Disparities in the access to atrial fibrillation ablation in Denmark - Who gets ablated, who neglected?

BACKGROUND: Atrial fibrillation (AF) is a common arrhythmia associated with reduced quality of life that can lead to serious complications such as stroke, and heart failure. Ablation is a safe and effective treatment for AF but is not offered equally to all patients. PURPOSE: To identify the demographic groups more or less likely to undergo AF ablation. METHODS: All patients with newly diagnosed AF between 2010 and 2018 were identified in the Danish nationwide registries. The association between gender, age, level of education and attachment to the job market, and the likelihood of receiving AF ablation was investigated using multivariable Cox proportional-hazard analysis. Cumulative incidence was calculated using the Aalen-Johansen estimator. RESULTS: A total of 176,248 patients were included. Men were more likely to receive ablation than women (7% vs 3%). Patients aged 25-44 and 45-64 were most likely to receive ablation, while only 0.7% of patients aged 80 or above received ablation. The rate of ablation significantly decreased with decreasing level of education. Full-time employed patients were most likely to receive ablation, followed by self-employed, unemployed, on sick leave, undergoing education, and early retired patients. Retired patients were the least likely to receive ablation (3%). CONCLUSION: This study found that women, older patients, patients with lower levels of education, and patients on social benefits are less likely to receive AF ablation. These findings suggest that there are significant social and economic disparities in AF ablation treatment in Denmark.

Tracking Real-World Physical Activity in Chronic Obstructive Pulmonary Disease Over One Year: Results from a Monocentric, Prospective, Observational Cohort Study.

Introduction: Lung function constraints and comorbidities such as coronary heart disease, sarcopenia, and mood disorders make chronic obstructive pulmonary disease (COPD) patients avoid physical activity (PA). However, PA represents an important pillar of COPD management and is explicitly recommended by professional associations to enhance physical functioning and positively modulate disease progression. Methods: In this monocentric, prospective, observational feasibility study, it was our primary objective to investigate the association between PA and the evolution of the COPD assessment test (CAT) and the occurrence of acute exacerbations of COPD (AECOPD), respectively. To this end, we equipped 42 COPD patients with an activity tracking wearable and telemonitored their daily PA levels over one year using a dedicated web-based interface. Patients additionally provided weekly CAT scores using the same telehealth platform and came in for 3 study visits to assess functional parameters and biochemical markers related to nutrition and inflammation. Results: A principal study finding was that PA was inversely associated with CAT score (drop of 0.21 points associated with an increase of 1000 daily steps, p = 0.004), and that the 50% of patients with higher PA levels showed less CAT score progression over time (0.42 points per year) than the 50% of patients with lower PA levels (3.26 points per year) (p < 0.001). In addition, higher PA levels were significantly associated with a lower likelihood of experiencing a moderate-to-severe AECOPD (31% risk reduction associated with an increase of 1000 daily steps, p = 0.0097). Discussion: Our study demonstrates the relevance of PA for key COPD outcome metrics in a real-world setting and underpins the importance of PA for COPD self-management in everyday life. Our study paves the way for future intervention trials to prospectively identify medically relevant PA thresholds and establish training recommendations for different patient subgroups.

Deterministic photon source of genuine three-qubit entanglement.

Deterministic photon sources allow long-term advancements in quantum optics. A single quantum emitter embedded in a photonic resonator or waveguide may be triggered to emit one photon at a time into a desired optical mode. By coherently controlling a single spin in the emitter, multi-photon entanglement can be realized. We demonstrate a deterministic source of three-qubit entanglement based on a single electron spin trapped in a quantum dot embedded in a planar nanophotonic waveguide. We implement nuclear spin narrowing to increase the spin dephasing time to T 2 * ≃ 33 ns, which enables high-fidelity coherent optical spin rotations, and realize a spin-echo pulse sequence for sequential generation of spin-photon and spin-photon-photon entanglement. The emitted photons are highly indistinguishable, which is a key requirement for scalability and enables subsequent photon fusions to realize larger entangled states. This work presents a scalable deterministic source of multi-photon entanglement with a clear pathway for further improvements, offering promising applications in photonic quantum computing or quantum networks.

Early Outcomes of the Surgical Treatment of Non-traumatic Massive Pericardial Effusion in the University of the Philippines - Philippine General Hospital COVID-19 Referral Center.

Objective: To describe the treatment outcomes of patients who underwent tube pericardiostomy for all etiologies of non-traumatic massive pericardial effusion or tamponade during the COVID-19 pandemic and determine the association between patient profile and treatment outcomes. Methods: Data were obtained from patients with massive pericardial effusion or cardiac tamponade who underwent surgical drainage from January 1, 2020, to September 1, 2022, in the University of the Philippines - Philippine General Hospital (UP-PGH). These patients' demographic and clinical profiles, and treatment outcomes were evaluated using frequencies and percentages. Chi-squared and Fisher's tests determined the differences between COVID (+) and (-) groups. Odds Ratio was used to assess the risk of complications and mortality. Results: The study population comprised 90 patients with a mean age of 45 years. 54.4% were females. Fifteen (16.67%) were COVID-19 (+) and 75 (83.33%) were COVID-19 (-). Most of the patients were of O+ blood type (34.4%), with no smoking history (67.8%) and no COVID-19 vaccination (76.7%). Common comorbidities were cancer (70%), tuberculosis infection (32.2%), and hypertension (25.6%). No significant difference was found between the two study groups. The presentation was subacute (one week to three months) (62.2%), with the most common symptoms of dyspnea (81.1%), orthopnea (61.1%), and cough (52.2%). Tachycardia (80%) and tachypnea (57.8%) were the most common presenting signs. Hypotension was found more frequently among COVID-19 (+) patients (46.7% vs. 12.0%, p = 0,003, 95% CI). Most patients had abnormal WBC, coagulopathy, elevated inflammatory markers, and cardiac biomarkers. Sinus tachycardia, regular sinus rhythm, ST-T wave changes, and low voltage QRS were common ECG findings. The most common chest X-ray results were pleural effusion (80%), pneumonia (71.1%), and enlarged cardiac border (42.2%). Majority of echocardiographic findings were large effusion (>2 cm) (97.8%), RV collapse (40%), and RA collapse (23.3%). An average of 628 ml of pericardial effusion was drained, predominantly serous and exudative. One specimen yielded a positive AFB culture. 6.7% showed carcinoma cells on fluid cytology. The pericardium was normal in 78.9%. 10.0% of the pericardial biopsy specimen had carcinoma, with metastatic cancer being the most common etiology. The most common cancers were lymphoma (22.7%), breast (25.8%), and lung (16.7%). Hospital length of stay was 18 days in COVID-19 (+) patients and 12 days in COVID (-). The complication and in-hospital mortality rate in the COVID-19 (+) compared to the (-) group (86.7% vs. 73.3% and 46.7% vs. 41.3%, respectively) were not statistically significant. The most common complications were respiratory failure (60%), shock (53.3%), and nosocomial pneumonia (40%). There was no association between clinical factors and the risk for complications. Any complication increased the risk for mortality (OR 15.0, 95% CI 3.2-19.7, p=0.002). The presence of hypertension (OR 0.08, 95% CI 0.02 to 0.4, p=0.001) and subacute duration (OR 0.3, 95% CI 0.09 -0.9, p=0.045) decreased the mortality risk. Conclusions: Profiles were similar in both groups. There was no association between patient profile and complications. Having COVID-19 did not affect patient outcome. The presence of any complication increases the risk of mortality. In-hospital mortality was high at 42.2%.

Evaluation of guided reporting: quality and reading time of automatically generated radiology report in breast magnetic resonance imaging using a dedicated software solution.

PURPOSE: Unstructured, free-text dictation (FT), the current standard in breast magnetic resonance imaging (MRI) reporting, is considered time-consuming and prone to error. The purpose of this study is to assess the usability and performance of a novel, software-based guided reporting (GR) strategy in breast MRI. METHODS: Eighty examinations previously evaluated for a clinical indication (e.g., mass and focus/non-mass enhancement) with FT were reevaluated by three specialized radiologists using GR. Each radiologist had a different number of cases (R1, n = 24; R2, n = 20; R3, n = 36). Usability was assessed by subjective feedback, and quality was assessed by comparing the completeness of automatically generated GR reports with that of their FT counterparts. Errors in GR were categorized and analyzed for debugging with a final software version. Combined reading and reporting times and learning curves were analyzed. RESULTS: Usability was rated high by all readers. No non-sense, omission/commission, or translational errors were detected with the GR method. Spelling and grammar errors were observed in 3/80 patient reports (3.8%) with GR (exclusively in the discussion section) and in 36/80 patient reports (45%) with FT. Between FT and GR, 41 patient reports revealed no content differences, 33 revealed minor differences, and 6 revealed major differences that resulted in changes in treatment. The errors in all patient reports with major content differences were categorized as content omission errors caused by improper software operation (n = 2) or by missing content in software v. 0.8 displayable with v. 1.7 (n = 4). The mean combined reading and reporting time was 576 s (standard deviation: 327 s; min: 155 s; max: 1,517 s). The mean times for each reader were 485, 557, and 754 s, and the respective learning curves evaluated by regression models revealed statistically significant slopes (P = 0.002; P = 0.0002; P < 0.0001). Overall times were shorter compared with external references that used FT. The mean combined reading and reporting time of MRI examinations using FT was 1,043 s and decreased by 44.8% with GR. CONCLUSION: GR allows for complete reporting with minimized error rates and reduced combined reading and reporting times. The streamlining of the process (evidenced by lower reading times) for the readers in this study proves that GR can be learned quickly. Reducing reporting errors leads to fewer therapeutic faults and lawsuits against radiologists. It is known that delays in radiology reporting hinder early treatment and lead to poorer patient outcomes. CLINICAL SIGNIFICANCE: While the number of scans and images per examination is continuously rising, staff shortages create a bottleneck in radiology departments. The IT-based GR method can be a major boon, improving radiologist efficiency, report quality, and the quality of simultaneously generated data.

High toxinogenic potential of Staphylococcus aureus from wild ungulates in Brandenburg, Germany with a low level of antibiotic resistance.

Introduction: Data regarding the occurrence and virulence of Staphylococcus (S.) aureus in wild living animals is rare. However, S. aureus may carry a multitude of virulence factors and express resistance to several antimicrobial substances. Handling game meat may thus lead to serious infections or food poisoning. The aim of this study was to provide insights into the occurrence and characteristics of S. aureus in wild ungulates from Brandenburg, Germany. Methods: Nasal swabs of externally healthy-looking wild boars, roe, fallow and red deer were collected in hunts during season 2021/2022 and analyzed for S. aureus by selective enrichment. Species were determined using matrix assisted laser desorption ionization mass spectrometry and tested for phenotypic antimicrobial resistance. Whole-genome sequencing was conducted for genotyping, determination of virulence associated genes and analysis of phylogenetic relationships. Results: S. aureus were recovered from approximately 8% of nasal swabs. However, the strains were only obtained from the sampled wild ruminants. S. aureus isolates were associated with sequence types (ST) 1, ST30, ST133, ST425, ST582 and ST6238. Isolates of ST1 clustered closely together in the phylogenetic analysis. Genes encoding staphylococcal enterotoxin (SE) or SE-like (SEl) were found in 14/17 isolates. In particular, a seh gene was present in 12/17 isolates. Moreover, two isolates harbored a multiplicity of genes encoding SE or SEl. In addition, the toxic shock syndrome toxin encoding tst gene was detected in one isolate. This isolate was resistant to penicillin and cefoxitin and accordingly harbored the blaZ gene. Discussion: Wild ungulates intended for human consumption may carry potentially virulent S. aureus. In one case, the close phylogenetic relationship of S. aureus isolates indicates a possible intraspecific spread within a common territory. However, for others, the origin or the spread pattern can only be inferred. Handling of animals or their carcasses might contribute to staphylococcal infections in humans. Moreover, food poisoning due to SE producing strains may occur, if recommended hygiene practices are not applied during processing of game meat.

Prion protein gene (PRNP) variation in German and Danish cervids.

The structure of cellular prion proteins encoded by the prion protein gene (PRNP) impacts susceptibility to transmissible spongiform encephalopathies, including chronic wasting disease (CWD) in deer. The recent emergence of CWD in Northern European reindeer (Rangifer tarandus), moose (Alces alces alces) and red deer (Cervus elaphus), in parallel with the outbreak in North America, gives reason to investigate PRNP variation in European deer, to implement risk assessments and adjust CWD management for deer populations under threat. We here report PRNP-sequence data from 911 samples of German red, roe (Capreolus capreolus), sika (Cervus nippon) and fallow deer (Dama dama) as well as additional data from 26 Danish red deer close to the German border and four zoo species not native to Germany. No PRNP sequence variation was observed in roe and fallow deer, as previously described for populations across Europe. In contrast, a broad PRNP variation was detected in red deer, with non-synonymous polymorphisms at codons 98, 226 and 247 as well as synonymous mutations at codons 21, 78, 136 and 185. Moreover, a novel 24 bp deletion within the octapeptide repeat was detected. In summary, 14 genotypes were seen in red deer with significant differences in their geographical distribution and frequencies, including geographical clustering of certain genotypes, suggesting "PRNP-linages" in this species. Based on data from North American CWD and the genotyping results of the European CWD cases, we would predict that large proportions of wild cervids in Europe might be susceptible to CWD once introduced to naive populations.

Absence of Crimean-Congo hemorrhagic fever virus in wild lagomorphs and their ticks in Spanish Mediterranean ecosystems.

Crimean-Congo hemorrhagic fever virus (CCHFV) is an emerging tick-borne pathogen in different European countries. Since 2013, clinical and fatality cases associated with CCHFV infection have been reported in humans in Spain. During the last few years, endemic circulation of this virus has been detected in ticks and wild ungulates in this country, but the role of other sympatric wild species in the sylvatic cycle of this multi-host virus remains poorly understood. The aims of the present study were to assess exposure to CCHFV in wild lagomorphs in southern Spain, a CCHFV endemic area, and to determine the presence of the virus in ticks feeding on these species. Serum samples from 473 European wild rabbits (Oryctolagus cuniculus) and 162 Iberian hares (Lepus granatensis), and 120 ticks feeding on 85 of these wild lagomorphs were collected on 133 hunting grounds between 2018/2019 and 2021/2022 hunting seasons. The presence of antibodies against CCHFV was assessed in all serum samples using a commercial ELISA, whereas ticks were tested for the presence of CCHFV-RNA by a multiplex RT-qPCR that detects all known genotypes of this virus. None of the 635 (0.0 %; 95 %CI: 0.0-0.6) lagomorphs tested had anti-CCHFV antibodies and CCHFV-RNA was not found in any of the 120 (0.0 %; 95 %CI: 0.0-3.0) ticks analyzed. To the best of the authors knowledge, this is the first epidemiological study conducted on CCHFV in Iberian hare worldwide. Our findings indicate absence of exposure to CCHFV in European wild rabbit and Iberian hare populations, as well as in their ticks, which suggests that they do not seem to play a relevant role in the epidemiology of CCHFV in Mediterranean ecosystems of southern Spain.

General anaesthesia compared to conscious sedation for first-time atrial fibrillation catheter ablation-a Danish nationwide cohort study.

AIMS: Catheter ablation (CA) is a well-established treatment option for atrial fibrillation (AF), where sedation and analgesia are pivotal for patient comfort and lesion formation. The impact of anaesthesia type on AF recurrence rates remains uncertain. This study aimed to examine AF recurrence rates depending on conscious sedation (CS) vs. general anaesthesia (GA) during CA. METHODS AND RESULTS: Utilizing nationwide data from the Danish healthcare registries, we conducted this cohort study involving adults (≥18 years) undergoing first-time CA for AF between 2010 and 2018. Patients were categorized by anaesthesia type (CS or GA), with the primary endpoint being AF recurrence, defined by a composite endpoint of either antiarrhythmic drug (AAD) prescriptions, AF-related hospital admissions, electrical cardioversions, or AF re-ablation. The impact of anaesthesia type was evaluated using multivariable Cox proportional hazards analysis. The study cohort comprised 7957 (6421 CS and 1536 GA) patients. Persistent AF, hypertension, and heart failure, as well as use of AAD, were more prevalent in the GA group. Cumulative incidences of recurrent AF were higher in the CS group at 1 (46% vs. 37%) and at 5 (68% vs. 63%) years. Multivariate analysis revealed CS as significantly associated with increased risk of AF recurrence at 5-year follow-up [hazard ratio 1.26 (95% confidence interval 1.15-1.38)], consistent across paroxysmal and persistent AF subtypes. CONCLUSION: This nationwide cohort study suggests a higher risk of AF recurrence with CS during CA compared to GA. These results advocate for considering GA as the preferred anaesthesia type for improved CA outcomes.

Clinical Outcomes and Targeted Genomic Analysis of Renal Cell Carcinoma Brain Metastases Treated with Stereotactic Radiosurgery.

BACKGROUND: Molecular profiles of renal cell carcinoma (RCC) brain metastases (BMs) are not well characterized. Effective management with locoregional therapies, including stereotactic radiosurgery (SRS), is critical as systemic therapy advancements have improved overall survival (OS). OBJECTIVE: To identify clinicogenomic features of RCC BMs treated with SRS in a large patient cohort. DESIGN, SETTING, AND PARTICIPANTS: A single-institution retrospective analysis was conducted of all RCC BM patients treated with SRS from January 1, 2010 to March 31, 2021. INTERVENTION: SRS for RCC BMs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Next-generation sequencing was performed to identify gene alterations more prevalent in BM patients. Clinical factors and genes altered in ≥10% of samples were assessed per patient using Cox proportional hazards models and per individual BM using clustered competing risks regression with competing risk of death. RESULTS AND LIMITATIONS: Ninety-one RCC BM patients underwent SRS to 212 BMs, with a median follow-up of 38.8 mo for patients who survived. The median intracranial progression-free survival and OS were 7.8 (interquartile range [IQR] 5.7-11) and 21 (IQR 16-32) mo, respectively. Durable local control of 83% was achieved at 12 mo after SRS, and 59% of lesions initially meeting the radiographic criteria for progression at 3-mo evaluation would be considered to represent pseudoprogression at 6-mo evaluation. A comparison of genomic alterations at both the gene and the pathway level for BM+ patients compared with BM- patients revealed phosphoinositide 3-kinase (PI3K) pathway alterations to be more prevalent in BM+ patients (43% vs 16%, p = 0.001, q = 0.01), with the majority being PTEN alterations (17% vs 2.7%, p = 0.003, q = 0.041). CONCLUSIONS: To our knowledge, this is the largest study investigating genomic profiles of RCC BMs and the only such study with annotated intracranial outcomes. SRS provides durable in-field local control of BMs. Recognizing post-SRS pseudoprogression is crucial to ensure appropriate management. The incidence of PI3K pathway alterations is more prevalent in BM+ patients than in BM- patients and warrants further investigation in a prospective setting. PATIENT SUMMARY: We examined the outcomes of radiotherapy for the treatment of brain metastases in kidney cancer patients at a single large referral center. We found that radiation provides good control of brain tumors, and certain genetic mutations may be found more commonly in patients with brain metastasis.

Spinal column shortening with single-stage prone lateral vertebral osteotomy for tethered cord syndrome: illustrative case.

BACKGROUND: Tethered cord syndrome (TCS) is a rare neurological disorder characterized by longitudinal stretching on the distal end of the spinal cord. The condition commonly manifests in lumbosacral and lower-extremity pain and weakness, sensory disturbances, and incontinence. Traditionally, tethered cord release has been the first-line management for TCS, but retethering and complications such as cerebrospinal fluid leakage are commonly reported. As a result, spinal column shortening (SCS) vertebral osteotomy has emerged as a potential alternative. OBSERVATIONS: Herein, the authors describe the first single-stage prone lateral SCS vertebral osteotomy with simultaneous posterior exposure in a 48-year-old male patient with multiple prior direct detethering procedures. The authors highlight the case presentation, operative technique, and postoperative course. Following surgery, there were no immediate surgical complications, and the patient noted clinical improvement in his radicular pain and neurological function. LESSONS: This case further supports SCS vertebral osteotomy as an effective treatment option for patients with TCS. It also demonstrates the potential for a single-stage lateral approach with posterior exposure as a minimally invasive option for spinal shortening procedures. However, further studies using expanded cohorts and assessing various surgical techniques are warranted. https://thejns.org/doi/10.3171/CASE24185.

Prognostic importance of ischemic heart disease among patients with atrial fibrillation undergoing catheter ablation.

BACKGROUND: Ischemic heart disease (IHD) has been linked to an increased risk of atrial fibrillation (AF). However, data are sparse regarding the role of IHD in AF recurrence after catheter ablation. OBJECTIVE: To investigate whether preexisting or new-onset IHD is associated with a greater risk of AF recurrence after ablation. METHODS: Using Danish nationwide registries, all patients undergoing first-time AF ablation in Denmark from 2010 to 2020 were identified. The primary outcome was AF recurrence defined by AF-related hospital admission or antiarrhythmic drug use within 1 year after ablation excluding a 3-month blanking period. IHD was defined as an ICD-10 diagnosis of IHD and/or prior coronary revascularization. RESULTS: Among 12,162 patients undergoing first-time ablation for AF (mean age 62 years, 30% female), 20% had preexisting IHD. Preexisting IHD was associated with an increased risk of AF recurrence in univariable Log binomial logistic regression (relative risk (RR) 1.09, 95%CI 1.04-1-14, p<0.001). However, after multivariable adjustment including procedural year, preexisting IHD was no longer associated with an increased risk of AF recurrence (RR 1.02, 95%CI 0.97-1.06, p=0.42). In a nested case-control study among those without preexisting IHD prior to ablation (N=9,778), newly diagnosed IHD after ablation was associated with an increased risk of AF recurrence in multivariable analysis (hazard ratio 3.03, 95%CI 1.84-4.99, p<0.001). CONCLUSION: The presence of IHD does not appear to reduce the effectiveness of AF ablation procedures. However, the emergence of IHD after AF ablation may serve as a trigger for AF that is insufficiently suppressed by prior ablation.

Systemic oxidative stress associates with the development of post-COVID-19 syndrome in non-hospitalized individuals.

BACKGROUND: Post-COVID-19 syndrome (PCS) remains a major health issue worldwide, while its pathophysiology is still poorly understood. Systemic oxidative stress (OS) may be involved in PCS, which is reflected by lower circulating free thiols (R-SH, sulfhydryl groups), as they are receptive to rapid oxidation by reactive species. This study aimed to investigate the longitudinal dynamics of serum R-SH after SARS-CoV-2 infection and its association with the development of PCS in individuals with mild COVID-19. METHODS: Baseline serum R-SH concentrations were measured and compared between 135 non-hospitalized COVID-19 subjects and 82 healthy controls (HC). In COVID-19 subjects, serum R-SH concentrations were longitudinally measured during the acute disease phase (up to 3 weeks) and at 3, 6, and 12 months of follow-up, and their associations with relevant clinical parameters were investigated, including the development of PCS. RESULTS: Baseline albumin-adjusted serum R-SH were significantly reduced in non-hospitalized COVID-19 subjects as compared to HC (p = 0.041), reflecting systemic OS. In mild COVID-19 subjects, trajectories of albumin-adjusted serum R-SH levels over a course of 12 months were longitudinally associated with the future presence of PCS 18 months after initial infection (b = -9.48, p = 0.023). CONCLUSION: Non-hospitalized individuals with COVID-19 show evidence of systemic oxidative stress, which is longitudinally associated with the development of PCS. Our results provide a rationale for future studies to further investigate the value of R-SH as a monitoring biomarker and a potential therapeutic target in the development of PCS.

A Multiscale Inelastic Internal State Variable Corrosion Model.

We present a corrosion internal state variable (ISV) damage model based upon the integrated computational materials engineering (ICME) hierarchical multiscale paradigm. Structure-property experiments for magnesium alloys were used where the only inputs were the volume fractions of each element of the periodic table. This macroscale ISV corrosion model finds its basis in Horstemeyer's mechanical damage model, which includes three separate ISVs for damage nucleation, growth, and coalescence, as well as Walton's inclusion of corrosion, which introduces five new ISVs for pit nucleation, growth, and coalescence, along with general corrosion and intergranular corrosion. While Walton's corrosion ISVs are phenomenological in nature, herein we develop a multiscale physical basis for the corrosion ISVs. The parameters for the macroscale corrosion ISVs were garnered from the mesoscale Butler-Volmer equations. Pure magnesium with differing amounts of aluminum were used in corrosion tests to exemplify the different pitting, general corrosion, and intergranular corrosion rates, and the macroscale ISV model was calibrated with said data, in which the only inputs to the model are the volume percentages of the elements magnesium and aluminum. Although magnesium alloys were used to motivate and calibrate the model, the model is abstract enough to possibly capture other material systems as well.

Characterisation of European Field Goat Prion Isolates in Ovine PrP Overexpressing Transgenic Mice (Tgshp IX) Reveals Distinct Prion Strains.

After the detection of bovine spongiform encephalopathy (BSE), and a zoonotic transmissible spongiform encephalopathy (TSE) caused by the pathological prion protein (PrPSc) in two goats, the investigation of goat prions became of greater interest. Therefore, a broad collection of European goat TSE isolates, including atypical scrapie, CH1641 and goat BSE as reference prion strains were biochemically characterised and subsequently inoculated into seven rodent models for further analysis (already published results of this comprehensive study are reviewed here for comparative reasons). We report here the histopathological and immunohistochemical data of this goat TSE panel, obtained after the first passage in Tgshp IX (tg-shARQ) mice, which overexpress the ovine prion protein. In addition to the clear-cut discrimination of all reference prion strains from the classical scrapie (CS) isolates, we were further able to determine three categories of CS strains. The investigation further indicates the occurrence of sub-strains that slightly resemble distant TSE strains, such as BSE or CH1641, reinforcing the theory that CS is not a single strain but a mixture of sub-strains, existing at varying extents in one isolate. This study further proved that Tgshp IX is a potent and reliable tool for the in-depth characterisation of prion strains.

Physiological and clinical effects of trunk inclination adjustment in patients with respiratory failure: a scoping review and narrative synthesis.

BACKGROUND: Adjusting trunk inclination from a semi-recumbent position to a supine-flat position or vice versa in patients with respiratory failure significantly affects numerous aspects of respiratory physiology including respiratory mechanics, oxygenation, end-expiratory lung volume, and ventilatory efficiency. Despite these observed effects, the current clinical evidence regarding this positioning manoeuvre is limited. This study undertakes a scoping review of patients with respiratory failure undergoing mechanical ventilation to assess the effect of trunk inclination on physiological lung parameters. METHODS: The PubMed, Cochrane, and Scopus databases were systematically searched from 2003 to 2023. INTERVENTIONS: Changes in trunk inclination. MEASUREMENTS: Four domains were evaluated in this study: 1) respiratory mechanics, 2) ventilation distribution, 3) oxygenation, and 4) ventilatory efficiency. RESULTS: After searching the three databases and removing duplicates, 220 studies were screened. Of these, 37 were assessed in detail, and 13 were included in the final analysis, comprising 274 patients. All selected studies were experimental, and assessed respiratory mechanics, ventilation distribution, oxygenation, and ventilatory efficiency, primarily within 60 min post postural change. CONCLUSION: In patients with acute respiratory failure, transitioning from a supine to a semi-recumbent position leads to decreased respiratory system compliance and increased airway driving pressure. Additionally, C-ARDS patients experienced an improvement in ventilatory efficiency, which resulted in lower PaCO2 levels. Improvements in oxygenation were observed in a few patients and only in those who exhibited an increase in EELV upon moving to a semi-recumbent position. Therefore, the trunk inclination angle must be accurately reported in patients with respiratory failure under mechanical ventilation.

Immunisation of pigs with recombinant HEV vaccines does not protect from infection with HEV genotype 3.

Hepatitis E virus (HEV) is a major cause of acute viral hepatitis worldwide. Up to now, no approved treatment nor a globally licensed vaccine is available. Several recombinant HEV vaccines have been developed to protect against HEV infection in humans, including the commercially available Hecolin vaccine, which are mainly based on HEV genotype 1. However, the efficacy of these vaccines against other HEV genotypes, especially genotype 3 is unknown. In this study, we evaluated the protective efficacy of Hecolin® and a novel genotype 3-based vaccine p239(gt3) against HEV-3 in a pig infection model. Pigs were divided into three groups: one group was vaccinated with Hecolin®, the second group was vaccinated with p239(gt3), and the control group received no vaccine. All pigs were subsequently challenged with HEV genotype 3 to assess the effectiveness of the vaccines. Although all immunised animals developed a high titer of neutralizing antibodies, the results showed that both vaccine applications could not provide complete protection against HEV (gt3) infection: Two out of four animals of the Hecolin® group displayed even virus shedding, and viral RNA could be detected in bile and/or liver of three out of four animals in both vaccination groups. Only one out of four animals in each group was fully protected. Neither Hecolin® nor the novel p239(gt3) vaccine provided sufficient protection against genotype 3 infection. While Hecolin® only partial protected pigs from HEV shedding, the novel p239(gt3) vaccine was at least able to prevent infected pigs from virus shedding. The results highlight the need for further development of HEV vaccines that exhibit broad protection against multiple HEV genotypes and the use of appropriate animal infection models.

Treatment-free survival and partitioned survival analysis of patients with advanced renal cell carcinoma treated with nivolumab plus ipilimumab versus sunitinib: 5-year update of CheckMate 214.

BACKGROUND: Immunotherapy can be associated with prolonged disease control even after cessation of treatment without the need for further cancer-directed therapy. Treatment-related adverse events (TRAEs) can also persist after discontinuation of therapy. Treatment-free survival (TFS) with and without toxicity as a component of a partitioned survival model can characterize patient survival time, which is not captured by standard outcome measures. METHODS: Data from 1096 patients with advanced renal cell carcinoma treated with first-line nivolumab plus ipilimumab (NIVO+IPI) versus sunitinib (SUN) in the CheckMate 214 trial were analyzed. TFS was defined as the area between two Kaplan-Meier curves for time from randomization to protocol therapy discontinuation and time from randomization to subsequent systemic therapy initiation or death, estimated as the difference in 60-month restricted mean times with confidence intervals (CIs) obtained using bootstrap sampling. Time on protocol therapy and TFS were further characterized as time with and without grade 2+ and 3+TRAEs. Survival functions were estimated in subgroups including International Metastatic Renal Cell Carcinoma Database Consortium risk groups using the Kaplan-Meier method. RESULTS: At 5 years from randomization, 48% of patients treated with NIVO+IPI and 37% of patients treated with SUN were alive. In the intent-to-treat population, 18% of the NIVO+IPI-treated and 5% of SUN-treated patients are surviving treatment-free. For favorable-risk patients, the 60-month mean TFS was 14.4 months for NIVO+IPI versus 5.5 months for SUN (difference 8.9 months (95% CI 4.9 to 12.8)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 5.0 and 2.1 months, respectively, and with grade 3+TRAEs was 1.2 and 0.3 months, respectively. For intermediate/poor-risk patients, the 60-month mean TFS was 10.1 months for NIVO+IPI versus 4.1 months for SUN (difference 6.1 months (95% CI 4.2 to 7.9)). TFS for NIVO+IPI versus SUN with grade 2+TRAEs was 4.0 versus 2.0 months, respectively, and 0.6 versus 0.3 months with grade 3+TRAEs. CONCLUSIONS: Although overall survival was similar, favorable-risk patients treated with NIVO+IPI spent more time surviving treatment-free with and without toxicity versus SUN after 60 months of follow-up. Intermediate/poor-risk patients treated with NIVO+IPI had longer survival and longer TFS without toxicity versus SUN. TRIAL REGISTRATION NUMBER: NCT02231749.

Trophic effects of Bti-based mosquito control on two top predators in floodplain pond mesocosms.

Chironomid (Diptera: Chironomidae) larvae play a key role in aquatic food webs as prey for predators like amphibian and dragonfly larvae. This trophic link may be disrupted by anthropogenic stressors such as Bacillus thuringiensis var. israelensis (Bti), a biocide widely used in mosquito control. In a companion study, we recorded a 41% reduction of non-target larval chironomids abundance in outdoor floodplain pond mesocosms (FPMs) treated with Bti. Therefore, we examined the diet of two top predators in the FPMs, larvae of the palmate newt (Salamandridae: Lissotriton helveticus) and dragonfly (Aeshnidae: predominantly Anax imperator), using bulk stable isotope analyses of carbon and nitrogen. Additionally, we determined neutral lipid fatty acids in newt larvae to assess diet-related effects on their physiological condition. We did not find any effects of Bti on the diet proportions of newt larvae and no significant effects on the fatty acid content. We observed a trend in Aeshnidae larvae from Bti-FPMs consuming a higher proportion of large prey (Aeshnidae, newt, damselfly larvae; ~42%), and similar parts of smaller prey (chironomid, mayfly, Libellulidae, and zooplankton), compared to controls. Our findings may suggest bottom-up effects of Bti on aquatic predators but should be further evaluated, for instance, by using compound-specific stable isotope analyses of fatty acids or metabarcoding approaches.