Patient Acceptable Symptomatic State and Substantial Clinical Benefit Matter Most to Patients and Must Be Reported Correctly.

Despite a push for a focus on clinical rather than "statistical" significance, and an emphasis on reporting of outcome thresholds such as Patient Acceptable Symptomatic State (PASS) and Substantial Clinical Benefit (SCB), PASS and SCB are rarely reported, and when reported, are often reported incorrectly. Yet, patients require satisfaction (PASS) as a result of our treatments, and patients desire to improve substantially (SCB). Determining whether patients are satisfied and/or substantially improved is simple…just ask them. The questions are known as anchor questions. Obviously, different patients have different thresholds of PASS and SCB, and reliance on previously published literature for values of these thresholds can result in error-thus, the anchor questions. And, each patient must be assessed individually. Outcome thresholds are not group-level metrics, and must be reported as the percentage of individuals who achieve the clinically significant outcome. Certain patients, such as athletes, have high baseline function and may demand Maximum Outcome Improvement or (MOI). In contrast, Minimally Clinically Important Difference (MCID) is a less-than-ideal measure; patients do not desire "minimal" improvement. Journals must do a better job of publishing Patient Reported Outcome Measures (PROM) that matter most to patients: satisfaction and substantial benefit.

Endothelial-to-Mesenchymal Transition in Cardiovascular Pathophysiology.

Under different pathophysiological conditions, endothelial cells lose endothelial phenotype and gain mesenchymal cell-like phenotype via a process known as endothelial-to-mesenchymal transition (EndMT). At the molecular level, endothelial cells lose the expression of endothelial cell-specific markers such as CD31/platelet-endothelial cell adhesion molecule, von Willebrand factor, and vascular-endothelial cadherin and gain the expression of mesenchymal cell markers such as α-smooth muscle actin, N-cadherin, vimentin, fibroblast specific protein-1, and collagens. EndMT is induced by numerous different pathways triggered and modulated by multiple different and often redundant mechanisms in a context-dependent manner depending on the pathophysiological status of the cell. EndMT plays an essential role in embryonic development, particularly in atrioventricular valve development; however, EndMT is also implicated in the pathogenesis of several genetically determined and acquired diseases, including malignant, cardiovascular, inflammatory, and fibrotic disorders. Among cardiovascular diseases, aberrant EndMT is reported in atherosclerosis, pulmonary hypertension, valvular disease, fibroelastosis, and cardiac fibrosis. Accordingly, understanding the mechanisms behind the cause and/or effect of EndMT to eventually target EndMT appears to be a promising strategy for treating aberrant EndMT-associated diseases. However, this approach is limited by a lack of precise functional and molecular pathways, causes and/or effects, and a lack of robust animal models and human data about EndMT in different diseases. Here, we review different mechanisms in EndMT and the role of EndMT in various cardiovascular diseases.

Laser Doppler Fluximetry in Cutaneous Vasculature: Methods for Data Analyses.

INTRODUCTION: Acquisition of a deeper understanding of microvascular function across physiological and pathological conditions can be complicated by poor accessibility of the vascular networks and the necessary sophistication or intrusiveness of the equipment needed to acquire meaningful data. Laser Doppler fluximetry (LDF) provides a mechanism wherein investigators can readily acquire large amounts of data with minor inconvenience for the subject. However, beyond fairly basic analyses of erythrocyte perfusion (fluximetry) data within the cutaneous microcirculation (i.e., perfusion at rest and following imposed challenges), a deeper understanding of microvascular perfusion requires a more sophisticated approach that can be challenging for many investigators. METHODS: This manuscript provides investigators with clear guidance for data acquisition from human subjects for full analysis of fluximetry data, including levels of perfusion, single- and multiscale Lempel-Ziv complexity (LZC) and sample entropy (SampEn), and wavelet-based analyses for the major physiological components of the signal. Representative data and responses are presented from a recruited cohort of healthy volunteers, and computer codes for full data analysis (MATLAB) are provided to facilitate efforts by interested investigators. CONCLUSION: It is anticipated that these materials can reduce the challenge to investigators integrating these approaches into their research programs and facilitate translational research in cardiovascular science.

Protein Disulfide Isomerase 4 Is an Essential Regulator of Endothelial Function and Survival.

Endothelial autophagy plays an important role in the regulation of endothelial function. The inhibition of endothelial autophagy is associated with the reduced expression of protein disulfide isomerase 4 (PDIA-4); however, its role in endothelial cells is not known. Here, we report that endothelial cell-specific loss of PDIA-4 leads to impaired autophagic flux accompanied by loss of endothelial function and apoptosis. Endothelial cell-specific loss of PDIA-4 also induced marked changes in endothelial cell architecture, accompanied by the loss of endothelial markers and the gain of mesenchymal markers consistent with endothelial-to-mesenchymal transition (EndMT). The loss of PDIA-4 activated TGFß-signaling, and inhibition of TGFß-signaling suppressed EndMT in PDIA-4-silenced endothelial cells in vitro. Our findings help elucidate the role of PDIA-4 in endothelial autophagy and endothelial function and provide a potential target to modulate endothelial function and/or limit autophagy and EndMT in (patho-)physiological conditions.

The clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing.

RNA sequencing (RNA-seq) has recently been used in translational research settings to facilitate diagnoses of Mendelian disorders. A significant obstacle for clinical laboratories in adopting RNA-seq is the low or absent expression of a significant number of disease-associated genes/transcripts in clinically accessible samples. As this is especially problematic in neurological diseases, we developed a clinical diagnostic approach that enhanced the detection and evaluation of tissue-specific genes/transcripts through fibroblast-to-neuron cell transdifferentiation. The approach is designed specifically to suit clinical implementation, emphasizing simplicity, cost effectiveness, turnaround time, and reproducibility. For clinical validation, we generated induced neurons (iNeurons) from 71 individuals with primary neurological phenotypes recruited to the Undiagnosed Diseases Network. The overall diagnostic yield was 25.4%. Over a quarter of the diagnostic findings benefited from transdifferentiation and could not be achieved by fibroblast RNA-seq alone. This iNeuron transcriptomic approach can be effectively integrated into diagnostic whole-transcriptome evaluation of individuals with genetic disorders.

Cerebrovascular dysfunction and depressive symptoms in preclinical models: insights from a scoping review.

Although existing literature supports associations between cerebrovascular dysfunction and the emergence of depression and depressive symptoms, relatively little is known about underlying mechanistic pathways that may explain potential relationships. As such, an integrated understanding of these relationships in preclinical models could provide insight into the nature of the relationship, basic mechanistic linkages, and areas in which additional investment should be targeted. This scoping review was conducted in MEDLINE, EMBASE, and Scopus to outline the relationship between depressive symptoms and cerebrovascular dysfunction in preclinical animal models with an additional focus on the areas above. From 3,438 articles initially identified, 15 studies met the inclusion criteria and were included in the review. All studies reported a positive association between the severity of markers for cerebrovascular dysfunction and that for depressive symptoms in rodent models and this spanned all models for either pathology. Specific mechanistic links between the two such as chronic inflammation, elevated vascular oxidant stress, and altered serotonergic signaling were highlighted. Notably, almost all studies addressed outcomes in male animals, with a near complete lack of data from females, and there was little consistency in terms of how cerebrovascular dysfunction was assessed. Across nearly all studies was a lack of clarity for any "cause and effect" relationship between depressive symptoms and cerebrovascular dysfunction. At this time, it is reasonable to conclude that a correlative relationship clearly exists between the two, and future investigation will be required to parse out more specific aspects of this relationship.NEW & NOTEWORTHY This scoping review presents a structured evaluation of all relevant existing literature linking cerebral vasculopathy to depressive symptom emergence in preclinical models. Results support a definite connection between vascular dysfunction and depressive symptoms, highlighting the importance of chronic elevations in inflammation and oxidant stress, and impaired serotonergic signaling. The review also identified significant knowledge gaps addressing male versus female differences and limited clear mechanistic links between cerebral vasculopathy and depressive symptoms.

A constrained constructive optimization model of branching arteriolar networks in rat skeletal muscle.

Blood flow regulation within the microvasculature reflects a complex interaction of regulatory mechanisms and varies spatially and temporally according to conditions such as metabolism, growth, injury, and disease. Understanding the role of microvascular flow distributions across conditions is of interest to investigators spanning multiple disciplines; however, data collection within networks can be labor-intensive and challenging due to limited resolution. To overcome these experimental challenges, computational network models that can accurately simulate vascular behavior are highly beneficial. Constrained constructive optimization (CCO) is a commonly used algorithm for vascular simulation, particularly well known for its adaptability toward vascular modeling across tissues. The present work demonstrates an implementation of CCO aimed to simulate a branching arteriolar microvasculature in healthy skeletal muscle, validated against literature including comprehensive rat gluteus maximus vasculature datasets, and reviews a list of user-specified adjustable model parameters to understand how their variability affects the simulated networks. Network geometric properties, including mean element diameters, lengths, and numbers of bifurcations per order, Horton's law ratios, and fractal dimension, demonstrate good validation once model parameters are adjusted to experimental data. This model successfully demonstrates hemodynamic properties such as Murray's law and the network Fahraeus effect. Application of centrifugal and Strahler ordering schemes results in divergent descriptions of identical simulated networks. This work introduces a novel CCO-based model focused on generating branching skeletal muscle microvascular arteriolar networks based on adjustable model parameters, thus making it a valuable tool for investigations into skeletal muscle microvascular structure and tissue perfusion.NEW & NOTEWORTHY The present work introduces a CCO-based algorithm for generating branching arteriolar networks, with adjustable model parameters to enable modeling in varying skeletal muscle tissues. The geometric and hemodynamic parameters of the generated networks have been comprehensively validated using experimental data collected previously in-house and from literature. This is one of few validated CCO-based models to specialize in skeletal muscle microvasculature and acts as a beneficial tool for investigating the microvasculature for hypothesis testing and validation.

Extending the computational and experimental analysis of lipase active site selectivity.

Molecular docking is an important computational analysis widely used to predict the interaction of enzymes with several starting materials for developing new valuable products from several starting materials, including oils and fats. In the present study, molecular docking was used as an efficient in silico screening tool to select biocatalysts with the highest catalytic performance in butyl esters production in a solvent-free system, an eco-friendly approach, via direct esterification of free fatty acids from Licuri oil with butanol. For such purpose, three commercial lipase preparations were used to perform molecular docking studies such as Burkholderia cepacia (BCL), Porcine pancreatic (PPL), and Candida rugosa (CRL). Concurrently, the results obtained in BCL and CRL are the most efficient in the esterification process due to their higher preference for catalyzing the esterification of lauric acid, the main fatty acid found in the licuri oil composition. Meanwhile, PPL was the least efficient because it preferentially interacts with minor fatty acids. Molecular docking with the experimental results indicated the better performance in the synthesis of esters was BCL. In conclusion, experimental results analysis shows higher enzymatic productivity in esterification reactions of 1294.83 µmol/h.mg, while the CRL and PPL demonstrated the lowest performance (189.87 µmol / h.mg and 23.96 µmol / h.mg, respectively). Thus, molecular docking and experimental results indicate that BCL is a more efficient lipase to produce fatty acids and esters from licuri oil with a high content of lauric acid. In addition, this study also demonstrates the application of molecular docking as an important tool for lipase screening to achieve more sustainable production of butyl esters with a view synthesis of biolubricants.

Experimental and Computational Analysis of Synthesis Conditions of Hybrid Nanoflowers for Lipase Immobilization.

This work presents a framework for evaluating hybrid nanoflowers using Burkholderia cepacia lipase. It was expanded on previous findings by testing lipase hybrid nanoflowers (hNF-lipase) formation over a wide range of pH values (5-9) and buffer concentrations (10-100 mM). The free enzyme activity was compared with that of hNF-lipase. The analysis, performed by molecular docking, described the effect of lipase interaction with copper ions. The morphological characterization of hNF-lipase was performed using scanning electron microscopy. Fourier Transform Infrared Spectroscopy performed the physical-chemical characterization. The results show that all hNF-lipase activity presented values higher than that of the free enzyme. Activity is higher at pH 7.4 and has the highest buffer concentration of 100 mM. Molecular docking analysis has been used to understand the effect of enzyme protonation on hNF-lipase formation and identify the main the main binding sites of the enzyme with copper ions. The hNF-lipase nanostructures show the shape of flowers in their micrographs from pH 6 to 8. The spectra of the nanoflowers present peaks typical of the amide regions I and II, current in lipase, and areas with P-O vibrations, confirming the presence of the phosphate group. Therefore, hNF-lipase is an efficient biocatalyst with increased catalytic activity, good nanostructure formation, and improved stability.

Thromboxane-induced cerebral microvascular rarefaction predicts depressive symptom emergence in metabolic disease.

Previous studies have suggested that the loss of microvessel density in the peripheral circulation with evolving metabolic disease severity represents a significant contributor to impaired skeletal muscle oxygenation and fatigue-resistance. Based on this and our recent work, we hypothesized that cerebral microvascular rarefaction was initiated from the increased prooxidant and proinflammatory environment with metabolic disease and is predictive of the severity of the emergence of depressive symptoms in obese Zucker rats (OZRs). In male OZR, cerebrovascular rarefaction followed the emergence of elevated oxidant and inflammatory environments characterized by increased vascular production of thromboxane A2 (TxA2). The subsequent emergence of depressive symptoms in OZR was associated with the timing and severity of the rarefaction. Chronic intervention with antioxidant (TEMPOL) or anti-inflammation (pentoxifylline) therapy blunted the severity of rarefaction and depressive symptoms, although the effectiveness was limited. Blockade of TxA2 production (dazmegrel) or action (SQ-29548) resulted in a stronger therapeutic effect, suggesting that vascular production and action represent a significant contributor to rarefaction and the emergence of depressive symptoms with chronic metabolic disease (although other pathways clearly contribute as well). A de novo biosimulation of cerebrovascular oxygenation in the face of progressive rarefaction demonstrates the increased probability of generating hypoxic regions within the microvascular networks, which could contribute to impaired neuronal metabolism and the emergence of depressive symptoms. The results of the present study also implicate the potential importance of aggressive prodromic intervention in reducing the severity of chronic complications arising from metabolic disease.NEW & NOTEWORTHY With clinical studies linking vascular disease risk to depressive symptom emergence, we used obese Zucker rats, a model of chronic metabolic disease, to identify potential mechanistic links between these two negative outcomes. Depressive symptom severity correlated with the extent of cerebrovascular rarefaction, after increased vascular oxidant stress/inflammation and TxA2 production. Anti-TxA2 interventions prevasculopathy blunted rarefaction and depressive symptoms, while biosimulation indicated that cerebrovascular rarefaction increased hypoxia within capillary networks as a potential contributing mechanism.

Scoping Review: Integration of the Major Mechanisms Underlying the Regulation of Arteriolar Tone.

BACKGROUND: Cardiovascular diseases remain the leading cause of morbidity and mortality worldwide. Arteriolar tone regulation plays a critical role in maintaining appropriate organ blood flow and perfusion distribution, which is vital for both vascular and overall health. SUMMARY: This scoping review aimed to explore the interplay between five major regulators of arteriolar tone: metabolism (adenosine), adrenergic control (norepinephrine), myogenic activation (intravascular pressure), perivascular oxygen tension, and intraluminal flow rates. Specifically, the aim was to address how arteriolar reactivity changes in the presence of other vasoactive stimuli and by what mechanisms. The review focused on animal studies that investigated the impact of combining two or more of these stimuli on arteriolar diameter. Overall, 848 articles were identified through MEDLINE and EMBASE database searches, and 38 studies were included in the final review. KEY MESSAGES: The results indicate that arteriolar reactivity is influenced by multiple factors, including competitive processes, structural limitations, and indirect interactions among stimuli. Additionally, the review identified a lack of research involving female animal models and limited insight into the interaction of molecular signaling pathways, which represent gaps in the literature.

The Ultimate Goal of Medical Publishing is Practice-Changing Innovation.

New Year brings a new catchline: Practice-Changing Innovation. Publishing groundbreaking research and inventive techniques that translate to improvements in patient care is an ultimate goal.

Short-term glacier area changes, glacier geometry dependence, and regional climatic variations forcing, King George Island, Antarctica.

This study investigates the transient snowline (TSL) altitude for summer 2020, as well as glacial area loss in King George Island Icefields since 1988 using Sentinel-1 and 2 and Landsat Thematic Mapper (TM) imagery. Trends and anomalies in atmospheric temperature, U-wind, and V-wind were examined using ERA5 solutions. Results show the wet-snow zone corresponds to values of ≤ -13dB, and 44.3% of the glacial area is located above the TSL (≥ 300 m). Glacial area for 2020 is 999.95 km², and losses in the period represent 104.9 km² (error <1%) - a retreat of 3.17 km² / year. Glaciers in Keller Peninsula and Bellingshausen Dome lost the most area (28% and 17%, respectively) and did not have a TSL in 2020; followed by Warszawa (15%), Kraków (13%), and Eastern (10%), where the TSL was verified. Percentage area loss values increased with decreases in dimensions, area above TSL, and maximum elevation. Calving glaciers with ice-flow toward deeper and steeper submarine sectors (Bransfield Strait) exhibited greater glacier variations. The trend in warming atmospheric temperature was greater in the Bransfield Strait than in the Drake Passage. TSL and retreat difference between glaciers were influenced by climatic and ocean input, as well as multiple environmental factors.

Ionic and stable isotopic content in two Antarctic firn cores under different environment settings.

This article compares isotopic, ionic and climatic data from two firn cores from the West Antarctic Ice Sheet (WAIS). The IC-02 (88°01'21.3"S , 82°04'21.7"W) and the IC-05 (82°30'30.8"S , 79°28'02.7"W) closer to the coast. The IC-02 had 488 samples analyzed covering 14.58 meters depth while the IC-05 had 602 samples analyzed covering 19.73 meters depth. The time interval for both ice cores is 25 years ranging from 1978 to 2003. Sodium, sulfate and chloride were analyzed via ion chromatography using three DionexTM ionic chromatographers at the laboratories of Centro Polar e Climático (CPC) and at the Climate Change Institute. Stable isotope data was determined using cavity ring-down spectroscopy in a Picarro® spectrometer at the CPC. Annual accumulation was greater at IC-05 with an average of 0.35 m.eq.w.a-1 compared to 0.25 m.eq.w.a-1 at the IC-02. Stable isotope data was approximately 1.3 times more negative at the IC-02 which also presented higher d values. Na+ and Cl- were in higher concentrations at the IC-05 however Cl/Na was greater in the IC-02. The Cl excess was found to be derived from fractionation of sea salt aerosols and not related to volcanism. This work presents new insights regarding the chemical differences between ice cores.

Thermal variations of the active layer in Fildes Peninsula, King George Island, Maritime Antarctica.

This work aimed to characterize the variation in the thermal regime of the active layer in a permafrost area on Fildes Peninsula, Antarctica, and relate this variability with meteorological data between 2014 and 2016. The monitoring site was installed to continuously monitor the temperature and moisture of the active layer, radiation flow on the surface, and air temperature. We used data collected to generate the indexes freezing degree-days, thawing degree-days, frost number, n-factor, apparent thermal diffusivity, and active layer thickness. The temperature of the active layer is not homogeneous, varying with depth and position in the transect, with the greatest variations in soil with better drainage and lower moisture content. Among the evaluated factors, air and soil surface temperature are the ones that most influence the thermal gradient of the active layer. We identified that near the surface there is a greater influence of albedo and cloudiness and at -35 cm depth there is a greater influence of net radiation and soil moisture. The average depth of the active layer in 2014 was -44.3 cm and in 2015 -47.7 cm and the frost number index indicates that there was a predominance of continuous permafrost in the transect during the monitoring.

Glacier fluctuations and a proglacial evolution in King George Bay (King George Island), Antarctica, since 1980 decade.

This study aims to investigate the glacier shrinkage and recent proglacial environment in King George Bay, Antarctica, since 1988 in response to climate change. Remote sensing data (SPOT, Sentinel, Landsat and Planet Scope images) were applied to glacial landforms and ice-marginal fluctuations mapping. Annual mean near-surface air temperature reanalysis solutions from ERA-Interim were analyzed. Moraines and glaciofluvial landforms were identified. The Ana Northern Glacier has the highest retreat value (3.64 km) (and area loss of 31%) in response to higher depth in frontal ice-margin and reveal ocean-glacier linkages. The Ana South Glacier changed from a tidewater glacier to land-terminating after 1995, and had an outline minimum elevation variation of 89 meters, a shrinkage of 0.63 km, and a new proglacial subaerial sector. The Ana South Glacier foreland had recessional moraines (probably formed between 1995 and 2022), lagoons, and lakes. There are many flutings in low-relief environments. The 1980-1989, 1990-1999, 2000-2009, 2010-2019 anomaly plots concerning to the 1980-2019 average for atmospheric temperature, are shown to be a driver of the local glacial trends.

The use of sentinel-2 imagery to generate vegetations maps for the Northern Antarctic peninsula and offshore islands.

We used Sentinel-2 imagery time series to generate a vegetation map for the Northern part of the Antarctica Peninsula and offshore islands, including the South Shetlands. The vegetation cover was identified in the NDVI maximum value composite image. The NDVI values were associated with the occurrence of algae (0.15 - 0.20), lichens (0.20 - 0.50), and mosses (0.50 - 0.80). The vegetation cover distribution map was validated using the literature information. Generating a vegetation map distribution on an annual basis was not possible due to high cloud cover in the Antarctic region, especially in coastal áreas, so optical images from 2016 to 2021 were necessary to map the vegetation distribution in the entire study área. The final map analyzed in association with the weather data shows the occurrence of a microenvironment over the western islands of the Antarctic Peninsula that provided vegetation growth conditions. The Sentinel-2 images with 10m spatial resolution allow the assembly of accurate vegetation distribution maps for the Antarctica Peninsula and Islands, the Google Earth Engine cloud computing being essential to process a large amount of the satellite images necessary for processing these maps.

Stable-isotope ratios (δ18O and δD) in a firn core from West Antarctica.

A 22.48 m long ice core (BR-IC-4) was collected in the West Antarctic Ice Sheet (at 83°58'59.4" S, 80°07'01.4" W, 1,295 m above the sea level) during the Austral summer of 2004-2005, as a contribution to the International Trans-Antarctic Expedition program. The isotopic composition (δD and δ18O) of 599 samples, corresponding to the upper 12.98 m of the ice core, was determined by gas source mass spectrometry and cavity ring-down spectroscopy. Relative dating was based on the isotopic ratios and major ions (MS-, Na+, nssSO4 2-) and trace elements (Na, S, Sr) concentrations. The record covers approximately 13 years - from 1990 to 2003. The mean accumulation rate of 0.48 ± 0.09 m water equivalent per year (m eq H2O a1) is relatively high for the geographical area and possibly results from snowdrifting from near areas, as attested by ice glaze surfaces in other sites in the region. The stable isotope δD content varies between -367.90‰ and 256.30‰ (mean -314.42 ± 19.01‰); and δ18O ranges from -44.96‰ to 35.08‰ (mean -39.95 ± 2.05‰). Deuterium excess values (mean 3.70 ± 1.54‰) indicate episodic intense oceanic evaporation and high relative humidity in the moisture sources.