regions were defined only by a potential energy function. A full energy function without explicit solvent was employed to ensure that the calculated structures have good conformational energies and are physically reasonable. The effects of misalignment of the unknown and the template sequences were also explored in order to determine the feasibility of this homology modeling method for distinguishing possible sequence alignments based on considerations of the resulting conformational energies of modeled structures. Differences in the alignments of the unknown and the template sequences result in significant differences in the conformational energies of the calculated homology models. These results suggest that conformational energies and residual constraint violations in these homology-constrained simulated annealing calculations can be used as criteria to distinguish between correct and incorrect sequence alignments and chain folds. Proteins 33:558–566, 1998. © 1998 Wiley-Liss, Inc.

We demonstrate that laser beams can be converged toward a light-absorbing target through optically diffusive media by using photoacoustic-guided interferometric focusing. The convergence of light is achieved by shaping the wavefront of the incident light with a deformable mirror to maximize the photoacoustic signal, which is proportional to the scattered light intensity at the light absorber.

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