Advancements in diabetic kidney disease management: integrating innovative therapies and targeted drug development.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of individuals with diabetes . Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common comorbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. Sodium-glucose transporter type 2 (SGLT-2) inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including glucagon-like peptide 1 (GLP-1) agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, lixudebart, and tozorakimab; mesenchymal stem/stromal cell infusion; and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.

Complex percutaneous coronary intervention in patients unable to undergo coronary artery bypass grafting during the COVID-19 pandemic: insights from the UK-ReVasc Registry.

OBJECTIVES: Cardiac surgery for coronary artery disease was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with disease ordinarily treated with coronary artery bypass grafting (CABG) instead underwent percutaneous coronary intervention (PCI). We sought to describe 12-month outcomes following PCI in patients who would typically have undergone CABG. METHODS: Between March 1 and July 31, 2020, patients who received revascularization with PCI when CABG would have been the primary choice of revascularization were enrolled in the prospective, multicenter UK-ReVasc Registry. We evaluated the following major adverse cardiovascular events at 12 months: all-cause mortality, myocardial infarction, repeat revascularization, stroke, major bleeding, and stent thrombosis. RESULTS: A total of 215 patients were enrolled across 45 PCI centers in the United Kingdom. Twelve-month follow up data were obtained for 97% of the cases. There were 9 deaths (4.3%), 5 myocardial infarctions (2.4%), 12 repeat revascularizations (5.7%), 1 stroke (0.5%), 3 major bleeds (1.4%), and no cases of stent thrombosis. No difference in the primary endpoint was observed between patients who received complete vs incomplete revascularization (residual SYNTAX score £ 8 vs > 8) (P = .22). CONCLUSIONS: In patients with patterns of coronary disease in whom CABG would have been the primary therapeutic choice outside of the pandemic, PCI was associated with acceptable outcomes at 12 months of follow-up. Contemporary randomized trials that compare PCI to CABG in such patient cohorts may be warranted.

Assessment of Potential Accumulation of Trifluoroacetate in Terminal Lakes.

Trifluoroacetate (TFA) is the anionic form of the shortest perfluorocarboxylic acid (PFCA) and is ubiquitous in the environment at concentrations that are typically much higher than those of other PFCAs. As a stable and nonvolatile anion, it is expected to accumulate in terminal lakes in endorheic basins. This research sampled eight terminal lakes in the Western United States to determine the degree to which TFA is concentrating in these lakes and compare the data to samples collected from three of these lakes 25 years ago. The first observation was that three of the six terminal lakes sampled had higher TFA concentrations than their input streams, while the last two lakes lacked surface water inputs at the sampling time. The TFA concentrations in Mono Lake effectively remained constant over 25 years despite the input stream concentrations increasing 6.5-fold. In contrast, Pyramid Lake concentrations increased approximately the expected amount based on a simplistic analysis of input flows and concentrations. An additional observation was that lakes in basins with agricultural activity appeared to have higher TFA concentrations, which suggests an agricultural input.

Enhancing European capabilities for application of multi-omics studies in biology and biomedicine space research.

Following on from the NASA twins' study, there has been a tremendous interest in the use of omics techniques in spaceflight. Individual space agencies, NASA's GeneLab, JAXA's ibSLS, and the ESA-funded Space Omics Topical Team and the International Standards for Space Omics Processing (ISSOP) groups have established several initiatives to support this growth. Here, we present recommendations from the Space Omics Topical Team to promote standard application of space omics in Europe. We focus on four main themes: i) continued participation in and coordination with international omics endeavors, ii) strengthening of the European space omics infrastructure including workforce and facilities, iii) capitalizing on the emerging opportunities in the commercial space sector, and iv) capitalizing on the emerging opportunities in human subjects research.

Transcriptome Profiling Reveals Enhanced Mitochondrial Activity as a Cold Adaptive Strategy to Hypothermia in Zebrafish Muscle.

The utilisation of synthetic torpor for interplanetary travel once seemed farfetched. However, mounting evidence points to torpor-induced protective benefits from the main hazards of space travel, namely, exposure to radiation and microgravity. To determine the radio-protective effects of an induced torpor-like state we exploited the ectothermic nature of the Danio rerio (zebrafish) in reducing their body temperatures to replicate the hypothermic states seen during natural torpor. We also administered melatonin as a sedative to reduce physical activity. Zebrafish were then exposed to low-dose radiation (0.3 Gy) to simulate radiation exposure on long-term space missions. Transcriptomic analysis found that radiation exposure led to an upregulation of inflammatory and immune signatures and a differentiation and regeneration phenotype driven by STAT3 and MYOD1 transcription factors. In addition, DNA repair processes were downregulated in the muscle two days' post-irradiation. The effects of hypothermia led to an increase in mitochondrial translation including genes involved in oxidative phosphorylation and a downregulation of extracellular matrix and developmental genes. Upon radiation exposure, increases in endoplasmic reticulum stress genes were observed in a torpor+radiation group with downregulation of immune-related and ECM genes. Exposing hypothermic zebrafish to radiation also resulted in a downregulation of ECM and developmental genes however, immune/inflammatory related pathways were downregulated in contrast to that observed in the radiation only group. A cross-species comparison was performed with the muscle of hibernating Ursus arctos horribilis (brown bear) to define shared mechanisms of cold tolerance. Shared responses show an upregulation of protein translation and metabolism of amino acids, as well as a hypoxia response with the shared downregulation of glycolysis, ECM, and developmental genes.

Transcatheter aortic valve-in-valve implantation within stentless landing zones: Procedural insights from a single-center experience.

BACKGROUND: Valve-in-valve (VIV) transcatheter aortic valve implantation (TAVI) is a less invasive therapeutic option compared with redo surgical valve replacement for high-risk patients. Relative to procedures within stented surgical valves, VIV-TAVI within stentless valves is associated with a higher complication rate due to challenging underlying anatomy and absence of fluoroscopic landmarks. AIMS: We share a single-center experience with VIV-TAVI in stentless valves, discussing our procedural insights and associated outcomes. METHODS: Our institutional database was queried, and 25 patients who had undergone VIV-TAVI within a stentless bioprosthesis, homograft, or valve-sparing aortic root replacement between 2013 and 2022 were found. Outcome endpoints were based on the Valve Academic Research Consortium-3 criteria. RESULTS: The mean age of the cohort was 69.5 ± 13.6 years. VIV implantation was performed within a homograft in 11 patients, a stentless bioprothesis in 10 patients, and a valve-sparing aortic root replacement in 4 patients. Nineteen (76%) balloon-expandable valves, 5 (20%) self-expanding valves, and one mechanically-expandable (4%) valve were implanted with 100% procedural success, with no instances of significant paravalvular leak, coronary occlusion, or device embolization. There was one (4%) in-hospitality mortality after an emergency procedure; one (4%) patient experienced a transient ischemic attack; and two (8%) patients required permanent pacemaker implantation. The median length of hospital stay was 2 days. After a median follow-up time of 16.5 months, valve function was acceptable in all patients with available data. CONCLUSION: VIV-TAVI within stentless valves can be safely performed with methodical procedural technique and can provide clinical benefit in patients at high reoperation risk.

Bacteremia following different oral procedures: Systematic review and meta-analysis.

To evaluate the timing, duration and incidence of bacteremia following invasive dental procedures (IDPs) or activities of daily living (ADL). Eight databases were searched for randomized (RCTs) and nonrandomized controlled trials (nRCTs) evaluating bacteremia before and after IDPs or ADL in healthy individuals. The risk of bias was assessed by RoB 2.0 and ROBINS-I. For the meta-analysis, the primary outcomes were the timing and duration of bacteremia. The secondary outcome was the incidence of bacteremia, measuring the proportion of patients with bacteremia within 5 min after the end of the procedure compared with baseline. We included 64 nRCTs and 25 RCTs. Peak bacteremia occurred within 5 min after the procedure and then decreased over time. Dental extractions showed the highest incidence of bacteremia (62%-66%), followed by scaling and root planing (SRP) (44%-36%) and oral health procedures (OHP) (e.g., dental prophylaxis and dental probing without SRP) (27%-28%). Other ADL (flossing and chewing) (16%) and toothbrushing (8%-26%) resulted in bacteremia as well. The majority of studies had some concerns RCTs or moderate risk of bias nRCTs. Dental extractions, SRP and OHP, are associated with the highest frequency of bacteremia. Toothbrushing, flossing, and chewing also caused bacteremia in lower frequency.

Investigating the effects of chronic low-dose radiation exposure in the liver of a hypothermic zebrafish model.

Mankind's quest for a manned mission to Mars is placing increased emphasis on the development of innovative radio-protective countermeasures for long-term space travel. Hibernation confers radio-protective effects in hibernating animals, and this has led to the investigation of synthetic torpor to mitigate the deleterious effects of chronic low-dose-rate radiation exposure. Here we describe an induced torpor model we developed using the zebrafish. We explored the effects of radiation exposure on this model with a focus on the liver. Transcriptomic and behavioural analyses were performed. Radiation exposure resulted in transcriptomic perturbations in lipid metabolism and absorption, wound healing, immune response, and fibrogenic pathways. Induced torpor reduced metabolism and increased pro-survival, anti-apoptotic, and DNA repair pathways. Coupled with radiation exposure, induced torpor led to a stress response but also revealed maintenance of DNA repair mechanisms, pro-survival and anti-apoptotic signals. To further characterise our model of induced torpor, the zebrafish model was compared with hepatic transcriptomic data from hibernating grizzly bears (Ursus arctos horribilis) and active controls revealing conserved responses in gene expression associated with anti-apoptotic processes, DNA damage repair, cell survival, proliferation, and antioxidant response. Similarly, the radiation group was compared with space-flown mice revealing shared changes in lipid metabolism.

Comparison of State-Level Regulations for Cannabis Contaminants and Implications for Public Health.

BACKGROUND: The presence of contaminants in cannabis presents a potential health hazard to recreational users and susceptible patients with medical conditions. Because of the federally illegal status of cannabis, there are no unified regulatory guidelines mitigating the public health risk of cannabis contaminants. OBJECTIVE: To inform further research and provide solutions to the public health risk of cannabis contaminants at a national level, we examined the current landscape of state-level contaminant regulations, and cannabis contaminants of concern, as well as patient populations susceptible to contaminants. METHODS: We examined the regulatory documents for medical and recreational cannabis in all legalized U.S. jurisdictions and compiled a complete list of regulated contaminants, namely, pesticides, inorganics, solvents, microbes, and mycotoxins. We data mined the compliance testing records of 5,654 cured flower and 3,760 extract samples that accounted for ∼6% of California's legal cannabis production in 2020-2021. We also reviewed the publicly available medical cannabis use reports to tabulate the susceptible patient populations. RESULTS: As of 18 May 2022, 36 states and the District of Columbia listed a total of 679 cannabis contaminants as regulated in medical or recreational cannabis, including 551 pesticides, 74 solvents, 12 inorganics, 21 microbes, 5 mycotoxins, and 16 other contaminants. Different jurisdictions showed significant variations in regulated contaminants and action levels ranging up to four orders of magnitude. A failure rate of 2.3% was identified for flowers and 9.2% for extracts in the California samples. Insecticides and fungicides were the most prevalent categories of detected contaminants, with boscalid and chlorpyrifos being the most common. The contaminant concentrations fell below the regulatory action levels in many legalized jurisdictions, indicating a higher risk of contaminant exposure. Cannabis use reports indicated usage in several patient populations susceptible to contamination toxicity, including cancer (44,318) and seizure (21,195) patients. DISCUSSION: Although individual jurisdictions can implement their policies and regulations for legalized cannabis, this study demonstrates the urgent need to mitigate the public health risk of cannabis contamination by introducing national-level guidelines based on conventional risk assessment methodologies and knowledge of patients' susceptibility in medical use. https://doi.org/10.1289/EHP11206.

Impact of Right Ventricle-Pulmonary Artery Coupling on Clinical Outcomes in the PARTNER 3 Trial.

BACKGROUND: Physiologic right ventricle-pulmonary artery (RV-PA) coupling may be impaired in patients with aortic stenosis (AS). OBJECTIVES: This study aimed to assess the incidence and prognostic significance of impaired RV-PA coupling in low-risk patients with symptomatic severe AS undergoing transcatheter aortic valve replacement or surgical aortic valve replacement. METHODS: RV-PA coupling was measured by transthoracic echocardiography as the ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary artery systolic pressure (PASP) in patients in the PARTNER (Placement of Aortic Transcatheter Valve) 3 trial. The primary endpoint was the composite of all-cause mortality, stroke, and rehospitalization at the 2-year follow-up. RESULTS: Among 570 low-risk patients included in the analysis, RV-PA uncoupling was defined by a TAPSE/PASP ratio ≤ 0.55 mm/mm Hg. At baseline, 222 of 570 (38.9%) patients had RV-PA uncoupling. At 2 years, patients with baseline RV-PA uncoupling had an increased incidence of the primary endpoint (19.1% vs 9.9%, P = 0.002), all-cause mortality (5.9% vs 0.6%, P < 0.001), cardiovascular mortality (4.1% vs 0.6%, P = 0.003), and rehospitalization (13.5% vs 7.3%, P = 0.018). On multivariable analysis, baseline RV-PA uncoupling remained an independent predictor of the primary endpoint at 2 years (HR: 1.92; 95% CI: 1.04-3.57; P = 0.038). CONCLUSIONS: In patients with symptomatic severe AS at low surgical risk undergoing transcatheter aortic valve replacement or surgical aortic valve replacement, baseline RV-PA uncoupling defined by TAPSE/PASP ≤ 0.55 mm Hg was associated with adverse clinical outcomes at 2 years, including all-cause mortality, cardiovascular mortality, and rehospitalization.

3D Intracardiac Echocardiography in Mitral Transcatheter Edge-to-Edge Repair: When TEE Is Hard to Stomach.

Intracardiac echocardiography (ICE) has historically had limited utility in complex structural interventions. Newer 3-dimensional ICE catheters have enhanced imaging and real-time functionality. We present a novel case of mitral valve transcatheter edge-to-edge repair where transesophageal imaging was limited by massive hiatal hernia and where complementary 3D ICE imaging enabled procedural success. (Level of Difficulty: Intermediate.).

Comparison of the Accuracy and Efficiency of a 3-Dimensional Dynamic Navigation System for Osteotomy and Root-end Resection Performed by Novice and Experienced Endodontists.

INTRODUCTION: The aim of the study is to investigate whether the 3-dimensional dynamic navigation system (3D-DNS) can improve experienced endodontists' (EEs') and novice endodontists' (NEs') accuracy and efficiency in osteotomy and root-end resection (RER) and to verify that the 3D-DNS enables NEs to perform osteotomy and RER as accurately and efficiently as EEs. METHODS: Seventy-six roots in cadaver heads were randomly divided into 4 groups: 3D-DNS-NE, 3D-DNS-EE, freehanded (FH)-NE, and FH-EE (all, n = 19). Cone-beam computed tomography scans were taken preoperatively and postoperatively. Osteotomy and RER were planned virtually in the X-guided software (X-Nav Technologies, Lansdale). Accuracy was calculated by measuring the 2-dimensional and 3D virtual deviations and angular deflection using superimposing software (X-Nav technologies). Efficiency was determined by the time of operation and the number of mishaps. RESULTS: Accuracy deviations were significantly fewer in the 3D-DNS-EE group than those in the FH-EE group (P < .05). We found less 2-dimensional and 3D accuracy deviations comparing the 3D-DNS-NE group to the FH-NE group (P < .05). The time required for osteotomy and RER with the 3D-DNS was ∼ ½ of that required for the FH method for both EEs and NEs (P < .05). We found no difference in the number of mishaps between the 3D-DNS and FH groups for EEs and NEs (P > .05). CONCLUSIONS: The 3D-DNS improved EEs' and NEs' accuracy and efficiency in osteotomy and RER. The NEs were as efficient as the EEs using the 3D-DNS. Notably, the 3D-DNS improved the NEs' accuracy compared to the FH method, but the 3D-DNS did not enable the NEs to perform osteotomy and RER as accurately as the EEs.

Increases in Trifluoroacetate Concentrations in Surface Waters over Two Decades.

Trifluoroacetate (TFA) is a persistent perfluorinated alkanoic acid anion that has many anthropogenic sources, with fluorocarbon refrigerants being a major one. After an initial burst of research in the late 1990s and early 2000s, research on this ubiquitous pollutant declined as atmospheric emissions of the precursor compounds grew rapidly. Thus, there is little contemporaneous information about the concentrations of TFA in the environment and how they have changed over time. This research determined the change in TFA concentrations in streams by resampling a transect that was originally sampled in 1998. The transect was designed to determine the regional distribution of TFA both upwind and downwind of major metropolitan areas in Northern California as well as a set of globally remote sites in Alaska. The results showed that TFA concentrations increased by an average of 6-fold over the intervening 23 years, which resulted in a median concentration of 180 ng/L (range 21.3-2790). The highest concentrations were found in streams immediately downwind of the San Francisco Bay Area, while substantially lower concentrations were found in the upwind, regionally remote, and globally remote sites. The C3 to C5 perfluorinated alkanoic acids were also investigated, but they were rarely detected with this methodology.

Subclinical Leaflet Thrombosis and Anticoagulation After Transcatheter Aortic Valve Replacement: A Review.

Importance: Subclinical leaflet thrombosis affects approximately 15% of patients after transcatheter aortic valve replacement (TAVR). The pathophysiology and clinical significance of leaflet thrombosis remain incompletely understood. Defining the optimal management strategy in patients who are asymptomatic, including the role for oral anticoagulation (OAC), is a key challenge for the field. Observations: Three recent randomized trials have evaluated the role of OAC in patients after TAVR. These studies have confirmed prior observational data suggesting that OAC is effective at prevention of subclinical leaflet thrombosis. Overall, however, OAC does not lead to a clinical benefit over the period studied, and in some patients may be harmful owing to bleeding risk. Conclusions and Relevance: Strategies for identification of patients in whom the benefit of OAC outweighs the risks are required for optimization of long-term outcome after TAVR. This requires clearer insights into the mechanisms of asymptomatic leaflet thrombosis, its clinical significance, and patient-specific risks of bleeding and structural valve degeneration.

Risk of infective endocarditis after surgical and transcatheter aortic valve replacement.

OBJECTIVE: To define the incidence and risk factors for infective endocarditis (IE) following surgical aortic valve replacement (SAVR) and transcatheter aortic valve implantation (TAVI). METHODS: All patients who underwent first SAVR or TAVI in England between 2007 and 2016 were identified from the NICOR databases. Hospital admissions with a primary diagnosis of IE were identified by linkage with the NHS Hospital Episode Statistics database. Approval was obtained from the NHS Research Ethics Committee. RESULTS: 2057 of 91 962 patients undergoing SAVR developed IE over a median follow-up of 53.9 months-an overall incidence of 4.81 [95% CI 4.61 to 5.03] per 1000 person-years. Correspondingly, 140 of 14 195 patients undergoing TAVI developed IE over a median follow-up of 24.5 months-an overall incidence of 3.57 [95% CI 3.00 to 4.21] per 1000 person-years. The cumulative incidence of IE at 60 months was higher after SAVR than after TAVI (2.4% [95% CI 2.3 to 2.5] vs 1.5% [95% CI 1.3 to 1.8], HR 1.60, p<0.001). Across the entire cohort, SAVR remained an independent predictor of IE after multivariable adjustment. Risk factors for IE included younger age, male sex, atrial fibrillation, and dialysis. CONCLUSIONS: IE is a rare complication of SAVR and TAVI. In our population, the incidence of IE was higher after SAVR than after TAVI.

Outcomes following PCI in CABG candidates during the COVID-19 pandemic: The prospective multicentre UK-ReVasc registry.

OBJECTIVES: To describe outcomes following percutaneous coronary intervention (PCI) in patients who would usually have undergone coronary artery bypass grafting (CABG). BACKGROUND: In the United Kingdom, cardiac surgery for coronary artery disease (CAD) was dramatically reduced during the first wave of the COVID-19 pandemic. Many patients with "surgical disease" instead underwent PCI. METHODS: Between 1 March 2020 and 31 July 2020, 215 patients with recognized "surgical" CAD who underwent PCI were enrolled in the prospective UK-ReVasc Registry (ReVR). 30-day major cardiovascular event outcomes were collected. Findings in ReVR patients were directly compared to reference PCI and isolated CABG pre-COVID-19 data from British Cardiovascular Intervention Society (BCIS) and National Cardiac Audit Programme (NCAP) databases. RESULTS: ReVR patients had higher incidence of diabetes (34.4% vs 26.4%, P = .008), multi-vessel disease with left main stem disease (51.4% vs 3.0%, P < .001) and left anterior descending artery involvement (94.8% vs 67.2%, P < .001) compared to BCIS data. SYNTAX Score in ReVR was high (mean 28.0). Increased use of transradial access (93.3% vs 88.6%, P = .03), intracoronary imaging (43.6% vs 14.4%, P < .001) and calcium modification (23.6% vs 3.5%, P < .001) was observed. No difference in in-hospital mortality was demonstrated compared to PCI and CABG data (ReVR 1.4% vs BCIS 0.7%, P = .19; vs NCAP 1.0%, P = .48). Inpatient stay was half compared to CABG (3.0 vs 6.0 days). Low-event rates in ReVR were maintained to 30-day follow-up. CONCLUSIONS: PCI undertaken using contemporary techniques produces excellent short-term results in patients who would be otherwise CABG candidates. Longer-term follow-up is essential to determine whether these outcomes are maintained over time.

Mammalian and Invertebrate Models as Complementary Tools for Gaining Mechanistic Insight on Muscle Responses to Spaceflight.

Bioinformatics approaches have proven useful in understanding biological responses to spaceflight. Spaceflight experiments remain resource intensive and rare. One outstanding issue is how to maximize scientific output from a limited number of omics datasets from traditional animal models including nematodes, fruitfly, and rodents. The utility of omics data from invertebrate models in anticipating mammalian responses to spaceflight has not been fully explored. Hence, we performed comparative analyses of transcriptomes of soleus and extensor digitorum longus (EDL) in mice that underwent 37 days of spaceflight. Results indicate shared stress responses and altered circadian rhythm. EDL showed more robust growth signals and Pde2a downregulation, possibly underlying its resistance to atrophy versus soleus. Spaceflight and hindlimb unloading mice shared differential regulation of proliferation, circadian, and neuronal signaling. Shared gene regulation in muscles of humans on bedrest and space flown rodents suggest targets for mitigating muscle atrophy in space and on Earth. Spaceflight responses of C. elegans were more similar to EDL. Discrete life stages of D. melanogaster have distinct utility in anticipating EDL and soleus responses. In summary, spaceflight leads to shared and discrete molecular responses between muscle types and invertebrate models may augment mechanistic knowledge gained from rodent spaceflight and ground-based studies.

Real-World Experience With the SAPIEN 3 Ultra Transcatheter Heart Valve: A Propensity-Matched Analysis From the United States.

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