Procedural and Intermediate-term Results of the Electroanatomical-guided Cardioneuroablation for the Treatment of Supra-Hisian Second- or Advanced-degree Atrioventricular Block: the PIRECNA multicentre registry.

AIMS: Prior case series showed promising results for cardioneuroablation in patients with vagally induced atrioventricular blocks (VAVBs). We aimed to examine the acute procedural characteristics and intermediate-term outcomes of electroanatomical-guided cardioneuroablation (EACNA) in patients with VAVB. METHODS AND RESULTS: This international multicentre retrospective registry included data collected from 20 centres. Patients presenting with symptomatic paroxysmal or persistent VAVB were included in the study. All patients underwent EACNA. Procedural success was defined by the acute reversal of atrioventricular blocks (AVBs) and complete abolition of atropine response. The primary outcome was occurrence of syncope and daytime second- or advanced-degree AVB on serial prolonged electrocardiogram monitoring during follow-up. A total of 130 patients underwent EACNA. Acute procedural success was achieved in 96.2% of the cases. During a median follow-up of 300 days (150, 496), the primary outcome occurred in 17/125 (14%) cases with acute procedural success (recurrence of AVB in 9 and new syncope in 8 cases). Operator experience and use of extracardiac vagal stimulation were similar for patients with and without primary outcomes. A history of atrial fibrillation, hypertension, and coronary artery disease was associated with a higher primary outcome occurrence. Only four patients with primary outcome required pacemaker placement during follow-up. CONCLUSION: This is the largest multicentre study demonstrating the feasibility of EACNA with encouraging intermediate-term outcomes in selected patients with VAVB. Studies investigating the effect on burden of daytime symptoms caused by the AVB are required to confirm these findings.

Pseudofilariasis, a Presenting Sign of Alkaptonuria.

PURPOSE: To report the association of Pseudofilariasis as a presenting sign of Alkaptonuria. METHOD: Case Report. RESULTS: A 49-year-old Indian man was referred because of wormlike objects in his left conjunctiva. Ocular and family history was non-contributory. He had not been to India in 15 years. Past medical history revealed hypertension, hypercholesterolemia, arthritis, and a myocardial infarct. He had undergone two stents, bilateral Achilles tendon repairs and bilateral knee replacements. ROS showed longstanding back stiffness and pain. On ocular examination the vision was 20/25 in each eye and positive findings were in the left eye bulbar conjunctival which showed stationary black vermiform (filarial in appearance) foreign bodies along with 2 small corneal limbal pigmented deposits. Conjunctival biopsy showed dilated lymph channels with interstitial proteinaceous material of a light brown color consistent with Ochronotic pigment; hence diagnostic of Alkaptonuria. CONCLUSIONS: Pseudofilariasis may be a presenting sign of Alkaptonuria and occur years before a clinical diagnosis is made. Filariasis is always involves white worms and never black. Knowing the ophthalmic signs of this rare disease may lead to an accurate diagnosis earlier thusly avoiding unnecessary tests and examinations.

Detection of carbapenemase producing Acinetobacter baumannii ST19 from Georgia and Ukraine carrying bla OXA-23, bla OXA-72, and/or bla NDM-5, December 2019 to June 2023.

In 2003-2023, amid 5,436 Acinetobacter baumannii isolates collected globally through the Multidrug-Resistant Organism Repository and Surveillance Network, 97 were ST19PAS, 34 of which carbapenem-resistant. Strains (n = 32) sampled after 2019 harboured either bla OXA-23, bla OXA-72, and/or bla NDM-5. Phylogenetic analysis of the 97 isolates and 11 publicly available ST19 genomes revealed three sub-lineages of carbapenemase-producing isolates from mainly Ukraine and Georgia, including an epidemic clone carrying all three carbapenemase genes. Infection control and global surveillance of carbapenem-resistant A. baumannii remain important.

Low Risk of Periprosthetic Joint Infection After Aseptic Revision Total Knee Arthroplasty With Intraosseous Vancomycin.

BACKGROUND: Aseptic revisions are the most common reason for revision total knee arthroplasty (rTKA). Previous literature reports early periprosthetic joint infection (PJI) rates after aseptic rTKA to range from 3 to 9.4%. Intraosseous (IO) regional administration of vancomycin has previously been shown to produce high local tissue concentrations in primary and rTKA. However, no data exist on the effect of prophylactic IO vancomycin on early PJI rates in the setting of aseptic rTKA. The aim of this study was to determine the following: (1) what is the rate of early PJI during the first year after surgery in aseptic rTKA performed with IO vancomycin; and (2) how does this compare to previously published PJI rates after rTKA. METHODS: A consecutive series of 117 cases were included in this study who underwent rTKA between January 2016 and March 2022 by 1 of 2 fellowship-trained adult reconstruction surgeons and received IO vancomycin at the time of surgery in addition to standard intravenous antibiotic prophylaxis. Rates of PJI at 3 months, 1 year, and the final follow-up were evaluated and compared to prior literature. RESULTS: Follow-up at 3 months was available for 116 of the 117 rTKAs, with 1 lost to follow-up. The rate of PJI was 0% at 3 months postoperatively. Follow-up at 1 year was obtained for 113 of the 117 rTKAs, and the PJI rate remained 0%. The rate of PJI at the final follow-up of ≥ 1 year was 0.88% (95% confidence interval: -0.84 to 2.61). Previous literature reports PJI rates in aseptic rTKA to range from 3 to 9.4%. CONCLUSIONS: Dual prophylactic antibiotics with IO vancomycin in conjunction with intravenous cephalosporins or clindamycin were associated with a substantial reduction in early PJI compared to prior published literature. These data supplement the early evidence about the potential clinical benefits of IO vancomycin for infection prevention in high-risk cases. LEVEL OF EVIDENCE: Level III, therapeutic study.

Diagnostic Approach to Interstitial Lung Diseases Associated with Connective Tissue Diseases.

Interstitial lung disorders are a group of respiratory diseases characterized by interstitial compartment infiltration, varying degrees of infiltration, and fibrosis, with or without small airway involvement. Although some are idiopathic (e.g., idiopathic pulmonary fibrosis, idiopathic interstitial pneumonias, and sarcoidosis), the great majority have an underlying etiology, such as systemic autoimmune rheumatic disease (SARD, also called Connective Tissue Diseases or CTD), inhalational exposure to organic matter, medications, and rarely, genetic disorders. This review focuses on diagnostic approaches in interstitial lung diseases associated with SARDs. To make an accurate diagnosis, a multidisciplinary, personalized approach is required, with input from various specialties, including pulmonary, rheumatology, radiology, and pathology, to reach a consensus. In a minority of patients, a definitive diagnosis cannot be established. Their clinical presentations and prognosis can be variable even within subsets of SARDs.

Proteinase 3-specific antineutrophil cytoplasmic antibody-associated vasculitis.

Proteinase 3 (PR3)-specific antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis is one of two major ANCA-associated vasculitis variants and is pathogenically linked to granulomatosis with polyangiitis (GPA). GPA is characterised by necrotising granulomatous inflammation that preferentially affects the respiratory tract. The small vessel vasculitis features of GPA are shared with microscopic polyangiitis. Necrotising granulomatous inflammation of GPA can lead to PR3-ANCA and small vessel vasculitis via activation of neutrophils and monocytes. B cells are central to the pathogenesis of PR3-ANCA-associated vasculitis. They are targeted successfully by remission induction and maintenance therapy with rituximab. Relapses of PR3-ANCA-associated vasculitis and toxicities associated with current standard therapy contribute substantially to remaining mortality and damage-associated morbidity. More effective and less toxic treatments are sought to address this unmet need. Advances with cellular and novel antigen-specific immunotherapies hold promise for application in autoimmune disease, including PR3-ANCA-associated vasculitis. This Series paper describes the inter-related histopathological and clinical features, pathophysiology, as well as current and future targeted treatments for PR3-ANCA-associated vasculitis.

Laparoscopic Cholecystectomy vs Endoscopic Retrograde Cholangiopancreatography With Sphincterotomy in Elderly Patients With Acute Gallstone Pancreatitis.

BACKGROUND: Gallstone pancreatitis (GSP) is common in elderly patients and carries worse outcomes. Laparoscopic cholecystectomy (LC) is recommended for prevention of recurrent GSP. In frail populations, an endoscopic retrograde cholangiopancreatography with sphincterotomy (ERCP-s) is an alternative. Management guidelines of GSP in the elderly are lacking. This study aimed to investigate and compare management strategies for GSP in the elderly. MATERIALS AND METHODS: A retrospective comparison of outcome of patients aged ≥65 years with first presentation of GSP treated either with (1) LC only, (2) ERCP-s, (3) ERCP-S followed by LC, or (4) no intervention. RESULTS: 216 patients were included. Median age was 76 years (interquartile range 70-83). Most (80%, n = 172) had mild pancreatitis, whilst 12% (n = 26) had severe disease. 24% (n = 55) were treated with ERCP-s; 40% (n = 87) underwent LC alone; 11% (n = 23) had ERCP-s followed by LC; and 25% (n = 55) received no intervention. Patients without intervention were older (P < .001) and frailer (P < .001). The LC-only group had lower post-procedure re-admission rates of 6% (n = 5) compared to 27% (n = 14) for ERCP-s, 33% (n = 7) for ERCP-S + LC, and 31% (n = 17) for the no intervention group (P = .0001). Biliary cause mortality was highest in the no intervention group (n = 11, 20%). CONCLUSION: Laparoscopic cholecystectomy represents the gold standard for elderly patients with GSP.

Epigenetic Reprogramming of Autophagy Drives Mutant IDH1 Glioma Progression and Response to Radiation.

Mutant isocitrate dehydrogenase 1 (mIDH1; IDH1 R132H ) exhibits a gain of function mutation enabling 2-hydroxyglutarate (2HG) production. 2HG inhibits DNA and histone demethylases, inducing epigenetic reprogramming and corresponding changes to the transcriptome. We previously demonstrated 2HG-mediated epigenetic reprogramming enhances DNA-damage response and confers radioresistance in mIDH1 gliomas harboring p53 and ATRX loss of function mutations. In this study, RNA-seq and ChIP-seq data revealed human and mouse mIDH1 glioma neurospheres have downregulated gene ontologies related to mitochondrial metabolism and upregulated autophagy. Further analysis revealed that the decreased mitochondrial metabolism was paralleled by a decrease in glycolysis, rendering autophagy as a source of energy in mIDH1 glioma cells. Analysis of autophagy pathways showed that mIDH1 glioma cells exhibited increased expression of pULK1-S555 and enhanced LC3 I/II conversion, indicating augmented autophagy activity. This dependence is reflected by increased sensitivity of mIDH1 glioma cells to autophagy inhibition. Blocking autophagy selectively impairs the growth of cultured mIDH1 glioma cells but not wild-type IDH1 (wtIDH1) glioma cells. Targeting autophagy by systemic administration of synthetic protein nanoparticles packaged with siRNA targeting Atg7 (SPNP-siRNA-Atg7) sensitized mIDH1 glioma cells to radiation-induced cell death, resulting in tumor regression, long-term survival, and immunological memory, when used in combination with IR. Our results indicate autophagy as a critical pathway for survival and maintenance of mIDH1 glioma cells, a strategy that has significant potential for future clinical translation. One Sentence Summary: The inhibition of autophagy sensitizes mIDH1 glioma cells to radiation, thus creating a promising therapeutic strategy for mIDH1 glioma patients. Graphical abstract: Our genetically engineered mIDH1 mouse glioma model harbors IDH1 R132H in the context of ATRX and TP53 knockdown. The production of 2-HG elicited an epigenetic reprogramming associated with a disruption in mitochondrial activity and an enhancement of autophagy in mIDH1 glioma cells. Autophagy is a mechanism involved in cell homeostasis related with cell survival under energetic stress and DNA damage protection. Autophagy has been associated with radio resistance. The inhibition of autophagy thus radio sensitizes mIDH1 glioma cells and enhances survival of mIDH1 glioma-bearing mice, representing a novel therapeutic target for this glioma subtype with potential applicability in combined clinical strategies.

Nonequilibrium Anion Detection in Solid-Contact Ion-Selective Electrodes.

Low-cost and portable nitrate and phosphate sensors are needed to improve farming efficiency and reduce environmental and economic impact arising from the release of these nutrients into waterways. Ion selective electrodes (ISEs) could provide a convenient platform for detecting nitrate and phosphate, but existing ionophore-based nitrate and phosphate selective membrane layers used in ISEs are high cost, and ISEs using these membrane layers suffer from long equilibration time, reference potential drift, and poor selectivity. In this work, we demonstrate that constant current operation overcomes these shortcomings for ionophore-based anion-selective ISEs through a qualitatively different response mechanism arising from differences in ion mobility rather than differences in ion binding thermodynamics. We develop a theoretical treatment of phase boundary potential and ion diffusion that allows for quantitative prediction of electrode response under applied current. We also demonstrate that under pulsed current operation, we can create functional solid-contact ISEs using lower-cost molecularly imprinted polymers (MIPs). MIP-based nitrate sensors provide comparable selectivity against chloride to costlier ionophore-based sensors and exhibit >100,000 times higher selectivity against perchlorate. Likewise, MIP-based solid contact ion-selective electrode phosphate sensors operated under pulsed current provide competitive selectivity against chloride, nitrate, perchlorate, and carbonate anions. The theoretical treatment and conceptual demonstration of pulsed-current ISE operation we report will inform the development of new materials for membrane layers in ISEs based on differences in ion mobility and will allow for improved ISE sensor designs.

Rheumatoid Arthritis Is Not a Contraindication to Unicompartmental Knee Arthroplasty.

BACKGROUND: Rheumatoid arthritis (RA) has historically been considered a contraindication for unicompartmental knee arthroplasty (UKA). However, the widespread use of disease-modifying antirheumatic drugs has substantially improved the management of RA and prevented disease progression. The objective of this study was to ascertain whether RA impacts UKA revision-free survivorship. METHODS: Patients undergoing UKA from 2010 to 2021 were identified in an administrative claims database (n = 105,937) using Current Procedural Terminology code 27446. All patients who underwent UKA who had a diagnosis of RA with a minimum of 2-year follow-up (n = 1,422) were propensity score matched based on age, sex, and Elixhauser Comorbidity Index to those who did not have RA (n = 1,422). Laterality was identified using the 10th Revision of International Classification of Diseases codes. The primary outcome was ipsilateral revision to total knee arthroplasty (TKA) within 2 years, and the secondary outcome was ipsilateral revision at any time. RESULTS: Among the 1,422 patients who had a UKA and a diagnosis of RA, 37 patients (2.6%) underwent conversion to TKA within 2 years, and 48 patients (3.4%) underwent conversion to TKA at any point. In comparison, 28 patients (2.0%) in the propensity-matched control group underwent conversion to TKA within 2 years, and 40 patients (2.8%) underwent conversion to TKA at any point. Statistical analysis revealed no significant difference in conversion to TKA between patients who had and did not have RA, either within 2 years (P = .31) or anytime (P = .45). CONCLUSIONS: Patients who had RA and underwent UKA did not have an increased risk of revision to TKA compared to those who did not have RA. This may indicate that modern management of RA could allow for expanded UKA indications for RA patients.

In Vivo Findings of a Novel Focal Ablation Catheter: Focused Electric Field Catheter Tip.

Current catheter designs used for radiofrequency (RF) in cardiac tissue achieve limited ablation depth as lesion size is driven heavily by resistive heating at the tissue surface. A catheter with a truncated, dome-shaped tip with a toroidal surface designed for focal RF ablation was recently described. This in vivo study compares lesion characteristics between a second-generation focused electric field (FEF) catheter vs a standard irrigated catheter using RF energy in a beating heart model. We performed in vivo ablations using RF energy with the FEF ablation catheter tip (Focused Therapeutics) and an irrigated Blazer catheter (Boston Scientific) under identical power, duration, and irrigation rates. In addition, RF dosing at high power and duration was examined using the FEF catheter. Intracardiac echocardiography was used to evaluate steam pops and catheter tip angle relative to the tissue surface. Studies were terminal and lesion size was measured following 2,3,5-triphenyltetrazolium chloride staining. Ablations were performed in 6 swine (FEF, n = 31; control, n = 8). FEF ablation lesions (n = 7) were deeper (15.6 ± 2.6 mm vs 7.5 ± 1.9 mm; P < 0.001) and wider (18.4 ± 2.9 mm vs 12.6 ± 2.4 mm; P < 0.001) than lesions delivered with the control irrigated catheter (n = 8) under the same parameters. Thirty-two percent (n = 10 of 31) of lesions delivered from the left ventricle endocardial surface using the FEF catheter were transmural. No steam pops were observed with delivery of FEF lesions (n = 31). The angle of incidence did not significantly affect FEF lesion size. In this in vivo preclinical study, the FEF catheter, which provides focused energy delivery, resulted in significantly larger lesions than the irrigated control catheter without steam pops. Approximately one-third of ablations with the FEF catheter delivered from the endocardial left ventricular surface resulted in transmural lesions.

Cardioneuroablation for the management of patients with recurrent vasovagal syncope and symptomatic bradyarrhythmias: the CNA-FWRD Registry.

BACKGROUND: Cardioneuroablation has been emerging as a potential treatment alternative in appropriately selected patients with cardioinhibitory vasovagal syncope (VVS) and functional AV block (AVB). However the majority of available evidence has been derived from retrospective cohort studies performed by experienced operators. METHODS: The Cardioneuroablation for the Management of Patients with Recurrent Vasovagal Syncope and Symptomatic Bradyarrhythmias (CNA-FWRD) Registry is a multicenter prospective registry with cross-over design evaluating acute and long-term outcomes of VVS and AVB patients treated by conservative therapy and CNA. RESULTS: The study is a prospective observational registry with cross-over design for analysis of outcomes between a control group (i.e., behavioral and medical therapy only) and intervention group (Cardioneuroablation). Primary and secondary outcomes will only be assessed after enrollment in the registry. The follow-up period will be 3 years after enrollment. CONCLUSIONS: There remains a lack of prospective multicentered data for long-term outcomes comparing conservative therapy to radiofrequency CNA procedures particularly for key outcomes including recurrence of syncope, AV block, durable impact of disruption of the autonomic nervous system, and long-term complications after CNA. The CNA-FWRD registry has the potential to help fill this information gap.

Clostridium difficile Infection Prior to Total Hip Arthroplasty Independently Increases the Risk of Periprosthetic Joint Infection.

BACKGROUND: Periprosthetic joint infection (PJI) following total hip arthroplasty (THA) is associated with major morbidity. There may be a link between the gut microbiome and an individual's overall immune system. A Clostridium difficile (C. difficile) infection portends poor gut microbiome health and has been previously associated with increased 90-day complication rates in total joint arthroplasty (TJA). The purpose of this study was to determine the effect of a previous history of C. difficile infection within 2 years of undergoing THA on PJI within 2 years postoperatively. METHODS: Patients undergoing THA from 2010 to 2021 were identified in a patient claims database (n = 770,075). Patients who had active records 2 years before and after THA as well as a history of C. difficile infection within 2 years prior to THA (n = 1,836) were included and propensity matched to a control group using age, sex, and Elixhauser comorbidity index. The primary outcome was the 2-year incidence of postoperative PJI. The exposed C. difficile infection cohort was stratified into 4 groups based on the time proximity of the C. difficile infection. Chi-square tests and logistic regressions were used to compare the groups. RESULTS: A C. difficile infection anytime within 2 years prior to total hip arthroplasty was independently associated with higher odds of PJI (OR [odds ratio]: 1.49 [95% CI (confidence interval) 1.09 to 2.02, P = .014]). Proximity of C. difficile infection to arthroplasty was associated with increased risk of PJI (infection 0 to 3 months before THA: OR 2.01 [95% CI 1.23 to 3.20], infection 3 to 6 months before THA: OR 1.84 [95% CI 1.06 to 3.04], infection 6 to 12 months before THA: OR 1.10 [95% CI 0.65 to 1.77], infection 1 to 2 years before THA: OR 1.40 [95% CI 0.94 to 2.06]). CONCLUSIONS: A C. difficile infection prior to THA is an independent risk factor for PJI. Proximity of C. difficile infection is associated with increased risk of PJI. Future investigations should evaluate how to adequately optimize patients prior to THA and pursue strategies to determine appropriate timing for proceeding with THA.

Individualizing a Total Knee Arthroplasty with Three-Dimensional Planning.

Total knee arthroplasty (TKA) is evolving from mechanical alignment to more individualized alignment options in an attempt to improve patient satisfaction. Thirteen-year survival of kinematically aligned prostheses has recently been shown to be similar to mechanically aligned TKA, allaying concerns of long-term failure of this newer individualized technique. There is a complex inter-relationship of three-dimensional knee and limb alignment for a TKA. This article will review planning parameters necessary to individualize each knee, along with a discussion of how these parameters are related in three dimensions. Future use of computer software and machine learning has the potential to identify the ideal surgical plan for each patient. In the meantime, the material presented here can assist surgeons as newer individual alignment planning becomes a reality.

Erratum to: Association between Modifiable Risk Factors and Levels of Blood-Based Biomarkers of Alzheimer's and Related Dementias in the Look AHEAD Cohort.

[This corrects the article DOI: 10.14283/jarlife.2024.1.].

Quantifying forms and functions of intestinal bile acid pools in mice.

Bile acids (BAs) are gastrointestinal metabolites that serve dual functions in lipid absorption and cell signaling. BAs circulate actively between the liver and distal small intestine (i.e., ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with intestinal cells in vivo remain ill-defined. Through multi-site sampling of nearly 100 BA species in individual wild type mice, as well as mice lacking the ileal BA transporter, Asbt/Slc10a2, we calculate the ileal BA pool in fasting C57BL/6J mice to be ~0.3 µmoles/g. Asbt-mediated transport accounts for ~80% of this pool and amplifies size, whereas passive absorption explains the remaining ~20%, and generates diversity. Accordingly, ileal BA pools in mice lacking Asbt are ~5-fold smaller than in wild type controls, enriched in secondary BA species normally found in the colon, and elicit unique transcriptional responses in cultured ileal explants. This work quantitatively defines ileal BA pools in mice and reveals how BA dysmetabolism can impinge on intestinal physiology.

The impact of anticholinergic burden on clinical outcomes in older hospitalised surgical patients.

Polypharmacotherapy is an ever-increasing issue with an ageing patient population. Anticholinergic medications make up a large proportion of patient medication but cause significant side effects, contributing to well-documented issues within the older population and in hospital medicine. This review explores the documented impact of anticholinergic burden in older surgical patients on postoperative delirium, infection, length of stay and readmission, urinary retention, ileus and mortality. It also highlights the need for further high-quality research into anticholinergic burden management among older surgical patients to further impact practice and policy in the area.

Posteromedial Periarticular Injection in Total Knee Arthroplasty: A Cadaveric Study.

Achieving optimal pain control in total knee arthroplasty has improved with the use of regional anesthesia and periarticular injections (PAIs). When performing a PAI, the relative location of the anesthetic spread is not well defined in comparison with an adductor canal block (ACB). In this study, our aim was to evaluate the location of posteromedial PAI spread compared with a surgeon administered ACB. One PAI and one surgeon-administered ACB were performed in the contralateral limbs of four human cadavers. The injectate was composed of methylene blue dye to visually inspect the dye spread from the tip of the needle. Dissections were performed on each cadaver to quantify the dye spread from the tip of the needle and compare the location of the dye spread. Dye spread location was characterized as either entering the adductor canal or including the posterior capsule. The mean distance of dye spread from the needle tip to the proximal most aspect of the dyed tissue was 10.125 cm in the ACB group compared with 6.5 cm in the posteromedial PAI group. In the ACB group, 4 of 4 injections were present in the adductor canal block group compared with 3 of 4 in the posteromedial PAI group. The posteromedial PAI group also had 3 of 4 injections involve the area around the posterior capsule compared with 0 of 4 in the ACB group. Posteromedial PAI appears to provide local delivery to both the adductor canal and the posterior capsule. Intraoperative, surgeon-administered ACB reliably delivers injectate to the adductor canal only but may allow for more proximal dye spread. Posteromedial PAI may provide a benefit in delivering injectate to the posterior capsule in addition to the ACB. Additional clinical studies are necessary to determine the clinical effects of this finding.