Predictors of Shock-Reduction Programming and Its Impact on Implantable Cardioverter-Defibrillator Therapies and Mortality: The CERTITUDE Registry.

BACKGROUND: Shock-reduction implantable cardioverter-defibrillator programming (SRP) was associated with fewer therapies and improved survival in randomized controlled trials, but real-world studies investigating SRP and associated outcomes are limited. METHODS AND RESULTS: The BIOTRONIK CERTITUDE registry was linked with the Medicare database. We included all patients with an implantable cardioverter-defibrillator implanted between August 22, 2012 and September 30, 2021 in the United States. SRP was defined as programming to either a therapy rate cutoff ≥188 beats per minute or number of intervals to detection ≥30/40 for treatment. Among 6781 patients (mean 74±9 years; 27% women), 3393 (50%) had SRP. Older age, secondary prevention indication, and device implantation in the southern or western United States were associated with lower use of SRP. The cumulative incidence rate of implantable cardioverter-defibrillator shocks was lower in the SRP group (5.1% shocks/patient year) compared with the non-SRP group (7.2% shocks/patient year) (adjusted hazard ratio [HR], 0.83 [95% CI, 0.73-0.96]; P=0.005). Over a median follow-up of 2.9 years, 739 deaths occurred in the SRP group and 822 deaths occurred in the non-SRP group (adjusted HR, 0.97 [95% CI, 0.88-1.07]; P=0.569). SRP was associated with a lower all-cause mortality among patients without ischemic heart disease compared with patients with ischemic heart disease (adjusted HR, 0.64 [95% CI, 0.48-0.87] versus adjusted HR, 1.02 [95% CI, 0.92-1.14]; Pinteraction=0.004). CONCLUSIONS: Adoption of SRP is low in real-world clinical practice. Age, clinical variables, and geographic factors are associated with use of SRP. In this study, SRP-associated decrease in mortality was limited to patients without ischemic heart disease.

[New pacing strategies for heart failure]. / Neue Pacing-Strategien bei Herzinsuffizienz.

In patients with a reduced left ventricular (LV) systolic function (ejection fraction < 35%) and a left bundle branch block with a QRS duration > 130 ms, cardiac resynchronization therapy (CRT) can contribute to an improvement in the quality of life and a reduction in mortality. The resynchronization is mostly achieved by pacing via an epicardial LV lead in the coronary sinus; however, this approach is often limited by the patient's venous anatomy and an increase in the stimulation threshold over time. In addition, up to 30% of patients do not respond to the intervention. New treatment approaches involve direct stimulation of the conduction system by pacing of the bundle of His or left bundle branch. This enables a more physiological propagation of the stimulus. Pacing of the left bundle branch is achieved by advancing the lead into the right ventricle and screwing it deep into the interventricular septum. Due to the relatively large target area of the left bundle branch the success rate is very high (currently > 90%). Observational studies have shown a greater reduction in the QRS duration, a more pronounced improvement in systolic function and a lower hospitalization rate for heart failure associated with conduction system pacing compared to CRT using a coronary sinus lead. These findings have been confirmed in small randomized trials. Therefore, the use of left bundle branch pacing should be considered not only as a bail out in the case of failed resynchronization using coronary sinus lead placement but increasingly also as an initial pacing strategy. The results of the first large randomized trials are expected to be released in late 2024.

Effects of a randomized-controlled and online-supported physical activity intervention on exercise capacity, fatigue and health related quality of life in patients with post-COVID-19 syndrome.

BACKGROUND: The Post-COVID-19 syndrome (PCS), which can occur after acute respiratory syndrome coronavirus 2 infection, leads to restrictions in everyday activity. Our study assessed the impact of an online-guided intervention which intended to facilitate physical activity on the mental and physical capability of PCS patients. METHODS: We randomized 62 patients with PCS (20 male/ 42 female; age: 46 ± 12 years; body mass index: 28.7 ± 6.7 kg/m2) with a score ≥ 22 in the fatigue assessment scale (FAS) to a 3-month exercise-focused intervention (IG n = 30) or control period (CG n = 32). We assessed changes in exercise capacity (bicycle exercise test with measurements of gas exchange), fatigue, markers of health-related quality of life (HrQoL) and mental health. RESULTS: The FAS score decreased significantly in both study groups (IG: 35.1 ± 7.4 to 31.8 ± 8.5 points; CG: 35.6 ± 7.4 to 32.6 ± 7.5 points, both p < 0.01). Exercise capacity did not increase in the CG or IG (within-group changes for IG: peak oxygen uptake: 0.9 ± 2.6 ml/min/kg, p = 0.098; peak power output: 6.1 ± 17.8 W, p = 0.076) with no significant changes in HrQoL and work ability. Patients with a FAS score at baseline ≥ 35 (severe fatigue) showed no change in exercise capacity with the 3-month intervention whereas the sub-group of patients with FAS < 35 points (moderate fatigue) showed improvements, independent of the study group. CONCLUSIONS: Our 3-month intervention seems appropriate for patients with moderate fatigue, whereas those with more severe fatigue appear to be too restricted with respect to their mental or physical health status to perform exercise at a level which is sufficient to improve markers of physical performance. TRIAL REGISTRATION: German Clinical Trials Register (registration trial number: DRKS00026245) on September 2 2021.

Post-COVID-19 syndrome: Physical capacity, fatigue and quality of life.

PURPOSE: Post-Covid-19 syndrome is defined as the persistence of symptoms beyond 3 months after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. The most common symptoms include reduced exercise tolerance and capacity, fatigue, neurocognitive problems, muscle pain and dyspnea. The aim of our work was to investigate exercise capacity and markers of subjective wellbeing and their independent relation to post-COVID-19 syndrome. PATIENTS AND METHODS: We examined a total of 69 patients with post-COVID-19 syndrome (23 male/46 female; age 46±12 years; BMI 28.9±6.6 kg/m2) with fatigue and a score ≥22 in the Fatigue Assessment Scale (FAS). We assessed exercise capacity on a cycle ergometer, a 6-minute walk test, the extent of fatigue (FAS), markers of health-related quality of life (SF-36 questionnaire) and mental health (HADS). RESULTS: On average the Fatigue Assessment Scale was 35.0±7.4 points. Compared with normative values the VO2max/kg was reduced by 8.6±5.8 ml/min/kg (27.7%), the 6MWT by 71±96 m (11.9%), the health-related quality of life physical component score by 15.0±9.0 points (29.9%) and the mental component score by 10.6±12.8 points (20.6%). Subdivided into mild fatigue (FAS score 22-34) and severe fatigue (FAS score ≥35), patients with severe fatigue showed a significant reduction of the 6-minute walk test by 64±165 m (p<0.01) and the health-related quality of life physical component score by 5.8±17.2 points (p = 0.01). In multiple regression analysis age (ß = -0.24, p = 0.02), sex (ß = 0.22, p = 0.03), mental (ß = -0.51, p<0.01) and physical (ß = -0.44, p<0.01) health-related quality of life and by trend the 6-minute walk test (ß = -0.22, p = 0.07) were associated with the FAS. CONCLUSION: Patients with post-COVID-19 syndrome show reduced maximal and submaximal physical performance as well as limitations in quality of life, particularly pronounced in the physical components. These results are essentially influenced by the severity of fatigue and implicating the need for targeted treatments.

Engineered coumarin accumulation reduces mycotoxin-induced oxidative stress and disease susceptibility.

Coumarins can fight pathogens and are thus promising for crop protection. Their biosynthesis, however, has not yet been engineered in crops. We tailored the constitutive accumulation of coumarins in transgenic Nicotiana benthamiana, Glycine max and Arabidopsis thaliana plants, as well as in Nicotiana tabacum BY-2 suspension cells. We did so by overexpressing A. thaliana feruloyl-CoA 6-hydroxylase 1 (AtF6'H1), encoding the key enzyme of scopoletin biosynthesis. Besides scopoletin and its glucoside scopolin, esculin at low level was the only other coumarin detected in transgenic cells. Mechanical damage of scopolin-accumulating tissue led to a swift release of scopoletin, presumably from the scopolin pool. High scopolin levels in A. thaliana roots coincided with reduced susceptibility to the root-parasitic nematode Heterodera schachtii. In addition, transgenic soybean plants were more tolerant to the soil-borne pathogenic fungus Fusarium virguliforme. Because mycotoxin-induced accumulation of reactive oxygen species and cell death were reduced in the AtF6'H1-overexpressors, the weaker sensitivity to F. virguliforme may be caused by attenuated oxidative damage of coumarin-hyperaccumulating cells. Together, engineered coumarin accumulation is promising for enhanced disease resilience of crops.

Elective ascending aortic aneurysm repair outcomes in a nationwide US cohort.

OBJECTIVE: To quantify contemporary outcomes following elective ascending aortic aneurysm repair, to determine risk factors for adverse events and to evaluate difference by institutional surgical volume. METHODS: We included all elective hospitalisations of adult patients with an ascending aortic aneurysm who underwent aneurysm repair in the Nationwide Readmissions Database between 2016 and 2019. The primary outcome was a composite of in-hospital mortality, stroke (ischaemic and non-ischaemic) and myocardial infarction (MI). We identified independent predictor of adverse events and investigated outcomes by institutional volume. RESULTS: Among 12 043 patients (mean 62.8 years of age, 28.0% female), MI, stroke or in-hospital death occurred in 598 (4.9%) patients during the index admission (acute stroke: 2.7%, MI: 0.7%, in-hospital death: 2.0%). The strongest predictors of in-hospital death, stroke or MI were chronic weight loss, pulmonary circulation disorder and concomitant descending aortic surgery. Higher procedural volume was associated with a lower incidence of in-hospital death, stroke or MI (OR comparing the highest with the lowest tertile 0.71, 95% CI 0.57 to 0.87; p=0.001) and in-hospital death (OR 0.51, 95% CI 0.37 to 0.72; p<0.001), but no difference in 30-day readmissions. CONCLUSIONS: The overall rate of in-hospital death, stroke and MI is nearly 5% in patients undergoing elective ascending aortic aneurysm repair. Among several predictors, chronic weight loss is associated with the largest increase in the risk of poor outcomes. Higher hospital volume is associated with a lower in-hospital mortality, highlighting the importance to refer patients to high-volume centres while discussing the risks and benefits of proceeding with repair.

Metal-Organic Frameworks (MOFs) and Their Composites as Emerging Biomaterials for Osteoarthritis Treatment.

Metal-Organic Frameworks (MOFs) have emerged as a novel component in biomaterial formulations over the past 5 years. The bioactivity of MOFs in bone or cartilage tissue is mediated through the sustained delivery of metal ions, bioactive ligands, or drug molecules that are loaded into the porous MOF structures. Alternatively, bioactivity may also originate from structure-specific properties. The latter includes the availability and accessibility of open metal coordination sites for the catalytic conversion of biomolecules into active agents. This narrative highlight aims to inspire strategies to utilize MOFs for treating osteoarthritis (OA), with a special focus on augmenting hydrogel-based biomaterials with MOFs. The added value of MOFs in these hydrogel formulations is discussed, and the biological efficacy is compared to approaches applying classical injectable biomaterials for OA treatment. Possible future directions and pitfalls of these novel MOF-hydrogel composites are emphasized to assist future transition of MOFs into clinical applications.

Mechanochemically Synthesised Flexible Electrodes Based on Bimetallic Metal-Organic Framework Glasses for the Oxygen Evolution Reaction.

The melting behaviour of metal-organic frameworks (MOFs) has aroused significant research interest in the areas of materials science, condensed matter physics and chemical engineering. This work first introduces a novel method to fabricate a bimetallic MOF glass, through melt-quenching of the cobalt-based zeolitic imidazolate framework (ZIF) [ZIF-62(Co)] with an adsorbed ferric coordination complex. The high-temperature chemically reactive ZIF-62(Co) liquid facilitates the formation of coordinative bonds between Fe and imidazolate ligands, incorporating Fe nodes into the framework after quenching. The resultant Co-Fe bimetallic MOF glass therefore shows a significantly enhanced oxygen evolution reaction performance. The novel bimetallic MOF glass, when combined with the facile and scalable mechanochemical synthesis technique for both discrete powders and surface coatings on flexible substrates, enables significant opportunities for catalytic device assembly.

Interhospital Transfer for the Management of Acute Pulmonary Embolism.

BACKGROUND: There are increasing treatment options for the management of acute pulmonary embolism (PE), though many are only available at tertiary care centers. Patients with acute pulmonary embolism with high-risk features are often transferred for consideration of such therapies. There are limited data describing outcomes in patients transferred with acute pulmonary embolism. METHODS: We evaluated patients with acute pulmonary embolism at our tertiary care center from August 2012 through August 2018 and compared clinical characteristics, pulmonary embolism features, management, and outcomes in those transferred for acute pulmonary embolism to those that were not transferred. RESULTS: Of 2050 patients with pulmonary embolism included in the study, 432 (21.1%) were transferred from an outside hospital with a known diagnosis of pulmonary embolism. Patients transferred had a lower rate of malignancy (22.2% vs 33.3%; P < .001) and median Charlson comorbidity index (3 vs 4; P < .001). A higher percentage of patients transferred were classified as intermediate- or high-risk pulmonary embolism (62.5% vs 43.0%; P <.001) and more frequently received advanced therapy beyond anticoagulation alone (12.5% vs 3.2%, P < .001). Overall survival to discharge was similar between groups, though definite pulmonary embolism-related mortality was higher in the transferred group (38.5% vs 9.4%, P = .004). CONCLUSION: More than 1 in 5 patients treated for acute pulmonary embolism at a tertiary care center were transferred from an outside facility. Transferred patients had higher risk pulmonary embolism features, more often received advanced therapy, and had higher definite pulmonary embolism-related mortality. There are opportunities to further optimize outcomes of patients transferred for management of acute pulmonary embolism.

Exercise Capacity, Iron Status, Body Composition, and Mediterranean Diet in Patients with Chronic Heart Failure.

In addition to drug therapy, lifestyle modification, including physical activity, and nutrition management are an integral part of current guidelines for patients with chronic heart failure (CHF). However, evidence on which clinical parameters are most influenced by nutritional behaviour, exercise capacity, or iron status is scarce. For a multicenter intervention study, we included participants with diagnosed CHF (n = 165) as well as participants with elevated NT-proBNP values and risk factors for CHF (n = 74). Cardiorespiratory fitness was tested with a bicycle test, and adherence to the Mediterranean diet (MedDiet) was assessed with the MDS questionnaire. Our data strengthened previous results confirming that the higher a person's adherence to MedDiet, the higher the cardiorespiratory fitness and the lower the body fat. Furthermore, our results showed that anemia in patients with CHF has an impact in terms of cardiorespiratory fitness, and functional outcomes by questionnaire. Since our data revealed gaps in iron supply (37.9% with iron deficiency), malnutrition (only 7.8% with high adherence to MedDiet), and both symptomatic and non-symptomatic study participants failed to meet reference values for physical performance, we encourage the enforcement of the guidelines in the treatment of CHF more strongly.

Disclosure of salicylic acid and jasmonic acid-responsive genes provides a molecular tool for deciphering stress responses in soybean.

Hormones orchestrate the physiology of organisms. Measuring the activity of defense hormone-responsive genes can help understanding immune signaling and facilitate breeding for plant health. However, different from model species like Arabidopsis, genes that respond to defense hormones salicylic acid (SA) and jasmonic acid (JA) have not been disclosed in the soybean crop. We performed global transcriptome analyses to fill this knowledge gap. Upon exogenous application, endogenous levels of SA and JA increased in leaves. SA predominantly activated genes linked to systemic acquired resistance and defense signaling whereas JA mainly activated wound response-associated genes. In general, SA-responsive genes were activated earlier than those responding to JA. Consistent with the paradigm of biotrophic pathogens predominantly activating SA responses, free SA and here identified most robust SA marker genes GmNIMIN1, GmNIMIN1.2 and GmWRK40 were induced upon inoculation with Phakopsora pachyrhizi, whereas JA marker genes did not respond to infection with the biotrophic fungus. Spodoptera exigua larvae caused a strong accumulation of JA-Ile and JA-specific mRNA transcripts of GmBPI1, GmKTI1 and GmAAT whereas neither free SA nor SA-marker gene transcripts accumulated upon insect feeding. Our study provides molecular tools for monitoring the dynamic accumulation of SA and JA, e.g. in a given stress condition.

Skin-inspired gelatin-based flexible bio-electronic hydrogel for wound healing promotion and motion sensing.

Next generation tissue-engineered skin scaffolds promise to provide sensory restoration through electrical stimulation in addition to effectively rebuilding and repairing skin. The integration of real-time monitoring of the injury motion activities can fundamentally improve the therapeutic efficacy by providing detailed data to guide the clinical practice. Herein, a mechanically-flexible, electroactive, and self-healable hydrogels (MESGel) was engineered for the combinational function of electrically-stimulated accelerated wound healing and motion sensing. MESGel shows outstanding biocompatibility and multifunctional therapeutic properties including flexibility, self-healing characteristics, biodegradability, and bioelectroactivity. Moreover, MESGel shows its potential of being a novel flexible electronic skin sensor to record the injury motion activities. Comprehensive in vitro and in vivo experiments prove that MESGel can facilitate effective electrical stimulation, actively promoting proliferation in Chinese hamster lung epithelial cells and therefore can accelerate favorable epithelial biology during skin wound healing, demonstrating an effective therapeutic strategy for a full-thickness skin defect model and leading to new-type flexible bioelectronics.

Lectin Staining of Microvascular Glycocalyx in Microfluidic Cancer Cell Extravasation Assays.

The endothelial glycocalyx forms the inner-most lining of human microvasculature. It ensures the physiological function of blood vessels and plays a crucial role in the occurrence and progression of microvascular diseases. The present communication aims to highlight the usefulness of high-resolution imaging of lectin (Bandeiraea Simplicifolia) stained endothelial glycocalyx in 3-dimensional microfluidic cell cultures. The microfluidic system allowed visualizing cancer cell extravasation, which is a key event in metastasis formation in cancer pathologies. In brief, microvascular networks were created through spontaneous vasculogenesis. This occurred from 3 dimensional (3D) suspensions of human umbilical vein endothelial cells (HUVECs) in hydrogels confined within microfluidic devices. Extravasation of MDA-MB-231 breast cancer cells from perfusable endothelial lumens was observed with confocal imaging of lectin-stained microvascular networks. The present work provides guidance towards optimizing the methodology used to elucidate the role of the endothelial glycocalyx during cancer cell extravasation. In particular, a high-resolution view of the endothelial glycocalyx at the site of extravasation is presented. The occurrence of glycocalyx defects is well aligned with the contemporary notion in the field that glycocalyx shedding precedes cancer cell extravasation.

Metal-Organic Framework (MOF)-Based Biomaterials for Tissue Engineering and Regenerative Medicine.

The synthesis of Metal-organic Frameworks (MOFs) and their evaluation for various applications is one of the largest research areas within materials sciences and chemistry. Here, the use of MOFs in biomaterials and implants is summarized as narrative review addressing primarely the Tissue Engineering and Regenerative Medicine (TERM) community. Focus is given on MOFs as bioactive component to aid tissue engineering and to augment clinically established or future therapies in regenerative medicine. A summary of synthesis methods suitable for TERM laboratories and key properties of MOFs relevant to biomaterials is provided. The use of MOFs is categorized according to their targeted organ (bone, cardio-vascular, skin and nervous tissue) and whether the MOFs are used as intrinsically bioactive material or as drug delivery vehicle. Further distinction between in vitro and in vivo studies provides a clear assessment of literature on the current progress of MOF based biomaterials. Although the present review is narrative in nature, systematic literature analysis has been performed, allowing a concise overview of this emerging research direction till the point of writing. While a number of excellent studies have been published, future studies will need to clearly highlight the safety and added value of MOFs compared to established materials for clinical TERM applications. The scope of the present review is clearly delimited from the general 'biomedical application' of MOFs that focuses mainly on drug delivery or diagnostic applications not involving aspects of tissue healing or better implant integration.

Tailored Mobility in a Zeolite Imidazolate Framework (ZIF) Antibody Conjugate*.

Zeolitic imidazolate framework (ZIF) hybrid fluorescent nanoparticles and ZIF antibody conjugates have been synthesized, characterized, and employed in lateral-flow immunoassay (LFIA). The bright fluorescence of the conjugates and the possibility to tailor their mobility gives a huge potential for diagnostic assays. An enzyme-linked immunosorbent assay (ELISA) with horseradish peroxidase (HRP) as label, proved the integrity, stability, and dispersibility of the antibody conjugates, LC-MS/MS provided evidence that a covalent link was established between these metal-organic frameworks and lysine residues in IgG antibodies.

Programmable Phototaxis of Metal-Phenolic Particle Microswimmers.

Light-driven directional motion is common in nature but remains a challenge for synthetic microparticles, particularly regarding collective motion on a macroscopic scale. Successfully engineering microparticles with light-driven collective motion could lead to breakthroughs in drug delivery, contaminant sensing, environmental remediation, and artificial life. Herein, metal-phenolic particle microswimmers capable of autonomously sensing and swimming toward an external light source are reported, with the speed regulated by the wavelength and intensity of illumination. These microswimmers can travel macroscopic distances (centimeters) and can remain illuminated for hours without degradation of motility. Experimental and theoretical analyses demonstrate that motion is generated through chemical transformations of the organic component of the metal-phenolic complex. Furthermore, cargos with specific spectral absorption profiles can be loaded into the particles and endow the particle microswimmers with activated motion corresponding to these spectral characteristics. The programmable nature of the light navigation, tunable size of the particles, and versatility of cargo loading demonstrate the versatility of these metal-phenolic particle microswimmers.

Health Care Utilization Following Inpatient Femoropopliteal Revascularization With Drug-Coated Balloon Angioplasty: A Nationwide Cohort Analysis.

PURPOSE: To examine nationwide variations in inpatient use of drug-coated balloons (DCBs) for treating femoropopliteal segment occlusive disease and whether DCBs are associated with reduced early out-of-hospital health care utilization. MATERIALS AND METHODS: The study included 24,022 patients who survived hospitalization for femoropopliteal revascularization using DCB angioplasty (n=7850) or uncoated balloon angioplasty (n=16,172) in the 2016-2017 Nationwide Readmissions Database. Differences in patient, hospitalization, and institutional characteristics were compared between treatment strategies. Adjusted logistic regression models were used to examine differences in 6-month rates of readmission, amputation, and repeat intervention. Results are presented as the odds ratio (OR) and 95% confidence interval (CI). RESULTS: Patients treated with DCBs had a higher prevalence of chronic limb-threatening ischemia, diabetes, hypertension, and tobacco use. Revascularization with a DCB was associated with shorter hospitalizations, lower median hospitalization costs, and fewer inpatient lower extremity amputations. Readmissions at 6 months were decreased in patients treated with DCBs compared with uncoated balloon angioplasty (OR 0.90, 95% CI 0.83 to 0.98, p=0.014). The most common reasons for readmission were complications related to procedures (15.4%) and diabetes (15.4%). Compared to patients treated with DCBs, patients treated with uncoated balloon angioplasty were more often readmitted with early procedure-related complications (13.3% vs 17.5%). There were no between-group differences in readmission for sepsis, myocardial infarction, or congestive heart failure. CONCLUSION: DCBs are less often used compared to uncoated balloons during inpatient femoropopliteal procedures. While DCB utilization is associated with more severe comorbidities and advanced peripheral artery disease, readmission rates are decreased through the first 6 months.

Observation of early ZIF-8 crystallization stages with X-ray absorption spectroscopy.

The present study investigates early stages of ZIF-8 crystallization up to 5 minutes post mixing of precursor solutions. Dispersive X-ray Absorption Spectroscopy (DXAS) provides a refined understanding of the evolution of the coordination environment during ZIF-8 crystallization. Linear Combination Analysis (LCA) suggests tetrakis(1-methylimidazole)zinc2+ to be a suitable and stable mononuclear structure analogue for some early stage ZIF-8 intermediates. Our results pave the way for more detailed studies on physico-chemical aspects of ZIF-8 crystallization to better control tailoring ZIF-8 materials for specific applications.