Cyanotic congenital heart diseases, which occur in approximately 0.2% of live births in the United States, have high mortality rates if untreated, but survival to adulthood is common with current surgical interventions. Approximately 80% of all cyanotic congenital heart diseases are caused by tetralogy of Fallot (TOF), D-loop transposition of the great arteries (TGA), and congenital heart disease with single-ventricle circulation. Survivors of cyanotic congenital heart diseases benefit from multidisciplinary care including pediatric and adult cardiologists, congenital cardiac surgeons, and electrophysiologists. Ninety percent of patients with TOF survive more than 30 years after surgery to close the ventricular septal defect and repair the right ventricular outflow tract. Nearly all adults with repaired TOF develop right ventricular volume overload due to pulmonary regurgitation, and atrial tachycardias and atrial fibrillation occur in approximately 20% to 45% of patients by age 45 years. For D-loop TGA, which involves the aorta arising from the right ventricle and the pulmonary artery arising from the left ventricle, arterial switch procedures result in survival rates of 93% to 97% to age 30 years. After atrial switch operation, 30% to 50% of patients develop moderate or severe right ventricle dysfunction by age 25 years; atrial tachycardia occurs in 48% to 63% of patients at 32 to 40 years postsurgery, and sinus node dysfunction is common. Sudden cardiac death occurs at a mean age of 30 to 35 years (SD, 6.4 years) in up to 15% of adults who have undergone an atrial switch operation. Infants born with a single ventricle that supplies both systemic and pulmonary circulation are most often treated with staged open-heart surgical interventions, typically performed during a period from neonatal age to 6 years of age, culminating in the Fontan procedure, which connects the inferior and superior vena cava to the pulmonary arteries, allowing deoxygenated blood to flow to the lungs without a pumping ventricle. Survival rates for children who undergo the Fontan procedure are 50% to 80% at age 40 to 50 years, although these patients may develop New York Heart Association functional class III or IV (0.35% per person-year) and have increased risk of early death or heart transplant requirement (0.36% per person-year). With surgical intervention, survival to adulthood is common among patients with TOF, D-loop TGA, and single ventricle. However, these survivors of cyanotic congenital heart diseases are at risk of valve dysfunction, arrhythmias, heart failure, and premature death. Optimal care involves multidisciplinary management including pediatric and adult cardiologists, congenital cardiac surgeons, and electrophysiologists.
A consensus classification for idiopathic interstitial pneumonias was first published in 2002, providing terminology for clinicians, radiologists and pathologists as well as highlighting that a multidisciplinary approach was best clinical practice. This comprised seven histological patterns that had corresponding idiopathic multidisciplinary diagnoses. This classification was updated in 2013, with the addition of an eighth histological pattern. Since 2013, there have been further advances in our understanding of interstitial pneumonias, in particular relating to idiopathic versus secondary disease, advances in molecular pathology and recognition of progressive pulmonary fibrosis (PPF), which have led to a further update in 2025. This review highlights the changes relevant to pathologists reporting interstitial pneumonias. Major changes include (1) expansion beyond idiopathic interstitial pneumonias to also include secondary causes, (2) subclassification as interstitial (fibrotic vs non-fibrotic) and alveolar filling disorders, (3) expansion to include additional patterns (e.g. bronchiolocentric interstitial pneumonia), (4) improved terminology that better reflects histogenesis and (5) consideration of diagnostic confidence in biopsy evaluation. Pathologists also need to be aware of the advantages and limitations of cryobiopsy interpretation and the importance of reporting features that point towards a secondary cause rather than idiopathic disease. The 2025 classification provides a framework for a methodological approach to reporting biopsies in patients with interstitial pneumonia, which should be used prospectively for both diagnosis and research.
Gut-associated lymphoid tissue (GALT) is organized lymphoid tissue that responds chronically to antigens, including whole bacteria, sampled from the gut lumen. The ensuing immunoglobulin A (IgA) plasma cell response disseminates to regulate bacterial populations and to mediate intestinal immune homeostasis. GALT has roles in the development of the innate-like marginal zone B cell population and is associated with a B cell-mediated contribution to ulcerative colitis (UC) severity and response to therapy. Applying integrated multiomics methodologies, we identified key spatially resolved interactions of B cell subsets including broad regulatory features of double negative 2 (DN2) B cells with potential to maintain homeostasis within microbe-rich mucosa. By contrast, GALT in UC is distorted in composition and spatial distribution of B cell subsets that have altered immunomodulatory potential compared with healthy GALT. Thus, we identify interactions of strategically located B cells as mediators of immunological equilibrium in human gut.
Virtual reality simulation training (VRST) has been shown to improve laparoscopic skills; however, evidence for structured simulation curricula remains limited. This study aimed to prospectively assess the effect of a structured VRST curriculum on laparoscopic performance in a porcine cholecystectomy model in novice surgeons. In this single-blinded prospective study, novice surgical trainees (< 3 years of clinical experience) attending a basic laparoscopic course were allocated to either a structured, proficiency-based VRST curriculum or standard deliberate practice on the same simulator. Laparoscopic performance was assessed during a porcine laparoscopic cholecystectomy (Lap-C) by blinded raters using the Global Operative Assessment of Laparoscopic Skills (GOALS) and a numerical rating scale (NRS). Seventy-one participants were analyzed (19 intervention, 52 control). Trainees completing the structured VRST achieved significantly higher total GOALS scores compared with controls (median 17.6 vs. 14.0; p = 0.013). All GOALS subdomains -including depth perception, bimanual dexterity, efficiency, tissue handling, and autonomy-were significantly improved in the intervention group. Subjective performance ratings were also higher following structured VRST (median NRS 6.7 vs. 4.8; p = 0.036). Inter-rater reliability for the GOALS score was good (ICC = 0.80). Participation in a structured VR simulation curriculum improved laparoscopic performance during a standardized porcine cholecystectomy model post-test compared with deliberate practice. Integration of structured VRST curricula into surgical training programs may enhance early technical skill acquisition and procedural proficiency.
Voltage mapping is integral to substrate assessment for ventricular tachycardia (VT) ablation; however, the spatial extent of myocardium contributing to a recorded electrogram signal remains poorly defined. Recent preclinical data assessed the relevant field of view (FOV) of 3.5 mm and 0.167 mm2 electrodes using cardiac magnetic resonance to quantify extent of viable myocardium (VM) and found FOVs of 10 millimeters and 8 millimeters, respectively. However, this is yet to be investigated with clinical data. This study sought to assess the FOV of 1-mm and 460-μm electrodes clinically and to evaluate the ability of cardiac magnetic resonance and cardiac computed tomography (CCT) to predict voltage amplitude. Patients undergoing VT ablation received preprocedural late gadolinium-enhanced cardiac magnetic resonance (LGE-CMR) and CCT with extracellular volume (ECV) estimation. VM was identified using standard LGE-CMR thresholds, ECV maps were computed from CCT, and unipolar voltage was recorded during ablation procedure. VM volume and volume-weighted ECV within multisize spheres around each electrode recording site were correlated with local voltage amplitude. A total of 16 patients were included; 15 had imaging-derived LGE-CMR/CCT-ECV analysis and 13 underwent left ventricular endocardial voltage mapping for FOV assessment. The FOV of both electrode sizes was determined to be 13 millimeters. Of the imaging modalities assessed, LGE-derived volume of VM produced the strongest correlations with voltage (1-mm electrode: r = 0.53; P < 0.001; 460-μm electrode: r = 0.49; P < 0.001). Volume-weighted ECV demonstrated weaker correlations (r = -0.34 and -0.24; P < 0.001). Clinical evaluation of 1-mm and 460-μm electrodes suggests a larger FOV than preclinical investigations. This quantifies a larger scale across which myocardial viability can influence unipolar electrogram signals observed during ablation procedures and suggests that smaller electrodes can improve spatial sampling density but do not necessarily provide a distinctly more localized characterization of the electrophysiologic properties of the tissue. LGE-CMR best predicted unipolar voltage, whereas CCT-ECV performed less well. Correlations were lower than expected, indicating the need for electrophysiologic assessment alongside comprehensive imaging.
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Tricuspid regurgitation (TR) is related to heart failure (HF) progression in individuals with transposition of the great arteries (TGA) and a systemic right ventricle (sRV). While tricuspid valve (TV) variants have been described in the general population, their prevalence and impact in patients with congenital heart disease are still unknown. We aim to systematically describe TV morphology in patients with TGA and sRV and identify factors associated to more than mild regurgitation using transthoracic 3D echocardiography. Echocardiographic exams of adults (>18years) with a sRV, including TGA following Mustard/Senning repair and congenitally corrected TGA (ccTGA) followed at a single tertiary center were retrospectively reviewed by two independent observers. A dedicated software for tricuspid annulus (TA) measurements from 3D images was used. Among 85 patients with a sRV, TV anatomy assessment by 3D echo was feasible in 74 (87%, 41 ± 12 years, 35% female, 49% ccTGA): non-trileaflet morphology was demonstrated in 54% of ccTGA and in 42% of TGA patients. Bicuspid and pentacuspid TV were more frequent in TGA, while quadricuspid TV was the second most frequent TV morphology in ccTGA patients. Interobserver agreement for TV morphology, prolapse, tenting height and annular size was good. By logistic regression, age, sex, presence of one prolapsing leaflet and most 3D measurements of TA from the dedicated software were associated with TR severity, while TV anatomy was not. On multivariable analysis, sex, prolapsing leaflets (OR 20.2, 95% CI: 4.62-127.7; p = 0.002), TA area by 3D (OR 1.3, 95% CI:1.02-1.79; p = 0.04) and maximum leaflets tenting height (OR 31, 95% CI: 2.8-170; p = 0.02) retained significant association to moderate/severe TR. Assessment of TV morphology by 3D transthoracic echocardiography is feasible and reliable in TGA patients with sRV. In our cohort, some variants were more common than previously described prevalence in the general population. While non-trileaflet morphology is frequent, significant TR is mainly associated with annular dilation, leaflet tenting, and prolapse rather than valve anatomy alone. Further studies are required to investigate the clinical relevance of TV anatomical variants in this subset.
(I) To determine clinicopathological determinants of metachronous Upper Tract Urothelial Carcinoma (UTUC) requiring Radical Nephroureterectomy (RNU) after Radical Cystectomy (RC). (II) To evaluate long-term survival of patients who underwent RC + RNU compared with matched RC only controls. Patients undergoing RNU for metachronous UTUC were extracted from a multi-institutional RC database. A 1:2 Propensity Score Match (PSM) was performed based on age, gender, BMI, CCI, Smoking Status, and cT stage between RC only and RC + RNU patients. Simon-Makuch plots, landmark analyses and Multivariable Cox regressions were adopted to compare survival outcomes. Of 1804 RC patients, 85 (4.7%) underwent subsequent RNU. At multivariate regression, younger age, smoking history, BCG exposure, NMIBC, CIS and positive ureteric margins were identified as positive predictors of upper tract recurrence. After PSM, 81 RC + RNU patients were matched to 157 RC only controls. Median time from RC to RNU was 29 (18-47) months, with the majority of UTUC diagnosed at a muscle-invasive stage (70.9%). Simon-Makuch curves demonstrated worse Cancer Specific Survival (CSS) of the RC + RNU cohort (HR: 6.41, 95% CI 3.16-13.04). At landmark analyses, RNU was consistently associated with an increased mortality risk from the 24th month onward. Multivariable Cox regression identified RNU and pN + as the only significant predictors of worse CSS (respectively, HR: 6.55, 95% CI 2.93-14.64 and HR: 8.45, 95% CI 3.24-21.99). The worse survival outcomes and high rates of locally advanced disease found at RNU underscore the need for standardized, risk-stratified, long-term follow-up of the remnant urinary tract following RC.
Vestibular dysfunction is common following traumatic brain injury (TBI). Previous research has noted patients are not routinely assessed or treated acutely, due to uncertainty around healthcare professionals' roles and their limited knowledge and skills. This research however was limited to two UK London major trauma centres (MTCs). The present study aimed to explore current provision for acute post-traumatic vestibular assessment and treatment in UK and Ireland MTCs. An online survey was developed and refined with input from healthcare professionals. The final survey was distributed between April and August 2024 to healthcare professionals working in 32 adult MTCs in England, Wales, Scotland, and Ireland. Data were analysed using Excel. Surveys were completed at 28/32 (87.5%) MTCs. 13/28 (38%) of respondents indicated routine vestibular assessment and treatment were provided. Barriers to routine assessment and treatment included knowledge and skills deficiencies and the absence of protocols. Geographic variation was evident with 75% of centres in London and Scotland reporting higher rates of routine vestibular assessment and treatment compared to 20%-25% of centres in other regions. Our findings show adult acute vestibular service provision is inconsistent across MTCs in the UK and Ireland, with the potential to cause inequalities in health and care outcomes. Strategies to address inconsistent service provision include training and the development of pathways and guidelines both nationally and locally.
Cardiac cachexia (CC) is associated with advanced heart failure (AHF), characterized by unintentional weight loss (UWL) of fat/muscle. It is exacerbated by right ventricular systolic dysfunction (RVSD). The potential pathogenic role of gut microbiota (GM) changes has not been investigated in CC. We aimed to explore this. Patients with AHF with or without CC/UWL, stable chronic heart failure (HF), and healthy controls (HCs) were recruited following national ethical approval. Fecal bacterial DNA was extracted, quantified, and 16S rRNA gene sequencing was performed. GM composition, alpha, and beta diversity were compared between CC/UWL-AHF and the rest of the cohort (ROC). The secondary analyses compared AHF, HF, and HCs, and patients with and without RVSD. Sixty-seven patients returned samples, including 14 with CC/UWL-AHF. No taxonomic differences were observed between CC/UWL-AHF and ROC. A weak trend toward compositional differences was observed (beta diversity R²  =  0.016, p  =  0.071). No differences were observed in RVSD. Numerous significant GM alterations were observed across the HF spectrum, including changes to Streptococcus spp., Alistipes, and Bacteroides. CC/UWL-AHF may be associated with subtle GM compositional changes. Larger studies are required to investigate this further.
Myeloproliferative neoplasms (MPNs) are a heterogenous group of myeloid disorders including polycythemia vera (PV), essential thrombocythemia (ET) and myelofibrosis (MF). All these conditions can be associated with significant morbidity including increased risk of thrombotic events as well as reduced survival. Selecting therapy is dependent on patients' risk assessment and thus prognostication is vital in the management of these conditions. There have been significant developments in prognostic and risk stratification models for MPNs over the last few years, including incorporation of molecular markers. This narrative review article aims to summarize these prognostic models and provide practical advice on how clinicians can utilize these tools to develop personalized treatment strategies for MPN patients.
Neurological and mental health disorders affect over one-third of the global population. Healthcare systems continue to treat maternal brain health and neurodevelopment as separate domains. Critical intervention windows continue to be missed before and during the first 1,000 days after conception. Current fetal-neonatal neurology training reflects healthcare fragmentation. Specialty-siloed education impedes integrative critical thinking that more successfully capitalizes on pre-conception and gestational neuroprotective opportunities. This narrative review presents perspectives that argue for a transdisciplinary approach among stakeholders that advances life-course brain healthcare. Integrative women's and children's health, the developmental origins of health and disease, cultural neuroscience, and brain health capital frameworks collectively contribute to an educational, practice and research model. This methodology more productively addresses public health priorities to offer equitable global brain health care based on knowledge of intersectionality. We propose that every pregnancy represents a brain health intervention opportunity. Healthcare bundles have been defined as a set of three to five evidence-based interventions to assess the quality and outcome of medical care choices. Equity-informed brain care bundles similarly can be developed to assess proactive and reactive neuroprotective intervention outcomes. Gene-environment interactions will influence the dynamic neural exposome across each person's lifespan. More effective therapeutic options can shift intergenerational neurodevelopmental trajectories to improve neurologic and mental health for entire communities. Combining biological, social, and structural determinants determine the direction of vulnerability or resilience pathways based on time-sensitive shared healthcare decisions. Two clinical vignettes ground this theoretical framework with fetal-neonatal neurology practice experiences. Emphasis on fragmented care, limited genomic screening, structural inequity, and uncorrected environmental exposures diminish preventable neurological and maternal outcomes across generations. We propose five implementation recommendations: dismantle structural barriers to integrate care; redesign training around transdisciplinary competency frameworks; realign payment structures to incentivize coordinated care; reorient research priorities with integrated care models; and develop measurable metrics of integrated maternal-child brain health. Artificial intelligence-assisted monitoring and learning health system platforms offer infrastructural elements to enable equitable intervention scaling across diverse clinical settings. Implementation of this framework across each lifespan will reduce intergenerational burdens of neurological and mental health disorders to sustain global brain health equity.
United Kingdom National Institute for Health and Care Excellence (NICE) guidelines for evaluation of sepsis risk remain to be validated. This study aims to model the impact of the updated guidelines in patients identified as having a risk of sepsis based on the original guidelines. A single centre cohort study, between 2019 and 2022. Adult inpatients at risk of sepsis defined by red / amber flags in the original guideline were included. NICE criteria, based upon aggregate National Early Warning Score (NEWS2) and additional risk-factors (NEWS2 single parameter score three, lactate ≥2mmol/l, skin changes, acute kidney injury or deteriorating trajectory) were applied to this cohort to derive a revised risk classification. The primary outcome was the net reclassification index (NRI). Secondary outcomes were the association with a composite of critical care admission or death in hospital and the association with ICD-10 sepsis / Sepsis-3 status. 1303 hospital inpatients were included. Between red flag sepsis and NICE High-risk classification, there was agreement in 57.6%. The NICE model decreased the risk-classification in 471 (42.4%), of whom 216 experienced the composite outcome. The event RI deteriorated (-0.321), whilst the non-event RI improved (0.355). NICE High-risk had a similar C-statistic (0.57(0.55,0.60) vs. 0.56(0.54,0.58)) but with lower sensitivity (59.1% vs. 91.2%), higher specificity (55.1% vs. 20.2%) and PPV (55.9% vs. 52.1%) as compared to red flags. NICE High-risk had a greater C-statistic for association with Sepsis-3 status (0.66 (0.63, 0.69) vs. 0.55 (0.54, 0.57)). As implemented in this study, NICE criteria decreased the number of patients in a high-risk sepsis category, compared to a model using red flag criteria. These criteria decreased sensitivity and increased specificity for the outcome of critical care admission or death, whilst strengthening the association with Sepsis-3 criteria. Limited predictive performance advocates for clinically-led sepsis assessment.
The choice of comparator critically determines the interpretability and clinical relevance of trials evaluating minimally invasive surgical therapies (MISTs), with sham-controlled studies now considered insufficient for guideline integration. Active comparators, particularly pharmacological therapy and conventional surgery, provide the highest level of evidence, enabling a meaningful positioning of MISTs within the therapeutic algorithm of male lower urinary tract symptoms/benign prostatic obstruction.
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Mucoactive agents are widely used in patients with acute respiratory failure despite limited evidence of their effectiveness or safety. We conducted a multicenter, open-label, randomized trial with a 2-by-2 factorial design that involved critically ill, mechanically ventilated participants 16 years of age or older with acute respiratory failure and difficult-to-clear secretions. All participants received usual care along with carbocisteine (750 mg three times daily enterally), 6% or 7% nebulized hypertonic saline (HTS) (4 ml four times daily), both interventions, or usual care alone for up to 28 days. The primary outcome was duration of mechanical ventilation (from randomization to first successful unassisted breathing). The primary comparisons were between any carbocisteine and no carbocisteine and between any HTS and no HTS, with each comparison comprising two treatment groups. A total of 1956 participants underwent randomization: 486 were assigned to carbocisteine, 485 to HTS, 492 to both treatments, and 493 to usual care alone (472, 474, 479, and 478, respectively, were included in the primary analysis). No evidence of treatment interaction was found (hazard ratio, 1.01, 95% confidence interval [CI], 0.83 to 1.22; P = 0.91). The median duration of mechanical ventilation was 186.1 hours (95% CI, 168.3 to 196.6) with carbocisteine and 172.7 hours (95% CI, 165.2 to 190.4) with no carbocisteine (adjusted hazard ratio, 0.96; 95% CI, 0.87 to 1.05; P = 0.34) and 184.5 hours (95% CI, 165.6 to 194.1) with HTS and 174.3 hours (95% CI, 166.9 to 192.7) with no HTS (adjusted hazard ratio, 1.00; 95% CI, 0.91 to 1.10; P = 0.98). Clinically important upper gastrointestinal bleeding occurred significantly more often with carbocisteine than with no carbocisteine (13 of 965 [1.4%] vs. 2 of 966 [0.2%]; risk ratio, 6.51; 95% CI, 1.47 to 28.76; P = 0.01). Bronchoconstriction leading to bronchodilator use occurred significantly more often with HTS than with no HTS (23 of 967 [2.4%] vs. 4 of 964 [0.4%]; risk ratio, 5.73; 95% CI, 1.99 to 16.52; P = 0.001), as did hypoxemia during nebulization (40 of 967 [4.1%] vs. 3 of 964 [0.3%]; risk ratio, 13.29; 95% CI, 4.12 to 42.83; P<0.001). One serious adverse reaction was reported in the combination group. Among critically ill patients with acute respiratory failure, neither carbocisteine nor HTS significantly reduced the duration of mechanical ventilation, and each was associated with harm. (Funded by the NIHR Health Technology Assessment Programme and the Belfast Health and Social Care Trust Charitable Trust Fund; MARCH ISRCTN Registry number, ISRCTN17683568.).
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Endovascular aortic operations entail significant radiation exposure to healthcare personnel and patients. Therefore, development and implementation of techniques to achieve radiation reduction remains a key objective. This paper presents considerations and consensus from a roundtable discussion between physicians with experience in endovascular aortic surgery and medical physicists regarding promising radiation reducing techniques. A focused literature review was first performed to identify potentially eligible techniques. Subsequently, the items identified were discussed and a final list was approved by consensus: radiation reduction protocols; simulation training; electromagnetic tracking (EMT), Fiber Optic RealShape (FORS), fusion imaging, and intravascular ultrasound. Three main domains were evaluated for each technique: current status of the technique, potential impact on radiation reduction, and feasibility of implementation. The current status varies from the development to assessment phase, indicating that all techniques are already being used in clinical practice in some form. However, except for radiation reduction protocols, none has yet been widely adopted. All the studied techniques had a substantial (at least potential) impact on radiation reduction. Regarding feasibility and implementation, there is a wide variety among the techniques. Radiation reduction protocols are implemented in almost all hardware and therefore easy to implement, while FORS and EMT require substantial investment and specific hardware, which is not compatible with all vendors. This multidisciplinary consensus document provides expert driven, evidence based considerations on the current status of six techniques that may play a pivotal role toward achieving the zero radiation goal for endovascular aortic surgery, while balancing their radiation reduction potential against barriers for widespread adoption. Further refinement will come through close multidisciplinary collaboration between surgeons and industry. Educating physicians regarding benefits and limitations of all available modalities will assist with planning better operative approaches, and increasing radiation safety.