Catheter ablation for persistent atrial fibrillation: patterns of recurrence and impact on quality of life and health care utilisation.

BACKGROUND AND AIMS: Patterns of atrial fibrillation (AF) recurrence post catheter ablation for persistent AF are not well described. This study aimed to describe the pattern of AF recurrence seen following catheter ablation for persistent AF (PsAF) and the implications for healthcare utilisation and quality of life. METHODS: This was a post-hoc analysis of the CAPLA study, an international, multi-centre study that randomised patients with symptomatic PsAF to pulmonary vein isolation plus posterior wall isolation or pulmonary vein isolation alone. Patients underwent twice daily single lead ECG, implantable device monitoring or three monthly Holter monitoring. RESULTS: 154 of 333 (46.2%) patients (median age 67.3 years, 28% female) experienced AF recurrence at 12-month follow-up. Recurrence was paroxysmal in 97 (63%) patients and persistent in 57 (37%). Recurrence type did not differ between randomisation groups (p=0.508). Median AF burden was 27.4% in PsAF recurrence and 0.9% in paroxysmal AF (PAF) recurrence (p<0.001). Patients with PsAF recurrence had lower baseline left ventricular ejection fraction (PsAF 50% vs PAF 60%, p<0.001) and larger left atrial volume (PsAF 54.2±19.3 ml/m² vs PAF 44.8±11.6 ml/m², p=0.008). Healthcare utilisation was significantly higher in PsAF (45 patients [78.9%]) vs PAF recurrence (45 patients [46.4%], p<0.001) and lowest in those without recurrence (17 patients [9.5%], p<0.001). Patients without AF recurrence had greater improvements in quality of life as assessed by the Atrial Fibrillation Effect on Quality-of-Life (AFEQT) questionnaire (Δ33.3±25.2 points) compared to those with PAF (Δ24.0±25.0 points, p=0.012) or PsAF (Δ13.4±22.9 points, p<0.001) recurrence. CONCLUSIONS: AF recurrence is more often paroxysmal after catheter ablation for PsAF irrespective of ablation strategy. Recurrent PsAF was associated with higher AF burden, increased healthcare utilisation and antiarrhythmic drug use. The type of AF recurrence and AF burden may be considered important endpoints in clinical trials investigating ablation of PsAF.

Meet the Authors: Harkamal S. Jhajj and Peter M. Tessier.

In an interview with Dr. Mishtu Dey, Editor-in-chief of Cell Chemical Biology, two authors of the Technology article entitled "Facile generation of biepitopic antibodies with intrinsic agonism for activating tumor necrosis factor receptors"-Dr. Peter M. Tessier and Dr. Harkamal S. Jhajj-share more about their paper and their lives as scientists.

Targeting miR-181a/b in retinitis pigmentosa: implications for disease progression and therapy.

BACKGROUND: Retinitis pigmentosa (RP) is a genetically heterogeneous group of degenerative disorders causing progressive vision loss due to photoreceptor death. RP affects other retinal cells, including the retinal pigment epithelium (RPE). MicroRNAs (miRs) are implicated in RP pathogenesis, and downregulating miR-181a/b has shown therapeutic benefit in RP mouse models by improving mitochondrial function. This study investigates the expression profile of miR-181a/b in RPE cells and the neural retina during RP disease progression. We also evaluate how miR-181a/b downregulation, by knocking out miR-181a/b-1 cluster in RPE cells, confers therapeutic efficacy in an RP mouse model and explore the mechanisms underlying this process. RESULTS: Our findings reveal distinct expression profiles, with downregulated miR-181a/b in RPE cells suggesting a protective response and upregulated miR-181a/b in the neural retina indicating a role in disease progression. We found that miR-181a/b-2, encoded in a separate genomic cluster, compensates for miR-181a/b-1 ablation in RPE cells at late time points. The transient downregulation of miR-181a/b in RPE cells at post-natal week 6 (PW6) led to improved RPE morphology, retarded photoreceptor degeneration and decreased RPE aerobic glycolysis. CONCLUSIONS: Our study elucidates the underlying mechanisms associated with the therapeutic modulation of miR-181a/b, providing insights into the metabolic processes linked to its RPE-specific downregulation. Our data further highlights the impact of compensatory regulation between miR clusters with implications for the development of miR-based therapeutics.

Mutations in the tail and rod domains of the neurofilament heavy-chain gene increase the risk of ALS.

OBJECTIVE: Neurofilament heavy-chain gene (NEFH) variants are associated with multiple neurodegenerative diseases, however, their relationship with ALS has not been robustly explored. Still, NEFH is commonly included in genetic screening panels worldwide. We therefore aimed to determine if NEFH variants modify ALS risk. METHODS: Genetic data of 11,130 people with ALS and 7,416 controls from the literature and Project MinE were analysed. We performed meta-analyses of published case-control studies reporting NEFH variants, and variant analysis of NEFH in Project MinE whole-genome sequencing data. RESULTS: Fixed-effects meta-analysis found that rare (MAF <1%) missense variants in the tail domain of NEFH increase ALS risk (OR 4.55, 95% CI 2.13-9.71, p < 0.0001). In Project MinE, ultrarare NEFH variants increased ALS risk (OR 1.37 95% CI 1.14-1.63, p = 0.0007), with rod domain variants (mostly intronic) appearing to drive the association (OR 1.45 95% CI 1.18-1.77, pMadsen-Browning = 0.0007, pSKAT-O = 0.003). While in the tail domain, ultrarare (MAF <0.1%) pathogenic missense variants were also associated with higher risk of ALS (OR 1.94, 95% CI 0.86-4.37, pMadsen-Browning = 0.039), supporting the meta-analysis results. Finally, several tail in-frame deletions were also found to affect disease risk, however, both protective and pathogenic deletions were found in this domain, highlighting an intricated architecture that requires further investigation. INTERPRETATION: We showed that NEFH tail missense and in-frame deletion variants, and intronic rod variants are risk factors for ALS. However, they are not variants of large effect, and their functional impact needs to be clarified in further studies. Therefore, their inclusion in routine genetic screening panels should be reconsidered.

Columnar Cell Thyroid Carcinoma: A Heterogeneous Entity Demonstrating Overlap Between Papillary Thyroid Carcinoma and Follicular Neoplasms.

BACKGROUND: Columnar cell papillary thyroid carcinoma (CC-PTC) is a morphologic subtype of papillary thyroid carcinoma with a variable prognosis. It is characterized by neoplastic thyroid follicular-derived cells with pseudostratified columnar morphology arranged in papillary or follicular structures with supranuclear or subnuclear vacuoles. The molecular profile of this subtype has only recently come under scrutiny, with mixed results. The aim of this study is to further explore the morphologic, immunohistochemical, and genetic profile of CC-PTC, as well as to correlate these features with clinical outcomes. METHODS: CC-PTC cases were identified from 3 institutions. Immunohistochemistry (ER, CDX2) and molecular testing (DNA and RNA sequencing) were performed. Clinicopathologic parameters and patient outcomes were recorded. RESULTS: Twelve cases (2006-2023) were identified, all in adults (age 45-91). Two presented with disease outside the thyroid gland (neck and mediastinum) and two presented with distant metastasis. Four were high-grade differentiated thyroid carcinomas (necrosis or mitoses), one of which died of disease. Four were noninvasive or minimally invasive, one of which locally recurred. Three patients had lymph node metastases. ER and CDX2 were positive in 73% and 50%, respectively. Pathogenic mutations were found in TERT promoter (n = 3), RAS (n = 2), ATM, NOTCH1, APC, and ESR1, along with cases bearing AGK::BRAF fusion (n = 1), BRAF VE1 expression (n = 1), and NF2 loss (n = 1). CONCLUSIONS: This study represents the largest molecularly defined cohort of non-oncocytic thyroid carcinomas with columnar cell morphology. These tumors represent a genetically and behaviorally heterogeneous group of neoplasms, some of which have RAS-like or follicular neoplasm-like genetics, some of which have BRAF-p.V600E-like or classic papillary thyroid carcinoma-like genetics, and some of which remain unclear. Noninvasive or minimally invasive tumors showed an indolent course compared to those with angioinvasion, gross extrathyroidal growth, or high-grade morphology. Consideration could be given to reclassification of this neoplasm outside of the subtyping of papillary thyroid carcinoma in light of its genetic diversity, distinct morphology, and clinical behavior more closely aligned with follicular thyroid neoplasms.

Patterns of Social Needs Predict Quality-of-Life and Healthcare Utilization Outcomes in Patients from a Large Hospital System.

BACKGROUND: Unmet social needs (SNs) often coexist in distinct patterns within specific population subgroups, yet these patterns are understudied. OBJECTIVE: To identify patterns of social needs (PSNs) and characterize their associations with health-related quality-of-life (HRQoL) and healthcare utilization (HCU). DESIGN: Observational study using data on SNs screening, HRQoL (i.e., low mental and physical health), and 90-day HCU (i.e., emergency visits and hospital admission). Among patients with any SNs, latent class analysis was conducted to identify unique PSNs. For all patients and by race and age subgroups, compared with no SNs, we calculated the risks of poor HRQoL and time to first HCU following SNs screening for each PSN. PATIENTS: Adult patients undergoing SNs screening at the Mass General Brigham healthcare system in Massachusetts, United States, between March 2018 and January 2023. MAIN MEASURES: SNs included: education, employment, family care, food, housing, medication, transportation, and ability to pay for household utilities. HRQoL was assessed using the Patient-Reported Outcomes Measurement Information System Global-10. KEY RESULTS: Six unique PSNs were identified: "high number of social needs," "food and utility access," "employment needs," "interested in education," "housing instability," and "transportation barriers." In 14,230 patients with HRQoL data, PSNs increased the risks of poor mental health, with risk ratios ranging from 1.07(95%CI:1.01-1.13) to 1.80(95%CI:1.74-1.86). Analysis of poor physical health yielded similar findings, except that the "interested in education" showed a mild protective effect (0.97[95%CI:0.94-1.00]). In 105,110 patients, PSNs increased the risk of 90-day HCU, with hazard ratios ranging from 1.09(95%CI:0.99-1.21) to 1.70(95%CI:1.52-1.90). Findings were generally consistent in subgroup analyses by race and age. CONCLUSIONS: Certain SNs coexist in distinct patterns and result in poorer HRQoL and more HCU. Understanding PSNs allows policymakers, public health practitioners, and social workers to identify at-risk patients and implement integrated, system-wide, and community-based interventions.

Patent Foramen Ovale Closure in Older Patients With Stroke: Patient Selection for Trial Feasibility.

BACKGROUND AND OBJECTIVES: Whether patent foramen ovale (PFO) closure benefits older patients with PFO and cryptogenic stroke is unknown because randomized controlled trials (RCTs) have predominantly enrolled patients younger than 60 years of age. Our objective was to estimate anticipated effects of PFO closure in older patients to predict the numbers needed to plan an RCT. METHODS: Effectiveness estimates are derived from major observational studies (Risk of Paradoxical Embolism [RoPE] Study and Oxford Vascular Study, together referred to as the "RoPE-Ox" database) and all 6 major RCTs (Systematic, Collaborative, PFO Closure Evaluation [SCOPE] Consortium). To estimate stroke recurrence risk, observed outcomes were calculated for patients older than 60 years in the age-inclusive observational databases (n = 549). To estimate the reduction in the rate of recurrent stroke associated with PFO closure vs medical therapy based on the RoPE score and the presence of high-risk PFO features, a Cox proportional hazards regression model was developed on the RCT data in the SCOPE database (n = 3,740). These estimates were used to calculate sample sizes required for a future RCT. RESULTS: Five-year risk of stroke recurrence using Kaplan-Meier estimates was 13.7 (95% CI 10.5-17.9) overall, 14.9% (95% CI 10.2-21.6) in those with high-risk PFO features. Predicted relative reduction in the event rate with PFO closure was 12.9% overall, 48.8% in those with a high-risk PFO feature. Using these estimates, enrolling all older patients with cryptogenic stroke and PFO would require much larger samples than those used for prior PFO closure trials, but selectively enrolling patients with high-risk PFO features would require totals of 630 patients for 90% power and 471 patients for 80% power, with an average of 5 years of follow-up. DISCUSSION: Based on our projections, anticipated effect sizes in older patients with high-risk features make a trial in these subjects feasible. With lengthening life expectancy in almost all regions of the world, the utility of PFO closure in older adults is increasingly important to explore.

2023 Cardiac Society of Australia and New Zealand Expert Position Statement on Catheter and Surgical Ablation for Atrial Fibrillation.

Catheter ablation for atrial fibrillation (AF) has increased exponentially in many developed countries, including Australia and New Zealand. This Expert Position Statement on Catheter and Surgical Ablation for Atrial Fibrillation from the Cardiac Society of Australia and New Zealand (CSANZ) recognises healthcare factors, expertise and expenditure relevant to the Australian and New Zealand healthcare environments including considerations of potential implications for First Nations Peoples. The statement is cognisant of international advice but tailored to local conditions and populations, and is intended to be used by electrophysiologists, cardiologists and general physicians across all disciplines caring for patients with AF. They are also intended to provide guidance to healthcare facilities seeking to establish or maintain catheter ablation for AF.

The Ring-Closing Reaction of Cyclopentadiene Probed with Ultrafast X-ray Scattering.

The dynamics of cyclopentadiene (CP) following optical excitation at 243 nm was investigated by time-resolved pump-probe X-ray scattering using 16.2 keV X-rays at the Linac Coherent Light Source (LCLS). We present the first ultrafast structural evidence that the reaction leads directly to the formation of bicyclo[2.1.0]pentene (BP), a strained molecule with three- and four-membered rings. The bicyclic compound decays via a thermal backreaction to the vibrationally hot CP with a time constant of 21 ± 3 ps. A minor channel leads to ring-opened structures on a subpicosecond time scale.

Improving Exposure Therapy: Rationale and Design of an International Consortium.

The Exposure Therapy Consortium (ETC) was established to advance the science and practice of exposure therapy. To encourage participation from researchers and clinicians, this article describes the organizational structure and activities of the ETC. Initial research working group experiences and a proof-of-principle study underscore the potential of team science and larger-scale collaborative research in this area. Clinical working groups have begun to identify opportunities to enhance access to helpful resources for implementing exposure therapy effectively. This article discusses directions for expanding the consortium's activities and its impact on a global scale.

Global mapping of the Chlamydia trachomatis conventional secreted effector - host interactome reveals CebN interacts with nucleoporins and Rae1 to impede STAT1 nuclear translocation.

Chlamydia trachomatis (C.t.), the leading cause of bacterial sexually transmitted infections, employs a type III secretion system (T3SS) to translocate two classes of effectors, inclusion membrane proteins and conventional T3SS (cT3SS) effectors, into the host cell to counter host defense mechanisms. Here we employed three assays to directly evaluate secretion during infection, validating secretion for 23 cT3SS effectors. As bioinformatic analyses have been largely unrevealing, we conducted affinity purification-mass spectrometry to identify host targets and gain insights into the functions of these effectors, identifying high confidence interacting partners for 21 cT3SS effectors. We demonstrate that CebN localizes to the nuclear envelope in infected and bystander cells where it interacts with multiple nucleoporins and Rae1, blocking STAT1 nuclear import following IFN-γ stimulation. By building a cT3SS effector-host interactome, we have identified novel pathways that are targeted during bacterial infection and have begun to address how C.t. effectors combat cell autonomous immunity.

Native ion mobility-mass spectrometry reveals the binding mechanisms of anti-amyloid therapeutic antibodies.

One of the most important attributes of anti-amyloid antibodies is their selective binding to oligomeric and amyloid aggregates. However, current methods of examining the binding specificities of anti-amyloid ß (Aß) antibodies have limited ability to differentiate between complexes that form between antibodies and monomeric or oligomeric Aß species during the dynamic Aß aggregation process. Here, we present a high-resolution native ion-mobility mass spectrometry (nIM-MS) method to investigate complexes formed between a variety of Aß oligomers and three Aß-specific IgGs, namely two antibodies with relatively high conformational specificity (aducanumab and A34) and one antibody with low conformational specificity (crenezumab). We found that crenezumab primarily binds Aß monomers, while aducanumab preferentially binds Aß monomers and dimers and A34 preferentially binds Aß dimers, trimers, and tetrameters. Through collision induced unfolding (CIU) analysis, our data indicate that antibody stability is increased upon Aß binding and, surprisingly, this stabilization involves the Fc region. Together, we conclude that nIM-MS and CIU enable the identification of Aß antibody binding stoichiometries and provide important details regarding antibody binding mechanisms.

Methods for making and observing model lipid droplets.

We present methods for making and testing the membrane biophysics of model lipid droplets (LDs). Methods are described for imaging LDs ranging in size from 0.1 to 40 µm in diameter with high-resolution microscopy and spectroscopy. With known LD compositions, membrane binding, sorting, diffusion, and tension were measured via fluorescence correlation spectroscopy (FCS), fluorescence recovery after photobleaching (FRAP), fluorescence lifetime imaging microscopy (FLIM), atomic force microscopy (AFM), and imaging flow cytometry. Additionally, a custom, small-volume pendant droplet tensiometer is described and used to measure the association of phospholipids to the LD surface. These complementary, cross-validating methods of measuring LD membrane behavior reveal the interplay of biophysical processes on lipid droplet monolayers.

Effect of emphysema on AI software and human reader performance in lung nodule detection from low-dose chest CT.

BACKGROUND: Emphysema influences the appearance of lung tissue in computed tomography (CT). We evaluated whether this affects lung nodule detection by artificial intelligence (AI) and human readers (HR). METHODS: Individuals were selected from the "Lifelines" cohort who had undergone low-dose chest CT. Nodules in individuals without emphysema were matched to similar-sized nodules in individuals with at least moderate emphysema. AI results for nodular findings of 30-100 mm3 and 101-300 mm3 were compared to those of HR; two expert radiologists blindly reviewed discrepancies. Sensitivity and false positives (FPs)/scan were compared for emphysema and non-emphysema groups. RESULTS: Thirty-nine participants with and 82 without emphysema were included (n = 121, aged 61 ± 8 years (mean ± standard deviation), 58/121 males (47.9%)). AI and HR detected 196 and 206 nodular findings, respectively, yielding 109 concordant nodules and 184 discrepancies, including 118 true nodules. For AI, sensitivity was 0.68 (95% confidence interval 0.57-0.77) in emphysema versus 0.71 (0.62-0.78) in non-emphysema, with FPs/scan 0.51 and 0.22, respectively (p = 0.028). For HR, sensitivity was 0.76 (0.65-0.84) and 0.80 (0.72-0.86), with FPs/scan of 0.15 and 0.27 (p = 0.230). Overall sensitivity was slightly higher for HR than for AI, but this difference disappeared after the exclusion of benign lymph nodes. FPs/scan were higher for AI in emphysema than in non-emphysema (p = 0.028), while FPs/scan for HR were higher than AI for 30-100 mm3 nodules in non-emphysema (p = 0.009). CONCLUSIONS: AI resulted in more FPs/scan in emphysema compared to non-emphysema, a difference not observed for HR. RELEVANCE STATEMENT: In the creation of a benchmark dataset to validate AI software for lung nodule detection, the inclusion of emphysema cases is important due to the additional number of FPs. KEY POINTS: • The sensitivity of nodule detection by AI was similar in emphysema and non-emphysema. • AI had more FPs/scan in emphysema compared to non-emphysema. • Sensitivity and FPs/scan by the human reader were comparable for emphysema and non-emphysema. • Emphysema and non-emphysema representation in benchmark dataset is important for validating AI.

Shining a Light on How Soil Organic Carbon Behaves at Fine Scales under Long-Term Elevated CO2: An 8 Year Free-Air Carbon Dioxide Enrichment Study.

Building and protecting soil organic carbon (SOC) are critical to agricultural productivity, soil health, and climate change mitigation. We aim to understand how mechanisms at the organo-mineral interfaces influence SOC persistence in three contrasting soils (Luvisol, Vertisol, and Calcisol) under long-term free air CO2 enrichment conditions. A continuous wheat-field pea-canola rotation was maintained. For the first time, we provided evidence to a novel notion that persistent SOC is molecularly simple even under elevated CO2 conditions. We found that the elevated CO2 condition did not change the total SOC content or C forms compared with the soils under ambient CO2 as identified by synchrotron-based soft X-ray analyses. Furthermore, synchrotron-based infrared microspectroscopy confirmed a two-dimensional microscale distribution of similar and less diverse C forms in intact microaggregates under long-term elevated CO2 conditions. Strong correlations between the distribution of C forms and O-H groups of clays can explain the steady state of the total SOC content. However, the correlations between C forms and clay minerals were weakened in the coarse-textured Calcisol under long-term elevated CO2. Our findings suggested that we should emphasize identifying management practices that increase the physical protection of SOC instead of increasing complexity of C. Such information is valuable in developing more accurate C prediction models under elevated CO2 conditions and shift our thinking in developing management practices for maintaining and building SOC for better soil fertility and future environmental sustainability.

Toward Complete All-Optical Intensity Modulation of High-Harmonic Generation from Solids.

Optical modulation of high-harmonics generation in solids enables the detection of material properties, such as the band structure, and promising new applications, such as super-resolution imaging in semiconductors. Various recent studies have shown optical modulation of high-harmonics generation in solids, in particular, suppression of high-harmonics generation has been observed by synchronized or delayed multipulse sequences. Here we provide an overview of the underlying mechanisms attributed to this suppression and provide a perspective on the challenges and opportunities regarding these mechanisms. All-optical control of high-harmonic generation allows for femtosecond, and in the future possibly subfemtosecond, switching, which has numerous possible applications: These range from super-resolution microscopy to nanoscale controlled chemistry and highly tunable nonlinear light sources.

The Miami Framework for ALS and related neurodegenerative disorders: an integrated view of phenotype and biology.

Increasing appreciation of the phenotypic and biological overlap between amyotrophic lateral sclerosis (ALS) and frontotemporal dementia, alongside evolving biomarker evidence for a pre-symptomatic stage of disease and observations that this stage of disease might not always be clinically silent, is challenging traditional views of these disorders. These advances have highlighted the need to adapt ingrained notions of these clinical syndromes to include both the full phenotypic continuum - from clinically silent, to prodromal, to clinically manifest - and the expanded phenotypic spectrum that includes ALS, frontotemporal dementia and some movement disorders. The updated clinical paradigms should also align with our understanding of the biology of these disorders, reflected in measurable biomarkers. The Miami Framework, emerging from discussions at the Second International Pre-Symptomatic ALS Workshop in Miami (February 2023; a full list of attendees and their affiliations appears in the Supplementary Information) proposes a classification system built on: first, three parallel phenotypic axes - motor neuron, frontotemporal and extrapyramidal - rather than the unitary approach of combining all phenotypic elements into a single clinical entity; and second, biomarkers that reflect different aspects of the underlying pathology and biology of neurodegeneration. This framework decouples clinical syndromes from biomarker evidence of disease and builds on experiences from other neurodegenerative diseases to offer a unified approach to specifying the pleiotropic clinical manifestations of disease and describing the trajectory of emergent biomarkers.

Collagen mutation and age contribute to differential craniofacial phenotypes in mouse models of osteogenesis imperfecta.

Craniofacial and dentoalveolar abnormalities are present in all types of osteogenesis imperfecta (OI). Mouse models of the disorder are critical to understand these abnormalities and underlying OI pathogenesis. Previous studies on severely affected OI mice report a broad spectrum of craniofacial phenotypes, exhibiting some similarities to the human disorder. The Brtl/+ and G610c/+ are moderately severe and mild-type IV OI, respectively. Little is known about the aging effects on the craniofacial bones of these models and their homology to human OI. This study aimed to analyze the Brtl/+ and G610c/+ craniofacial morphometries during aging to establish suitability for further OI craniofacial bone intervention studies. We performed morphological measurements on the micro-CT-scanned heads of 3-wk-old, 3-mo-old, and 6-mo-old female Brtl/+ and G610c/+ mice. We observed that Brtl/+ skulls are shorter in length than WT (P < .05), whereas G610c/+ skulls are similar in length to their WT counterparts. The Brtl/+ mice exhibit alveolar bone with a porotic-like appearance that is not observed in G610c/+. As they age, Brtl/+ mice show severe bone resorption in both the maxilla and mandible (P < .05). By contrast, G610c/+ mice experience mandibular resorption consistently across all ages, but maxillary resorption is only evident at 6 mo (P < .05). Western blot shows high osteoclastic activities in the Brtl/+ maxilla. Both models exhibit delayed pre-functional eruptions of the third molars (P < .05), which are similar to those observed in some bisphosphonate-treated OI subjects. Our study shows that the Brtl/+ and G610c/+ mice display clear features found in type IV OI patients; both show age-related changes in the craniofacial growth phenotype. Therefore, understanding the craniofacial features of these models and how they age will allow us to select the most accurate mouse model, mouse age, and bone structure for the specific craniofacial bone treatment of differing OI groups.