An accurate assessment of intracardiac pressure and etiology of its pathologic change is crucial in assessing volume status and cardiac hemodynamics. The assessment for abnormal central venous pressure in heart failure has driven the development of noninvasive assessment of the central veins: the inferior vena cava and, more recently, ultrasound assessment of the jugular venous pressure. This article discusses the evidence, techniques, and limitations of estimating central venous pressure by ultrasound assessment of the inferior vena cava and internal jugular vein.

Introduction: Bedside central venous pressure assessment is integral to diagnosing and managing heart failure (HF). A noninvasive point of care ultrasound (POCUS) assessment of the jugular venous pressure (uJVP) was validated as accurate in predicting elevated right atrial pressure (RAP) on right heart catheterization (RHC) in HF patients. A qualitative assessment of uJVP in the upright position (uuJVP) was found to be highly specific for detecting elevated RAP. We compared the prognostic value of the distended uuJVP and elevated RAP in predicting one-year mortality. Hypothesis: We hypothesized that a distended uuJVP was predictive of all-cause mortality. Methods: Adult patients undergoing RHC underwent uuJVP assessment with POCUS. A distended uuJVP was defined as internal jugular venous distention to at least the same size as the adjacent common carotid artery during resting inspiration and expiration (Figure 1c). Patients were examined upright at 90 degrees with their back/neck supported, and followed for one year after undergoing same day uuJVP assessment and RHC. Elevated RAP was defined as ≥10 mmHg on RHC. Kaplan Maier analysis of all-cause mortality was performed. Results: 100 patients had a uuJVP assessment prior to RHC. The distended uuJVP correlated with a mean RAP of 15 mmhg (8.3-17.1 mmHg) (Figure 1d) with a specificity of 94.6% for predicting RAP of ≥10 mmHg. Multivariate cox regression analysis showed that patients with a distended uuJVP had an increased one-year mortality (HR 3.20, 95% [CI 1.24- 8.20], p=.02) similar to those with RAP ≥10 mmHg by RHC (HR 3.21, 95% CI [1.20-8.64], p=.02) (Figure 1a/1b). Of 27 deaths, 11 (40.7%) had positive uuJVP with a specificity of 79.7%, 95% CI (69.2%-88%). Conclusions: The bedside distended uuJVP was similarly predictive of all-cause one-year mortality as elevated RAP by RHC. The clinical application of this simple, qualitative ultrasound estimate of RAP warrants further investigation.

ABSTRACT:Pigmented villonodular synovitis (PVNS) is a rare proliferative synovial benign disorder, which is characterized by villonodular hyperplasia of joints, tendon sheath, and synovium; invasion of adjacent tissue; and sometimes visible hemosiderin deposition. Studies regarding bone scan findings of PVNS were relatively limited. Here, we report our findings on 99mTc-MDP 3-phase bone scan with SPECT/CT images on delayed phase in 3 patients with joint PVNS.

This cohort study investigates the association of wearable device use with pulse rate and health care use among adults with atrial fibrillation (AF).

The Aphelinus asychis female adult is an important arrhenotocous parthenogenesis parasitoid of Myzus persicae, and its reproductive mode is beneficial for the population continuation of A. asychis by way of multiple mating and backcross. To explore the effect of mating on the population fitness and control efficiency of A. asychis, its mating frequency and backcross were observed under laboratory conditions. The results showed that most matings in A. asychis involved four distinct stages: courtship, pre-copulatory, copulation, and post-copulatory behaviours. Only the duration of courtship increased significantly with an increase in copulation frequency for females, and the courtship duration of A. asychis females mated with different males were significantly shorter than those mated with the same male at the same mating times, which suggested that A. asychis females might prefer to mate with different males to enrich the genotype of their offspring. The total number of mummified aphids and the female and male longevity decreased significantly with an increase in mating frequency. On the contrary, female progenies increased significantly with an increase of mating frequency, suggesting that sperm limitation might occur in females when they only mated once. These results imply that females might prefer to receive more sperm by mating multiple times in their life span. In addition, we found that the intrinsic rate of increase (r) of A. asychis of the control group (0.2858 d−1) was significantly greater than that in the backcross treatment (0.2687 d−1). The finite killing rate (θ) of A. asychis of the control group was similar to that in the backcross treatment, which showed that this treatment had a negligible negative effect on the control efficiency of A. asychis. In conclusion, the results showed that multiple mating increased the number and proportion of A. asychis female progenies but shortened the longevity of female and male adults, while the negative effect of backcross on the control efficiency of A. asychis was negligible.

Aphelinus asychis, a polyphagous parasitoid, has been widely used as an efficient biological control agent against the aphid Myzus persicae. Aiming to evaluate the influence of temperature on the biological characteristics and control potential of A. asychis for M. persicae, we compared the life table parameters and control potential of A. asychis, which included the developmental time, longevity, fecundity, intrinsic rate of increase (r), and finite killing rate (θ). The results showed that increasing the temperature significantly decreased the developmental time and longevity of A. asychis. The r at 24 (0.2360 d−1) and 28 °C (0.2441 d−1) were significantly greater than those at 20 (0.1848 d−1) and 32 °C (0.1676 d−1). The θ at 24 (0.4495), 28 (0.5414), and 32 °C (0.4312) were also significantly greater than that at 20 °C (0.3140). The relationship between population fitness (r and θ) and temperature followed a unary quadratic function (R2 > 0.95). The temperatures for the expected maximum intrinsic rate of increase (rmax) and the maximum finite killing rate (θmax) were 25.7 and 27.4 °C, respectively. In conclusion, A. asychis could develop and produce progenies within the temperature range of 20–32 °C, and its control efficiency for M. persicae at 24, 28, and 32 °C was greater than that at 20 °C. The most suitable temperature range for controlling M. persicae with A. asychis in the field might be between 25.7 and 27.4 °C.

Introduction: Accurate intravascular volume status assessment is central to heart failure management, but current non-invasive bedside techniques remain a challenge. Visual inspection of jugular venous pulsation (JVP) is used as a surrogate for central venous pressure (CVP). Studies have shown variability and inaccuracy of the JVP exam in estimating CVP or right atrial pressure (RAP). Published methods of RAP estimation through internal jugular vein (IJV) ultrasonography are either complex or require offline analysis. We validated a simplified approach to ultrasonography of the JVP (uJVP) as a method to predict RAP. Methods: Adult patients undergoing right heart catheterization (RHC) were enrolled prior for IJV imaging with point of care ultrasound (POCUS) device, Butterfly iQ™. The IJV was identified on ultrasound with the patient reclined (head of bed between 30-45°) and followed cranially until tapering smaller than the adjacent carotid artery throughout the entirety of the respiratory cycle. The height of this collapse point from the sternal angle added to 5 centimeters was defined as ultrasound JVP (uJVP). Results: 77 participants underwent uJVP assessment on the same day prior to RHC. Average BMI was 33 kg/m 2 . The area under the curve (AUC) of uJVP and RAP greater than 10mmHg on RHC was 0.879 (95% CI 0.759-0.931, p<0.001), with AUC of 0.972 and 0.818 for non-obese and obese subgroups respectively, and AUC of 0.876 for elevated RAP and pulmonary capillary wedge pressure (PCWP). A uJVP cutoff of 9 or higher was 85% sensitive and 72% specific at identifying RAP greater than 10mmHg. Conclusion: We developed and validated a novel technique identifying the uJVP using POCUS which correlates with invasive RAP regardless of obesity. This technique predicted combined elevated left and right sided intracardiac pressures. The uJVP’s potential to enhance the diagnostic value of the bed-side examination in an increasingly obese heart failure population warrants further research.

Microfluidic modulation spectroscopy (MMS) is a novel automated infrared spectroscopic technique with high sensitivity and repeatability. Here, the authors present a series of experimental studies showcasing the performance of MMS in the secondary structure characterization of biopharmaceutical products and compare the MMS results with the conventional Fourier transform infrared data.

Introduction: Accurate volume status assessment is central to heart failure management, but current non-invasive bedside techniques remain a challenge, particularly in obese patients. Studies have shown variability and inaccuracy of the jugular venous pulse (JVP) exam in estimating right atrial pressure (RAP). Hypothesis: The accuracy of POCUS imaging of the JVP (uJVP) is preserved in obesity. Methods: Prior to undergoing right heart catheterization (RHC), subjects were enrolled for internal jugular vein imaging with a POCUS device, Butterfly iQ™. The vJVP was identified by traditional examination technique along with pIVC (an IVC>2.1 cm and <50% collapsible was considered greater or equal to 10mmHg in RAP). The IJV was identified by POCUS with the patient reclined (head of bed between 30-45°) and followed cranially until tapering smaller than the adjacent carotid artery throughout the entirety of the respiratory cycle. The height of this collapse point from the sternal angle added to 5 centimeters was defined as uJVP. Results: 41 participants, 24 of whom were obese (BMI > 30 kg/m2), underwent vJVP, pIVC diameter, and uJVP assessments prior to RHC. The receiver operator curve (ROC) or Area under the Curve (AUC) was robust for uJVP and did not significantly differ between non-obese and obese participants (AUC=0.923 and AUC=0.852 respectively) in predicting RAP >=10mmHg. AUC decreased significantly with obesity for vJVP. The AUC was modest for pIVC in the non-obese, but performed poorly in obesity (Figure 1B, 1C). Conclusions: This is the first comparative study of bedside, non-invasive methods of volume assessment. The accuracy of vJVP and pIVC deteriorated with obesity, whereas the uJVP, maintained good predictive value irrespective of obesity. The novel uJVP is a promising bed-side tool for volume assessment in the obesity and warrants further study.

Protein higher order structure (HOS) is an important product quality attribute that governs the structure-function characteristics, safety, and efficacy of therapeutic proteins. Infrared (IR) spectroscopy has long been recognized as a powerful biophysical tool in determining protein secondary structure and monitoring the dynamic structural changes. Such biophysics analyses help establish process and product knowledge, understand the impact of upstream (cell culture) and downstream (purification) process conditions, create stable formulations, monitor product stability, and assess product comparability when process improvements are implemented (or establish biosimilarity to originator products). This paper provides an overview of a novel automated mid-IR spectroscopic technique called microfluidic modulation spectroscopy (MMS) for the characterization of protein secondary structure. The study demonstrates that MMS secondary structure analysis of therapeutic monoclonal antibodies (mAb) is comparable with a conventional Fourier transform infrared (FTIR) method. More importantly the study shows MMS exhibits higher sensitivity and repeatability for low concentration samples over FTIR, as well as provides automated operation and superior robustness with simplified data analysis, increasing the utility of the instrument in determination of mAb secondary structure. Therefore, we propose that the MMS method can be widely applied in characterization and comparability/biosimilarity studies for biopharmaceutical process and product development.

Introduction: Accurate intravascular volume status assessment is central to heart failure management, but current non-invasive bedside techniques remain a challenge. The visual inspection of jugular venous pulsation (JVP) in a reclined position and measuring its height from the sternal notch has been used as a surrogate for right atrial pressure (RAP). There are no studies on the predictive value of a visible internal jugular vein (IJV) in the upright position (U 2 JVP). Hypothesis: Point of care ultrasound (POCUS) for volume assessment in the upright position is predictive of clinically significant hypervolemia. Methods: Adult patients undergoing right heart catheterization (RHC) were enrolled prior for IJV imaging with point of care ultrasound (POCUS) device, Butterfly iQ™. The IJV and its size in comparison to the carotid artery was identified on ultrasound with the patient upright. Elevated RAP and PCWP was present if the IJV was still visible and not collapsed throughout the entirety of the respiratory cycle. Valsalva was used to confirm the position of a collapsed IJV. Results: 72 participants underwent U 2 JVP assessment on the same day prior to RHC. Average BMI was 31.9 kg/m2. The area under the curve (AUC) of U 2 JVP predicting RAP greater than 10 mmHg and PCWP of 15 mmhg or higher on RHC was 0.78 (95% CI 0.66-0.9, p<0.001), with AUC of 0.86 and 0.74 for non-obese and obese subgroups respectively, p= 0.38. The finding of a visible U 2 JVP in the upright position was 70.6 % sensitive and 85.5 % specific with a negative predictive value of 90.4% for identifying both RAP greater than 10 mmHg and PCWP equal or greater than 15 mmHg. Conclusions: The U 2 JVP is novel and pragmatic bed-side approach to the assessment of clinically significant elevated intra-cardiac pressures in our increasingly obese heart failure population.

High hydrostatic pressure is a thermodynamic driver causing unfolding of proteins orthogonal to the action of temperature or various chaotropic reagents. Pressure effects on protein conformation are explained by hydration of solvent-excluded cavities that are populated with solvent upon unfolding. Infrared spectroscopy, together with circular dichroism and fluorescence, is a popular methods of monitoring protein structure changes. Recently introduced Microfluidic Modulation Spectroscopy (MMS) represents a major advancement of infrared spectroscopy specifically developed to simplify protein structure analysis. Pressure effects on proteins is highly reproducible and can be controlled very precisely. Pressure perturbation approach coupled with MMS can be used to study stability of human immunoglobulins as a model system for formulations development of monoclonal antibody products and other biopharmaceuticals. In this study, we demonstrate that pressure unfolding of human immunoglobulins in specific chemical environments promotes quantitative conversion of parallel beta sheet structures to the anti-parallel beta structures, a characteristic indicator of amyloid protein aggregation. We explore pressure effects on aggregation kinetics in a series of co-solvents, chaotropes and popular stabilizing excipients. Pressure perturbation approach coupled with MMS can be used to study stability of human immunoglobulins as a model system for formulations development of monoclonal antibody products and other biopharmaceuticals.

Measurement and characterization of the secondary structure of proteins are critical in many research applications, especially the formulation and development of biotherapeutics. Traditional analytical tools are not optimized for the demanding requirements of these applications, which include high sensitivity, wide dynamic range, simplified workflow, and high repeatability. This article introduces a new infrared (IR) technique, microfluidic modulation spectroscopy (MMS), that is designed to address these needs, and presents data from measurements of commercially available proteins. The data demonstrate significant increases in sensitivity, dynamic range, and utility for the determination of protein similarity (fingerprinting), quantitation, protein secondary structure, and protein stability and aggregation through thermal and chemical denaturation methods.

Protein secondary structures are frequently assessed using infrared and circular dichroism spectroscopies during drug development (e.g., during product comparability and biosimilarity studies, reference standard characterization, etc.) However, there is little information on the lower limits of quantitation of structural misfolds and impurities for these methods. A model system using a monoclonal antibody reference material was spiked at various levels with a protein that had a significantly different secondary structure to represent the presence of a stable and discreet structural misfold. The ability of circular dichroism, transmission Fourier transform infrared spectroscopy and microfluidic modulation spectroscopy, along with various spectral comparison algorithms, were assessed for their ability to detect the presence and quantify the amount of the misfolded structure.

Alzheimer’s disease (AD) is characterized by the deposition of β-sheet–rich, insoluble amyloid β-peptide (Aβ) plaques; however, plaque burden is not correlated with cognitive impairment in AD patients; instead, it is correlated with the presence of toxic soluble oligomers. Here, we show, by a variety of different techniques, that these Aβ oligomers adopt a nonstandard secondary structure, termed “α-sheet.” These oligomers form in the lag phase of aggregation, when Aβ-associated cytotoxicity peaks, en route to forming nontoxic β-sheet fibrils. De novo-designed α-sheet peptides specifically and tightly bind the toxic oligomers over monomeric and fibrillar forms of Aβ, leading to inhibition of aggregation in vitro and neurotoxicity in neuroblastoma cells. Based on this specific binding, a soluble oligomer-binding assay (SOBA) was developed as an indirect probe of α-sheet content. Combined SOBA and toxicity experiments demonstrate a strong correlation between α-sheet content and toxicity. The designed α-sheet peptides are also active in vivo where they inhibit Aβ-induced paralysis in a transgenic Aβ Caenorhabditis elegans model and specifically target and clear soluble, toxic oligomers in a transgenic APPsw mouse model. The α-sheet hypothesis has profound implications for further understanding the mechanism behind AD pathogenesis.