A systematic review and meta-analysis of mediastinoscopy-assisted transhiatal esophagectomy (MATHE).

BACKGROUND: Transhiatal esophagectomy (THE) avoids thoracotomy but sacrifices mediastinal lymphadenectomy. Mediastinoscopy-assisted transhiatal esophagectomy (MATHE) allows for visualisation and en-bloc dissection of mediastinal lymph nodes while retaining the benefits of THE. However, given its novel inception, there is a paucity of literature. This study aimed to conduct the first meta-analysis to explore the efficacy of MATHE and clarify its role in the future of esophagectomy. METHODS: Four databases (PubMed, EMBASE, Scopus, and Cochrane Library) were searched from inception to May 1, 2023. Studies were included if they reported outcomes for patients with esophageal cancer who underwent MATHE. Meta-analyses of proportions and pooled means were performed for the outcomes of intraoperative blood loss, lymph node (LN) harvest, mean hospital length of stay (LOS), mean operative time, R0 resection, conversion rates, 30-day mortality rate, 5-year OS, and surgical complications (anastomotic leak, cardiovascular [CVS] and pulmonary complications, chyle leak and recurrent laryngeal nerve palsy [RLN]). Sensitivity analyses were performed for outcomes with substantial statistical heterogeneity. RESULTS: The search yielded 223 articles; 28 studies and 1128 patients were included in our analysis. Meta-analyses of proportions yielded proportion rates: 30-day mortality (0 %, 95 %CI 0-0), 5-year OS (60.5 %, 95 %CI 47.6-72.7), R0 resection (100 %, 95 %CI 99.3-100), conversion rate (0.1 %, 95 %CI 0-1.2). Among surgical complications, RLN palsy (14.6 %, 95 %CI 9.5-20.4) were most observed, followed by pulmonary complications (11.3 %, 95 %CI 7-16.2), anastomotic leak (9.7 %, 95 %CI 6.8-12.8), CVS complications (2.3 %, 95 %CI 0.9-4.1) and chyle leak (0.02 %, 95 %CI 0-0.8). Meta-analysis of pooled means yielded means: LN harvest (18.6, 95 %CI 14.3-22.9), intraoperative blood loss (247.1 ml, 95 %CI 173.6-320.6), hospital LOS (18.1 days, 95 %CI 14.4-21.8), and operative time (301.5 min, 95 %CI 238.4-364.6). There was moderate-to-high statistical heterogeneity. Findings were robust to sensitivity analyses. CONCLUSION: MATHE is associated with encouraging post-operative mortality and complication rates, while allowing for radical mediastinal lymphadenectomy with reasonable lymph node harvest.

Co-culture models of endothelial cells, macrophages, and vascular smooth muscle cells for the study of the natural history of atherosclerosis.

BACKGROUND: This work aims to present a fast, affordable, and reproducible three-cell co-culture system that could represent the different cellular mechanisms of atherosclerosis, extending from atherogenesis to pathological intimal thickening. METHODS AND RESULTS: We built four culture models: (i) Culture model #1 (representing normal arterial intima), where human coronary artery endothelial cells were added on top of Matrigel-coated collagen type I matrix, (ii) Culture model #2 (representing atherogenesis), which demonstrated the subendothelial accumulation and oxidative modification of low-density lipoproteins (LDL), (iii) Culture model #3 (representing intimal xanthomas), which demonstrated the monocyte adhesion to the endothelial cell monolayer, transmigration into the subendothelial space, and transformation to lipid-laden macrophages, (iv) Culture model #4 (representing pathological intimal thickening), which incorporated multiple layers of human coronary artery smooth muscle cells within the matrix. Coupling this model with different shear stress conditions revealed the effect of low shear stress on the oxidative modification of LDL and the upregulation of pro-inflammatory molecules and matrix-degrading enzymes. Using electron microscopy, immunofluorescence confocal microscopy, protein and mRNA quantification assays, we showed that the behaviors exhibited by the endothelial cells, macrophages and vascular smooth muscle cells in these models were very similar to those exhibited by these cell types in nascent and intermediate atherosclerotic plaques in humans. The preparation time of the cultures was 24 hours. CONCLUSION: We present three-cell co-culture models of human atherosclerosis. These models have the potential to allow cost- and time-effective investigations of the mechanobiology of atherosclerosis and new anti-atherosclerotic drug therapies.

Preference and usage pattern of mobile medical apps for drug information purposes among hospital pharmacists in Sarawak, Malaysia.

INTRODUCTION: Pharmacists are frequent users of mobile medical apps (MMA) for drug information (DI) and clinical decision-making purposes. However, the wide range of available MMA may be of variable credibility and results in heterogeneous recommendations. The need for subscription may also influence choice of apps. OBJECTIVE: The objective of this study was to determine the usage pattern of MMA among hospital pharmacists, including their perceptions and factors affecting their choice of apps. METHODS: This cross-sectional study required respondents to fill in an online questionnaire. The questionnaire included sections on respondents' demographic data, MMA usage pattern, perceived usefulness and opinion on subscription fees. Items were adapted from available literature and validated locally. It was made accessible for 6 weeks starting November 2019 for all pharmacists working in the 23 public hospitals in Sarawak to response (universal sampling). Collected data were analysed using descriptive and inferential statistics. RESULTS: A response rate of 37.2% was achieved (n = 162). Respondents were heavily reliant on MMA, with 78.4% accessing them multiple times daily. The majority also agreed that MMA contain correct and up-to-date information. A median of 5 apps were downloaded, suggesting an ultimate app catering for all DI needs was lacking. The Malaysian Drug Formulary was the most downloaded app (88.3%), whereas Lexicomp® was the most "well-rounded" in terms of functionality. Clinical pharmacists were significantly more likely to purchase MMA, in particular UpToDate® (p < 0.01) due to their need to access clinical updates. Respondents highly recommended institutional access for either UpToDate® or Lexicomp® be made available. Pre-registration pharmacists should be guided on judicious MMA usage, as they downloaded significantly more apps and were more likely to indicate not knowing which DI recommendation to follow (both p < 0.01). CONCLUSION: MMA has become an indispensable tool for hospital pharmacists, however there was a tendency to download multiple apps for DI needs. Institutional access can be considered for credible apps identified to ensure accuracy and uniformity of DI recommendations, with purchase decision made after surveying the needs and preferences of end users.

Phase-averaged and cycle-to-cycle analysis of jet dynamics in a scaled up vocal-fold model.

Phase-averaged and cycle-to-cycle analysis of key contributors to sound production in phonation is examined in a scaled-up vocal-fold model. Simultaneous temporally and spatially resolved pressure and velocity measurements permitted examination of each term in the streamwise integral momentum equation. The relative sizes of these terms were used to address the issue of whether transglottal pressure is a surrogate for vocal-fold drag, a quantity directly related to sound production. Further, time traces of transglottal pressure and volume flow rate provided insight into the role of cycle-to-cycle variations in voiced sound production which affect voice quality. Experiments were conducted using a 10× scaled-up model in a free-surface water tunnel. Two-dimensional vocal-fold models with semi-circular ends inside a square duct were driven with constant opening and closing speeds. The time from opening to closed, To , was half the oscillation period. Time-resolved digital particle image velocimetry (DPIV) and pressure measurements along the duct centreline were made for 3650 ≤ Re ≤ 8100 and equivalent life frequencies from 52.5 to 97.5 Hz. Results showed that transglottal pressure does serve as a surrogate for the vocal-fold drag. However, smaller but non-negligible momentum flux and inertia terms, caused by the jet and vocal-fold motions, may also contribute to vocal-fold drag. Further, cycle-to-cycle variations including jet switching and modulation are inherent in flows of this type despite their high degrees of symmetry and repeatability. The origins of these variations and their potential role in sound production and voice quality are discussed.

Cycle-to-cycle flow variations in a square duct with a symmetrically oscillating constriction.

Spatially and temporally resolved Digital Particle Image Velocimetry (DPIV) measurements are presented of flow complexities in a nominally two-dimensional, symmetric, duct with an oscillating constriction. The motivation for this research lies in advancing the state-of-the-art in applying integral control volume analysis to modeling unsteady internal flows. The specific target is acoustic modeling of human phonation. The integral mass and momentum equations are directly coupled to the acoustic equations and provide quantitative insight into acoustic source strengths in addition to the dynamics of the fluid-structure interactions in the glottis. In this study, a square cross-section duct was constructed with symmetric, computer controlled, oscillating constrictions that incorporate both rocking as well as oscillatory open/close motions. Experiments were run in a free-surface water tunnel over a Strouhal number range, based on maximum jet speed and model length, of 0.012 - 0.048, for a fixed Reynolds number, based on maximum gap opening and maximum jet speed, of 8000. In this study, the constriction motions were continuous with one open-close cycle immediately following another. While the model and its motions were nominally two-dimensional and symmetric, flow asymmetries and oscillation frequency dependent cycle-to-cycle variations were observed. These are examined in the context of terms in the integral conservation equations.

Observations of Shear Stress Effects on Staphylococcus aureus Biofilm Formation.

Staphylococcus aureus bacteria form biofilms and distinctive microcolony or "tower" structures that facilitate their ability to tolerate antibiotic treatment and to spread within the human body. The formation of microcolonies, which break off, get carried downstream, and serve to initiate biofilms in other parts of the body, is of particular interest here. It is known that flow conditions play a role in the development, dispersion, and propagation of biofilms in general. The influence of flow on microcolony formation and, ultimately, what factors lead to microcolony development are, however, not well understood. The hypothesis being examined is that microcolony structures form within a specific range of levels of shear stress. In this study, laminar shear flow over a range of 0.15 to 1.5 dynes/cm2 was examined. It was found that microcolony structures form in a narrow range of shear stresses around 0.6 dynes/cm2 Further, measurements of cell density as a function of space and time showed that shear dependence can be observed hours before microcolonies form. This is significant because, among other physiologic flows, this is the same shear stress found in large veins in the human vasculature, which, along with catheters of similar diameters and flow rates, may therefore play a critical role in biofilm development and subsequent spreading of infections throughout the body.IMPORTANCE It is well known that flow plays an important role in the formation, transportation, and dispersion of Staphylococcus aureus biofilms. What was heretofore not known was that the formation of tower structures in these biofilms is strongly shear stress dependent; there is, in fact, a narrow range of shear stresses in which the phenomenon occurs. This work quantifies the observed shear dependence in terms of cell growth, distribution, and fluid mechanics. It represents an important first step in opening up a line of questioning as to the interaction of fluid forces and their influence on the dynamics of tower formation, break-off, and transportation in biofilms by identifying the parameter space in which this phenomenon occurs. We have also introduced state-of-the-art flow measurement techniques to address this problem.

Flow patterns through vascular graft models with and without cuffs.

The shape of a bypass graft plays an important role on its efficacy. Here, we investigated flow through two vascular graft designs-with and without cuff at the anastomosis. We conducted Digital Particle Image Velocimetry (DPIV) measurements to obtain the flow field information through these vascular grafts. Two pulsatile flow waveforms corresponding to cardiac cycles during the rest and the excitation states, with 10% and without retrograde flow out the proximal end of the native artery were examined. In the absence of retrograde flow, the straight end-to-side graft showed recirculation and stagnation regions that lasted throughout the full cardiac cycle with the stagnation region more pronounced in the excitation state. The contoured end-to-side graft had stagnation region that lasted only for a portion of the cardiac cycle and was less pronounced. With 10% retrograde flow, extended stagnation regions under both rest and excitation states for both bypass grafts were eliminated. Our results show that bypass graft designers need to consider both the type of flow waveform and presence of retrograde flow when sculpting an optimal bypass graft geometry.

Proteomic analysis reveals age-related changes in tendon matrix composition, with age- and injury-specific matrix fragmentation.

Energy storing tendons, such as the human Achilles and equine superficial digital flexor tendon (SDFT), are highly prone to injury, the incidence of which increases with aging. The cellular and molecular mechanisms that result in increased injury in aged tendons are not well established but are thought to result in altered matrix turnover. However, little attempt has been made to fully characterize the tendon proteome nor determine how the abundance of specific tendon proteins changes with aging and/or injury. The aim of this study was, therefore, to assess the protein profile of normal SDFTs from young and old horses using label-free relative quantification to identify differentially abundant proteins and peptide fragments between age groups. The protein profile of injured SDFTs from young and old horses was also assessed. The results demonstrate distinct proteomic profiles in young and old tendon, with alterations in the levels of proteins involved in matrix organization and regulation of cell tension. Furthermore, we identified several new peptide fragments (neopeptides) present in aged tendons, suggesting that there are age-specific cleavage patterns within the SDFT. Proteomic profile also differed between young and old injured tendon, with a greater number of neopeptides identified in young injured tendon. This study has increased the knowledge of molecular events associated with tendon aging and injury, suggesting that maintenance and repair of tendon tissue may be reduced in aged individuals and may help to explain why the risk of injury increases with aging.

Measurement of hydrodynamic force generation by swimming dolphins using bubble DPIV.

Attempts to measure the propulsive forces produced by swimming dolphins have been limited. Previous uses of computational hydrodynamic models and gliding experiments have provided estimates of thrust production by dolphins, but these were indirect tests that relied on various assumptions. The thrust produced by two actively swimming bottlenose dolphins (Tursiops truncatus) was directly measured using digital particle image velocimetry (DPIV). For dolphins swimming in a large outdoor pool, the DPIV method used illuminated microbubbles that were generated in a narrow sheet from a finely porous hose and a compressed air source. The movement of the bubbles was tracked with a high-speed video camera. Dolphins swam at speeds of 0.7 to 3.4 m s(-1) within the bubble sheet oriented along the midsagittal plane of the animal. The wake of the dolphin was visualized as the microbubbles were displaced because of the action of the propulsive flukes and jet flow. The oscillations of the dolphin flukes were shown to generate strong vortices in the wake. Thrust production was measured from the vortex strength through the Kutta-Joukowski theorem of aerodynamics. The dolphins generated up to 700 N during small amplitude swimming and up to 1468 N during large amplitude starts. The results of this study demonstrated that bubble DPIV can be used effectively to measure the thrust produced by large-bodied dolphins.

Flow bioreactor design for quantitative measurements over endothelial cells using micro-particle image velocimetry.

Mechanotransduction in endothelial cells (ECs) is a highly complex process through which cells respond to changes in hemodynamic loading by generating biochemical signals involving gene and protein expression. To study the effects of mechanical loading on ECs in a controlled fashion, different in vitro devices have been designed to simulate or replicate various aspects of these physiological phenomena. This paper describes the design, use, and validation of a flow chamber which allows for spatially and temporally resolved micro-particle image velocimetry measurements of endothelial surface topography and stresses over living ECs immersed in pulsatile flow. This flow chamber also allows the study of co-cultures (i.e., ECs and smooth muscle cells) and the effect of different substrates (i.e., coverslip and∕or polyethylene terepthalate (PET) membrane) on cellular response. In this report, the results of steady and pulsatile flow on fixed endothelial cells seeded on PET membrane and coverslip, respectively, are presented. Surface topography of ECs is computed from multiple two-dimensional flow measurements. The distributions of shear stress and wall pressure on each individual cell are also determined and the importance of both types of stress in cell remodeling is highlighted.

Magnetic resonance velocity imaging derived pressure differential using control volume analysis.

BACKGROUND: Diagnosis and treatment of hydrocephalus is hindered by a lack of systemic understanding of the interrelationships between pressures and flow of cerebrospinal fluid in the brain. Control volume analysis provides a fluid physics approach to quantify and relate pressure and flow information. The objective of this study was to use control volume analysis and magnetic resonance velocity imaging to non-invasively estimate pressure differentials in vitro. METHOD: A flow phantom was constructed and water was the experimental fluid. The phantom was connected to a high-resolution differential pressure sensor and a computer controlled pump producing sinusoidal flow. Magnetic resonance velocity measurements were taken and subsequently analyzed to derive pressure differential waveforms using momentum conservation principles. Independent sensor measurements were obtained for comparison. RESULTS: Using magnetic resonance data the momentum balance in the phantom was computed. The measured differential pressure force had amplitude of 14.4 dynes (pressure gradient amplitude 0.30 Pa/cm). A 12.5% normalized root mean square deviation between derived and directly measured pressure differential was obtained. These experiments demonstrate one example of the potential utility of control volume analysis and the concepts involved in its application. CONCLUSIONS: This study validates a non-invasive measurement technique for relating velocity measurements to pressure differential. These methods may be applied to clinical measurements to estimate pressure differentials in vivo which could not be obtained with current clinical sensors.

Dynamics of temporal variations in phonatory flow.

This paper addresses the dynamic relevance of time variations of phonatory airflow, commonly neglected under the quasisteady phonatory flow assumption. In contrast to previous efforts, which relied on direct measurement of glottal impedance, this work uses spatially and temporally resolved measurements of the velocity field to estimate the unsteady and convective acceleration terms in the unsteady Bernoulli equation. Theoretical considerations suggest that phonatory flow is inherently unsteady when two related conditions apply: (1) that the unsteady and convective accelerations are commensurate, and (2) that the inertia of the glottal jet is non-negligible. Acceleration waveforms, computed from experimental data, show that unsteady and convective accelerations to be the same order of magnitude, throughout the cycle, and that the jet flow contributes significantly to the unsteady acceleration. In the middle of the cycle, however, jet inertia is negligible because the convective and unsteady accelerations nearly offset one another in the jet region. These results, consistent with previous findings treating quasisteady phonatory flow, emphasize that unsteady acceleration cannot be neglected during the final stages of the phonation cycle, during which voice sound power and spectral content are largely determined. Furthermore, glottal jet dynamics must be included in any model of phonatory airflow.

Development of a theoretical framework for analyzing cerebrospinal fluid dynamics.

BACKGROUND: To date hydrocephalus researchers acknowledge the need for rigorous but utilitarian fluid mechanics understanding and methodologies in studying normal and hydrocephalic intracranial dynamics. Pressure volume models and electric circuit analogs introduced pressure into volume conservation; but control volume analysis enforces independent conditions on pressure and volume. Previously, utilization of clinical measurements has been limited to understanding of the relative amplitude and timing of flow, volume and pressure waveforms; qualitative approaches without a clear framework for meaningful quantitative comparison. METHODS: Control volume analysis is presented to introduce the reader to the theoretical background of this foundational fluid mechanics technique for application to general control volumes. This approach is able to directly incorporate the diverse measurements obtained by clinicians to better elucidate intracranial dynamics and progression to disorder. RESULTS: Several examples of meaningful intracranial control volumes and the particular measurement sets needed for the analysis are discussed. CONCLUSION: Control volume analysis provides a framework to guide the type and location of measurements and also a way to interpret the resulting data within a fundamental fluid physics analysis.

Unsteady behavior of flow in a scaled-up vocal folds model.

Measurements of the fluid flow through a scaled-up model of the human glottis are presented to determine whether glottal flow may be approximated as unsteady. Time- and space-resolved velocity vector fields from digital particle image velocimetry (DPIV) measurements of the flow through the gap between two moving, rigid walls are presented in four cases, over a range of Strouhal numbers: 0.010, 0.018, 0.035, 0.040, corresponding to life-scale f(0) of 30, 58, 109, and 126 Hz, respectively, at a Reynolds number of 8000. It is observed that (1) glottal flow onset is delayed after glottal opening and (2) glottal flow shutoff occurs prior to closure. A comparison between flow through a fully open, nonmoving glottis and that through the moving vocal folds shows a marked difference in spatial structure of the glottal jet. The following features of the flow are seen to exhibit strong dependence on cycle frequency: (a) glottal exit plane velocity, (b) volume flow, (c) vortex shedding rates, and (d) vortex amplitude. Vortex shedding appears to be a factor both in controlling flow resistance and in cycle-to-cycle volume flow variations. All these observations strongly suggest that glottal flow is inherently unsteady.

Theoretical assessment of unsteady aerodynamic effects in phonation.

This paper ranks the importance of unsteady aerodynamic mechanisms in glottal flow. Particular emphasis is given to separation point motion, acceleration of glottal airflow by vocal fold motion, and viscous blockage. How nondimensional parameters such as the Reynolds, Strouhal, and Womersley numbers help in this ranking is also addressed. An equation of motion is derived which includes terms explicitly describing the effects of interest, assuming (1) a symmetrical glottis, (2) zero pressure recovery downstream of the vocal folds, and (3) a quasisteady glottal jet. Estimating the order of magnitude of the terms in this equation, it is shown that the flow is characterized by two temporal regimes: (1) a flow initiation/shutoff regime where local unsteady acceleration and wall motion dominate, and (2) a "quasisteady" regime where the flow is dominated by convective acceleration. In the latter case, separation point motion and viscous blockage are shown to be out of phase with motion of the vocal folds, thereby impacting the shape of the glottal volume flow waveform. The analysis suggests that glottal flow may be considered quasisteady only insofar as traditional assumptions concerning glottal jet behavior can be confirmed.

Expression and biological effect of urodele fibroblast growth factor 1: relationship to limb regeneration.

Fibroblast growth factors (FGFs) have been previously implicated in urodele limb regeneration. Here, we examined expression of FGF-1 by blastema cells and neurons and investigated its involvement in wound epithelial formation and function and in the trophic effect of nerves. Neurons innervating the limb and blastema cells in vivo and in vitro expressed the FGF-1 gene. The peptide was present in blastemas in vivo. Wound epithelium thickened when recombinant newt FGF-1 was provided on heparin-coated beads, demonstrating that the FGF-1 was biologically active and that the wound epithelium is a possible target tissue of FGF. FGF-1 did not stimulate accessory limb formation. FGF-1 was as effective as 10% fetal bovine serum in maintaining proliferative activity of blastema cells in vitro but was unable to maintain growth of denervated, nerve-dependent stage blastemas when provided on beads or by injection. FGF-1 had a strong stimulating effect on blastema cell accumulation and proliferation of limbs inserted into the body cavity that were devoid of an apical epithelial cap (AEC). These results show that FGF-1 can signal wound epithelium cap formation and/or function and can stimulate mesenchyme accumulation/proliferation in the absence of the AEC but that FGF-1 is not directly involved in the neural effect on blastema growth.