Course Of Disease Research Articles

Considerations in Paediatric and Adolescent Inflammatory Bowel Disease.

The incidence of inflammatory bowel disease [IBD] is rising most rapidly among children and adolescents. Paediatric-onset IBD is associated with a more extensive and severe disease course compared to adult-onset IBD. At a young age, screening for underlying genetic and immunological disorders is important and may impact treatment management. Early and effective treatment is crucial to reach disease remission and prevent complications of ongoing active disease. In children with Crohn's disease, exclusive enteral nutrition is an effective induction therapy. Other promising dietary therapies, such as the Crohn's disease exclusion diet, are emerging. Within paediatric IBD, anti-tumour necrosis factor therapy is the only approved biological thus far and additional treatment options are crucially needed. Other biological therapies, such as vedolizumab and ustekinumab, are currently prescribed off-label in this population. A specific challenge in paediatric IBD is the unacceptable and major delay in approval of drugs for children with IBD. A guided transfer period of paediatric patients to adult care is associated with improved disease outcomes and is required. Major knowledge gaps and challenges within paediatric IBD include the aetiology, diagnostics, and monitoring of disease, tailoring of treatment, and both understanding and coping with the physical and psychological consequences of living with IBD. Challenges and research gaps in paediatrics should be addressed without any delay in comparison with the adult field, in order to ensure a high quality of care for all patients with IBD, irrespective of the age of onset.

Epidemiology of Inflammatory Bowel Disease across the Ages in the Era of Advanced Therapies.

The incidence of inflammatory bowel diseases [IBD] has risen over the past decade to become a global issue. The objectives of this review were to describe the incidence and/or prevalence of IBD in the era of advanced therapies, and to describe the association between environmental risk factors and both pathogenesis and disease course across the ages. We performed a search of English language publications listed in PubMed regarding the epidemiology of IBD and key environmental factors implicated in IBD from January 2000 to December 2023. Annual incidence rates varied by geographical region with IBD estimates ranging from 10.5 to 46.14 per 100 000 in Europe, 1.37 to 1.5 per 100 000 in Asia and the Middle East, 23.67 to 39.8 per 100 000 in Oceania, 0.21 to 3.67 per 100 000 in South America, and 7.3 to 30.2 per 100 000 in North America. The burden of IBD among children and adolescents, and older people is rising globally. Key environmental factors implicated in IBD pathogenesis include exposure to tobacco smoking, antibiotics, non-steroidal anti-inflammatory drugs, oral contraceptives, infections, and ultra-high processed foods. Breastfeeding and a high-quality diet rich in fruit, vegetables, fish, and other fibre sources are important protective factors. Smoking has consistently been shown to negatively impact disease outcomes for Crohn's disease. The epidemiology of IBD has undergone considerable change in recent decades, with an increase in the burden of disease worldwide. Optimally studying and targeting environmental triggers in IBD may offer future opportunities for disease modification.

An Integrative Migraine Polygenic Risk Score Is Associated with Age at Onset But Not Chronification.

Background/Objective: Genome-wide association studies (GWASs) demonstrate a complex genetic landscape for migraine risk. Migraine polygenic risk scores (PRSs) developed from GWAS data may have utility for predicting disease course. We analyzed the strength of association between an integrative migraine PRS and age at onset and chronification. Methods: In this retrospective clinical/genetic case-control study, PGS004799 was calculated for adults with European ancestry from two real-world community cohorts. In the DodoNA cohort, 1653 treated, deeply phenotyped migraine cases, diagnosed using International Classification of Headache Disorders 3rd edition criteria, were followed for a mean (range) of 2.3 (1-10) years and compared to 3460 controls (without migraine diagnosis). In the GHI cohort, 2443 cases were identified using the first migraine ICD code as a proxy for migraine onset and compared to 8576 controls (without migraine ICD codes). PRS associations with age at onset (DodoNA) or first migraine ICD code (GHI) and chronification (DodoNA) were evaluated. Results: In both cohorts, PRS was higher in cases (DodoNA mean (range) cases: 0.82 (0.07-1.76), controls: 0.78 (0.04-1.56); t (5111) = -6.1, p = 1.4 × 10-9, GHI: cases: 0.79 (0.003-1.68), controls: 0.75 (-0.06-1.53); t (11,017) = -7.69, p = 1.6 × 10-14), and a higher PRS was associated with earlier onset in females (HR [95% CI] DodoNA: 2.1 [1.6-2.6, p < 0.001; GHI: 1.8 [1.4-2.1], p < 0.001) and in males (DodoNA: 2.5 [1.3-4.7], p = 0.005; GHI: 1.6 [1.1-2.6], p = 0.027). PRS was not different in cases with or without chronification (t (1651) = -1.67, p = 0.094) and was not associated with earlier chronification (1.2 [0.8-1.6], p = 0.424). Conclusions: Higher genetic risk was associated with earlier onset and increased risk of migraine well into adulthood, but not with chronification. This suggests that the PRS quantifies genetic susceptibility that is distinct from factors influencing disease course.

The clinical effect of thoracoscopic segmentectomy in the treatment of lung malignancies less than 2CM in diameter

ObjectiveTo investigate the clinical effect of thoracoscopic segmentectomy in the treatment of lung malignancies less than 2CM in diameter.MethodsIn this retrospective study, a total of 103 patients with lung cancer who received outpatient or inpatient treatment from December 2020 to May 2022 were selected and divided into the lobectomy group (n = 48) and the segmentectomy group (n = 55) according to different surgical methods. The lobectomy group was treated with thoracoscopic lobectomy, while the segmentectomy group was treated with thoracoscopic segmentectomy. The prognostic effect, complications, blood gas level and respiratory function indexes of the two groups were observed and compared.ResultsThe general data of the two groups of patients, such as gender, age, course of disease, body mass index, lesion diameter, lesion site and pathological type, were analyzed by statistical software. There was no statistical significance in the operation time and the number of lymph node dissection between the two groups (P > 0.05), while the drainage volume and intraoperative blood loss in the segmentectomy group were lower than those in the lobectomy group, and the drainage time and hospital stay were shorter than those in the lobectomy group, with statistical significance (P < 0.05). Before treatment, there were no statistically significant differences in various lung function indexes between the two groups (P > 0.05). After treatment, the values of FVC, FEV1 and FEV1/FVC in each group had different amplitude changes, and the values of FVC, FEV1 and FEV1/FVC in the segmentectomy group were significantly higher than those in the lobectomy group, with statistical significance (P < 0.05). Thoracoscopic segmentectomy showed a lower incidence of respiratory complications (P = 0.042) and higher pulmonary air leak (P = 0.023) than thoracoscopic lobectomy. After propensity score-matched analysis, respiratory complications remained significantly higher in thoracoscopic segmentectomy (P = 0.017). However, the difference in the total complication rate between the two groups was not statistically significant (P > 0.05). There were no differences during the 2-year follow-up (median follow-up in months: 18.4; interquartile range, 14.8–21.3) in terms of overall survival (P = 0.49) and disease-free survival (P = 0.34) between groups (P > 0.05).ConclusionsFor patients with lung cancer less than 2 cm in diameter, thoracoscopic segmentectomy can achieve good short-term efficacy, with rapid postoperative recovery and little impact on lung function, which may be helpful to improve patients’ postoperative quality of life.

Ultrasound radiomics: evaluating early nerve injury and its relationship with leprosy reactions in patients with leprosy

Objectives: Leprosy is an infectious disease that can be accompanied by disability caused by peripheral neuropathy. The prevalence of grade 2 disability leprosy in 2023 has reached 0.012-55.429 per million people worldwide. Early detection of leprosy is essential to reduce its debilitating sequelae. Radiomics is an emerging field related to the extraction and quantification of information, which may provide new solutions for early detection of leprosy. The present study is the first to combine radiomics and ultrasonography to evaluate nerve damage in the early stages of leprosy in China by September 2024. Methods: Patients were enrolled at the Wenshan Prefecture Institute of Dermatology between October 2018 and December 2022. High-resolution ultrasound imaging of the peripheral nerves was performed. Quantitative ultrasound features were extracted from the follow-up imaging. Radiomic features were selected for a comparative analysis of the disease course using a linear mixed-effects model to control for potential confounding effects. Results: Nine patients with leprosy were enrolled in this study. After treatment, ultrasonography at different nerve sites showed partial improvement in nerve density (mean, skewness), recovery of the fascicular structure (kurtosis), and a decrease in abnormal morphological characteristics in some of the detected sites (P ≤ 0.05). Patients with type 1 leprosy reactions exhibited a lower mean and skewness, higher kurtosis, and increased quantitative morphological characteristics. Conclusion: The study provided the feasibility of ultrasound radiomics to digitally visualize the progression of nerve damage in leprosy patients, and ultrasound radiomics circumvented the adverse influence of different operators with differing levels of experience. The study provided the evidence of ultrasound radiomics as a low-cost method with high-throughput characteristics for clinical use of early nerve injury detection of leprosy.

FDG-PET patterns associate with survival in patients with prion disease.

Prion disease classically presents with rapidly progressive dementia, leading to death within months of diagnosis. Advances in diagnostic testing have improved recognition of patients with atypical presentations and protracted disease courses, raising key questions surrounding the relationship between patterns of neurodegeneration and survival. We assessed the contribution of fluorodeoxyglucose (FDG-PET) imaging for this purpose. FDG-PET were performed in 40 clinic patients with prion disease. FDG-PET images were projected onto latent factors generated in an external dataset to yield patient-specific eigenvalues. Eigenvalues were input into a clustering algorithm to generate data-driven clusters, which were compared by survival time. Median age at FDG-PET was 65.3 years (range 23-85). Median time from FDG-PET to death was 3.7 months (range 0.3-19.0). Four data-driven clusters were generated, termed "Neocortical" (n = 7), "Transitional" (n = 12), "Temporo-parietal" (n = 13), and "Deep nuclei" (n = 6). Deep nuclei and transitional clusters had a shorter survival time than the neocortical cluster. Subsequent analyses suggested that this difference was driven by greater hypometabolism of deep nuclei relative to neocortical areas. FDG-PET-patterns were not associated with demographic (age and sex) or clinical (CSF total-tau, 14-3-3) variables. Greater hypometabolism within deep nuclei relative to neocortical areas associated with more rapid decline in patients with prion disease and vice versa. FDG-PET informs large-scale network physiology and may inform the relationship between spreading pathology and survival in patients with prion disease. Future studies should consider whether FDG-PET may enrich multimodal prion disease prognostication models.

CPMP rescue of a neonate with severe molybdenum cofactor deficiency after serendipitous early diagnosis, and characterisation of a novel MOCS1 variant

We report the first, and so far, only index patient with neonatal onset MoCD type A who was diagnosed and treated early enough with cPMP to avoid severe brain injury and disability. The child presented with hypoglycemia at the age of 10 h and was diagnosed because of the incidental finding of severely decreased L-cystine in plasma. Due to a high level of awareness and excellent co-operation between metabolic laboratory and clinical services, cPMP substitution could be initiated before severe encephalopathy set in, and the child subsequently had a normal motor development. The child has been continued on daily substitution with cPMP until today (age 7 years) and has shown a satisfying long-term developmental outcome. Long-term follow-up, however, revealed significant communication difficulties and cognitive abilities in the range of mild to moderate learning disability. The severity of the metabolic disease was confirmed by the extent of biochemical abnormalities and further functional characterisation of the underlying genetic variants. This case provides further evidence that cPMP substitution does significantly alter the disease course when applied early enough. Postnatal treatment in this case was not sufficient to enable an entirely normal cognitive development, despite sustained complete normalization of the biochemical abnormalities.

CYP2C19 loss-of-function variants are independent risk factors for premature cerebral infarction: a hospital based retrospective study

ObjectiveCytochrome P450 2C19 (CYP2C19) plays an vital role in the course of cardiovascular and cerebrovascular diseases by affecting lipid metabolism. Triglyceride-glucose (TyG) is a comprehensive index composed of triglyceride and blood glucose, has relationship with some diseases. There was no research report on the association CYP2C19 polymorphisms, TyG with premature cerebral infarction (CI) (onset ≤ 65 years old) susceptibility.MethodsThis study retrospectively analyzed 1953 CI patients aged ≤ 65 years old from December 2018 to March 2024, and 1919 age-matched individuals with non-CI as controls. The relationship between CYP2C19 polymorphisms, TyG and premature CI risk were analyzed.ResultsThe proportion of hypertension, and diabetes mellitus in patients with premature CI was higher than those in controls. The serum total cholesterol (TC), triglycerides (TG), low-density lipoprotein-cholesterol (LDL-C), and TyG levels in patients with premature CI were significantly higher than those in controls (all p < 0.05). The patients had lower CYP2C19 *1 allele frequency (63.3% vs. 69.6%, p < 0.001) and higher CYP2C19 *2 allele frequency (31.3% vs. 25.4%, p < 0.001) than controls. Logistic regression analysis showed that smoking history (odds ratio (OR): 1.193, 95% confidence interval (CI): 1.002–1.422, p = 0.048), hypertension (OR: 3.371, 95% CI: 2.914–3.898, p < 0.001), diabetes mellitus (OR: 1.911, 95% CI: 1.632–2.237, p < 0.001), CYP2C19 intermediate metabolizer (IM) + poor metabolizer (PM) phenotypes (OR: 1.424, 95% CI: 1.243–1.631, p < 0.001), and dyslipidemia (OR: 1.294, 95% CI: 1.077–1.554, p = 0.006) were independent risk factors for premature CI.ConclusionsHistory of smoking, hypertension, diabetes mellitus, dyslipidemia, and CYP2C19 IM + PM phenotypes were independently associated with premature CI susceptibility.

The role of angiotensin II and endothelin receptor antibodies in COVID19 patients with HFpEF

Abstract Background The infection caused by the coronavirus SARS-COV-2, is associated with an unusual pattern of organ damage in comparison to other viral-induced pathologies. A theory of autoimmunity induced by ACE-2/SARS-COV-2 spike protein complex or its degradation products, was proposed as a possible explanation for the versatile and multiorgan damage in COVID-19. Aim The aim of the study is to determine whether antibodies against angiotensin II receptor type 1 (AT1R) or endothelin-1 receptor type A (ETAR) do exist in plasma of COVID -19 patients with heart failure with preserved ejection fraction and whether they correlate to the severity of the disease. Methods A total of 61 patients with COVID-19 and heart failure with preserved ejection fraction and 48 controls (free of COVID19) with heart failure with preserved ejection fraction were included. Patients were divided into two groups: patients with severe disease (admitted at the intensive care (n=30)), patients with milder clinical presentation that remained in the general therapeutical department (n=31). The plasma levels of IL-6 and auto-antibodies against AT1R or ETAR in peripheral blood were measured and compared between COVID19 patients with severe and milder disease and age matched controls. Clinical and standard laboratory parameters were also collected and their association with the research biomarkers was analysed. Results Auto-antibodies against AT1R were significantly increased in severe disease course (median 19.60 U/mL, IQR 4.8-34.75) compared to milder disease (median 10.95 U/mL, IQR 7.69 – 17.67, p=0.017) and the control group (median 6.79 U/mL, IQR 5.10 – 14.05, p&amp;lt; 0.001). ETAR antibody titers were also significantly increased in severe disease (median 14.52, IQR 6.76-32.94), compared to milder disease course (median 8.73 U/mL, IQR 6.59 –13.45, p=0.023) and to the control group (median 6.64, IQR 6.79 – 17.92, p &amp;lt;0.001). The same was the trend regarding IL-6 antibodies. Severe disease (median 12.11 U/mL, IQR 5.59–19.38); milder disease disease (median 8.64U/mL, IQR 1.84 – 14.13, p=0.039); control group (median 4.28U/mL, IQR 0.11–1.43, p&amp;lt;0.001).Both AT1R and ETAR correlated to IL-6 plasma levels. The results did not show association with the concomitant therapy. Conclusion In conclusion, we establishеd the presence of AT1R and ETAR autoantibodies in COVID-19 patients with heart failure with preserved ejection fraction. They correlated to IL-6 plasma levels (systemic inflammation) and are associated with severe form of the disease.

A novel murine wire injury based infectious endocarditis model aggravates aortic valve stenosis

Abstract Background With mortality rates up to 40% under optimal medical treatment, infectious endocarditis (IE) remains one of the deadliest infectious diseases worldwide. In the early stages of IE, diagnosis and treatment initiation are often difficult and research is limited due to unreliable models. Most murine IE models rely on permanent prosthetic wire placement and i.v. bacterial injection, thus making it inadequate to study IE pathophysiology with the aim to reflect the course of disease in humans. Purpose To develop a reproducible murine IE model, based on aortic valve injury preceding intravenous S. aureus bacterial challenge. Methods Using a wire-injury model we induced endothelial lesions. 72h after wire injury (WI), we performed intravenous bacterial challenge using S. aureus. Echocardiography was performed to confirm bacterial vegetations and assess valvular function. Cross sections of valvular leaflets were prepared for scanning electron microscopy (SEM). Macrophage, neutrophil and S. aureus-specific immunofluorescence staining was performed and visualized by immunofluorescence microscopy. Bacterial cultivation was performed from peripheral blood and valve tissue. Systemic immune response was analyzed using flow cytometry. Results WI induced endothelial damage in all mice verified using scanning electron microscopy imaging. The combination of wire injury and injection of 10^5 and 10^6 colonies-forming-units (CFU) S. aureus reliably caused IE validated via in vivo echocardiography as well as S.aureus immunofluorescence staining and SEM imaging. Mice undergoing bacterial challenge responded with significant neutrophilia in the blood. Using 10^6 CFU S. aureus was associated with an increased mortality, liver and kidney abscess formation due to systemic bacterial spreading compared to 10^5 CFU. Peak velocity across the aortic valve and aortic valve leaflet thickness as markers for aortic valve stenosis were increased in IE compared to WI only mice. Aortic regurgitation was more prevalent after bacterial challenge mediating increased left ventricular volumes, meanwhile ejection fraction was not altered. Immunofluorescence staining revealed a pro-inflammatory milieu including increased macrophage and neutrophil infiltration in IE compared to WI only mice. Conclusion In vivo echocardiography and ex vivo histological staining revealed reliable IE induction using our new model with S. aureus concentrations of 10^5 CFU. The additional bacterial challenge causes a more severe aortic valve stenosis compared to WI only mice, potentially due to an observed increase in valvular inflammation.Fig 1 Scanning electron microscopy after

Mortality and patient stratification 30 days after Staphylococcus aureus bacteraemia in patients with cardiac implantable electronic devices - a Danish nationwide cohort study

Abstract Background Staphylococcus aureus bacteraemia (SAB) is a high-risk condition with a reported 30-day mortality of up to 25% even with timely and correct treatment. Patients with cardiac implantable electronic devices (CIEDs) are at increased risk of a complicated course of disease due to the risk of device infection. Purpose We aimed to estimate the 30-day mortality rate following SAB among adult Danish patients with a de novo CIED. Furthermore, we aimed to identify patients with low, intermediate, and high mortality risk following SAB. Methods Using The National Danish Staphylococcus Aureus Bacteriemia Database and The Danish Pacemaker and ICD Register, we identified all Danish patients aged 18 to 99 years with a de novo CIED implantation between 2000 and 2020, and subsequently positive Staphylococcus aureus blood culture. The primary outcome was 30-day all-cause mortality from date of SAB. Clinical variables significantly associated with increased 30-day mortality following SAB were identified (p&amp;lt;0.05 and 95% CI not including 1) using adjusted multivariable Cox regression modelling. We tested variables related to age, sex, calendar year of SAB, device type, timing of infection, previous SAB, concomitant medication, and clinically relevant pre-existing co-morbidities including valvular replacement, recent surgery, and renal dialysis. Patients were awarded 1 point for each of the significant variables present, and the sum was used to stratify into low-, intermediate-, and high-risk groups. The cut-offs between the groups were set at 0 and 2 points (0 points = low risk, 1-2 points = intermediate risk, ≥3 = high risk). Results We identified 1,393 patients with de novo CIED (pacemaker: n=983, implantable cardioverter defibrillator: n=230, cardiac resynchronization therapy w/wo defibrillator capacity: n=180) and subsequent SAB (median time to SAB from CIED implantation: 679 days [IQR 168-1,525]). Median age at the time of SAB diagnosis was 77 years [IQR 68-84] with 72.4% being males. In total, 469 patients died within the first 30 days from SAB, equivalent to an overall 30-day mortality rate of 33.7% (95% CI 31.2-36.2). We identified high age, left sided valvular disease, use of systemic corticosteroids, and SAB occurring &amp;gt;6 months from CIED implantation to be associated with an increased hazard of 30-day mortality following the SAB diagnosis (Fig. 1). The median total sum obtained from the stratification model was 2 points [IQR 1-2]. 30-day all-cause mortality was estimated to 16.2%, 31.6% and 54.9% for the low-, intermediate- and high-risk groups, respectively (Fig. 2). Conclusions In patients with a de novo cardiac implantable electronic device and subsequent Staphylococcus aureus bacteraemia the overall 30-day mortality from date of SAB was 33.7%. Patients with high age, recent surgery, left sided valvular disease, and use of systemic corticosteroids were particularly at risk.Fig. 1.Simplified stratification modelFig. 2.30-day mortality following SAB

PI3 kinase delta governs regulatory T-cell biology and thus confers protection against atherosclerosis progression in mice

Abstract Introduction and Purpose Atherosclerosis is a chronic inflammatory disease of arteries, critically involving innate and adaptive immune cells like macrophages as well as T and B lymphocytes. Macrophages are major drivers of disease through the ingestion of lipoproteins, foam cell formation, and secretion of inflammatory mediators. Although macrophages outnumber other leukocytes in atherosclerotic plaques, T and B cells can shape the course of disease by promoting or mitigating inflammatory responses. The phosphoinositide 3-kinase delta (PI3Kd) exerts a key role in the regulation of immune responses including activation, proliferation, differentiation, and effector function of lymphocytes. Therefore, PI3Kd may represent a promising target for the modulation of inflammatory diseases. Consequently, we aimed to analyse the role of PI3Kd during atherogenesis. Methods and Results To investigate the role of haematopoietic PI3Kd in atherosclerosis, bone marrow from PI3Kd-/- or PI3Kd+/+ mice was transplanted into Ldlr-/- mice. After a 6-weeks-challenge by high fat diet, PI3Kd-/- recipient Ldlr-/- mice displayed profoundly impaired CD4+ and CD8+ T-cell numbers, CD4+ T-cell activation, CD4+ effector T-cell differentiation, and proatherogenic CD4+ T-helper (Th) 1 responses in para-aortic lymph nodes and spleen compared with PI3Kd+/+ transplanted controls. Surprisingly, the net effect of PI3Kd deficiency was a substantial increase of aortic inflammation and atherosclerosis in Ldlr-/- mice. Whereas plaque content and functions of macrophages including foam cell formation, efferocytosis, and cytokine secretion remained largely unaffected, haematopoietic PI3Kd ablation strongly reduced mature B cells and serum immunoglobulins in Ldlr-/- mice. Importantly, PI3Kd deficiency severely impaired numbers, proliferation, immunosuppressive functions, and stability of regulatory CD4+ T cells (Tregs). Consequently, adoptive transfer of PI3Kd+/+ Tregs fully restrained the atherosclerotic plaque burden in PI3Kd-/- transplanted Ldlr-/- mice without affecting B-cell numbers and serum immunoglobulins, whereas transferred PI3Kd-/- Tregs failed to relieve atherosclerosis progression. Conclusions Here, we demonstrate that PI3Kd plays a crucial role in Tregs, Th1 cells, and B cells during atherogenesis. Lack of PI3Kd signalling specifically in atheroprotective Treg responses outplays its impact on B-cell and proatherogenic Th1 responses, thus leading to aggravated atherosclerosis. Hence, PI3Kd is a key regulator of Treg biology and thereby protects against atherosclerosis, suggesting that fine-tuning PI3Kd signalling may represent a promising target for Treg-directed therapy.

Long-term effects of patisiran on survival and cardiac parameters in patients with transthyretin-mediated cardiac amyloidosis: post hoc analysis of APOLLO-B and cardiac subpopulation of APOLLO OLE

Abstract Introduction Transthyretin-mediated (ATTR) amyloidosis is a progressive, fatal disease in which the most serious manifestations are polyneuropathy and cardiomyopathy. Patients with hereditary ATTR (ATTRv; v for variant) amyloidosis commonly develop a mixed phenotype, and patients with wild-type ATTR amyloidosis predominantly have cardiomyopathy, although polyneuropathy may coexist. Patisiran, an RNAi therapeutic that rapidly knocks down TTR, has shown long-term benefit on measures of polyneuropathy in the APOLLO open-label extension (OLE) study in patients with ATTRv amyloidosis. Purpose To evaluate the long-term benefit of patisiran on survival, hospitalisations and cardiac parameters in a pooled cohort of patients with ATTR amyloidosis and evidence of cardiac involvement, across the patisiran clinical programme (Phase [Ph] 2 launched in 2012). Methods Post hoc analysis of pooled data from cardiac subpopulations of patients with ATTRv amyloidosis and polyneuropathy from 5-year Global OLE (Ph 2 OLE and Ph 3 APOLLO; patients with baseline left ventricular [LV] wall thickness ≥13 mm; absence of history of aortic valve disease or hypertension), and Ph 3 APOLLO-B (patients with wild-type or ATTRv cardiac amyloidosis). Patients received patisiran or placebo every 3 weeks for 18 months in APOLLO and 12 months in APOLLO-B; all patients received patisiran thereafter. Analyses included Kaplan-Meier estimates and Cox regression of survival and all-cause hospitalisations, and summary statistics of cardiac biomarkers and echocardiographic parameters by initial treatment arm. Results Pooled analysis included 496 patients (initial arm placebo, n=214; initial arm patisiran, n=282). Compared with placebo, patients initially receiving patisiran had better long-term survival and fewer hospitalisations (hazard ratio [95% confidence interval] over 84 months for all-cause mortality and all-cause hospitalisations: 0.59 [0.37–0.93] [Figure 1] and 0.77 [0.60–0.99], respectively). At baseline, NT-proBNP and troponin I levels, peak longitudinal strain and LV wall thickness were comparable between patisiran vs placebo-treated patients. Placebo-treated patients showed worsening of all these parameters whilst on placebo; the rates of worsening decreased once the patients initiated patisiran. In contrast, patients who initially received patisiran demonstrated relative stability over 84 months in the Global OLE and significant benefit compared with those initially treated with placebo. Conclusion Long-term benefit of patisiran in patients with cardiomyopathy was observed on survival, hospitalisations, cardiac biomarkers and echocardiographic parameters. Outcomes were significantly more favourable for those initially randomised to patisiran than placebo, highlighting the impact of initiating treatment early in the course of disease.

Detection of ATTR cardiac amyloidosis using a novel artificial intelligence algorithm for wearable-adapted noisy single-lead electrocardiograms

Abstract Background Amyloid cardiomyopathy (ATTR-CM) is often underdiagnosed, with very few diagnosed before the onset of symptoms, leading to delayed use of disease-modifying therapies that could have substantial prognostic implications early in the disease course. In the US, the disease has a substantially higher prevalence among Black adults, who are further challenged by lower access to healthcare services and lower preventative care, further reducing the ability for clinician-led diagnosis. We sought to develop an approach for identifying ATTR-CM on noisy single-lead ECGs obtainable on portable and wearable ECG devices, allowing broad use in community screening. Purpose To develop a portable/wearable device-adapted AI-ECG algorithm capable of detecting ATTR-CM on noisy single-lead ECGs. Methods We identified patients with ATTR-CM from 2015 through June 2023 across 5 hospitals of a large U.S.-based hospital system using positive bone scintigraphy scans or pharmacotherapy with an approved transthyretin stabilizer. In the development cohort, we used lead I of 12 lead ECGs, commonly captured by portable and wearable ECG devices, to train a novel noise-adapted model explicitly designed to infer information against simulated real-world noises. For this, ECG signals were augmented using random Gaussian real-world noise within four frequency ranges at multiple signal-to-noise ratios. We tested the model in an independent set of cases and matched controls drawn from July through December 2023. Results The development cohort consisted of 1,011 ECGs from 234 patients (median age 79 years [IQR:70-85], 17% women), with 10:1 age- and sex-matched 10,110 controls with 10,110 ECGs (age 79 [IQR:70-85] years 17.7% female). In the independent test set of 139 ECGs from 47 patients (age 80 [75-86] years, 32% women) and matched controls (1390 ECGs and patients) from July through December 2023, the AUROC (area under the receiver operating characteristic curve) of the AI-ECG model for ATTR-CM was 0.90 [95%CI: 0.88-0.92] (A). The AUPRC was 0.44 [0.36-0.53]. The sensitivity and specificity of the model were 0.85 and 0.80. The positive predictive value ranged from 0.12 at a 3% prevalence level to 0.59 at a 25% prevalence (B). Conclusions A novel portable and wearable-devices adapted model demonstrates promising performance for detecting ATTR-CM on single-lead ECGs, representing a more accessible method for screening in community-dwelling adults.

Baricitinib in polymyalgia rheumatica and giant cell arteritis: report of six cases.

The objective of this case series is to describe the efficacy and safety of baricitinib (BARI) in a group of patients with polymyalgia rheumatica (PMR) and/or giant cell arteritis (GCA). These patients were treated with BARI due to either a refractory disease course or the unavailability of tocilizumab because of the pandemic. A total of six patients (five females and one male, median age 64 years, range 50-83) were treated with BARI. Two of them had isolated PMR, two had PMR with associated large vessel (LV)-GCA, one had LV-GCA presenting as fever of unknown origin, and one had cranial-GCA. All patients reported improvement with BARI. At the time of starting BARI, patients were taking a median prednisone dose of 8.75 mg/day (range 0-25), and the four patients with PMR had a median PMR-AS of 23.3 (indicating high disease activity), which decreased to 1.58 after 6 months of treatment with BARI. Two of them could stop glucocorticoids (GC) and continued BARI monotherapy. One patient suffered from pneumonia, and BARI was therefore stopped. No other adverse events attributable to BARI were detected. Our case series supports previous reports suggesting efficacy of Janus kinase inhibitors as a GC-sparing strategy in PMR and GCA.

Guideline-directed medical therapy titration for heart failure with ischaemic aetiology and its effect on cardiac remodelling and cardiovascular mortality-from a real world perspective

Abstract Background Contemporary Heart Failure (HF) pharmacological treatment has been reshaped by several landmark trials in recent years, and available evidence strongly encourages treatment up-titration to target doses. Recent literature regarding treatment sequencing demonstrated positive effects of up-titration on major outcomes regardless of HF aetiology. Purpose We investigated a contemporary Heart Failure with Reduced Ejection Fraction (HFrEF) patient cohort and ischaemic aetiology and sought to understand the effects both in terms of echocardiographic remodelling and upon mortality for cardiovascular (CV) causes of contemporary ESC guideline-directed medical therapy (GDMT) on a real-world level. Methods We retrospectively analysed data of consecutive patients with HFrEF and ischaemic genesis followed in our tertiary HF clinic between January 2019 and January 2022. Eligible patients were stratified into two groups: patients treated or not with full doses of ESC GDMT [including angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter-2 inhibitors (SGLT2i)]. Results Overall, 203 patients (mean age 70.1±12.3 years, 165 males) were included into the analysis. Over a mean follow-up of 1223±221.2 days, 115 (56.6) patients achieved the full recommended doses of each drug. Patients with an unsuccessful up-titration had higher end-diastolic volume at transthoracic echocardiography (p for difference at first and second follow-up &amp;lt;0.001; figure 1, panel A), lower left ventricular ejection fraction (40.1±4.3% vs 44.3±7.8 and 38.7±4.9% vs 42.3±5.6% at the first and second follow-up, respectively) and higher CV mortality rates compared to those treated with the maximal doses (figure 1, panel B). Conclusions Up-titration of pharmacotherapy in our real-world cohort of patients with HFrEF and ischaemic aetiology demonstrated a positive effect both on pivotal echocardiographic parameters and on CV mortality. Our data suggest that timely identification and referral of patients with coronary artery disease who fail to achieve complete positive remodelling after an acute event (or during chronic disease course) for HF contemporary treatment implementation should be envisaged.Figure 1

Improvement of left atrial function after ablation in patients with paroxysmal atrial fibrillation is associated with the presence of heart failure with preserved ejection fraction

Abstract Background Atrial fibrillation (AF) and heart failure with preserved ejection fraction (HFpEF) often coexist and left atrial (LA) function was impaired in both AF and HFpEF. However, It remains unclear if HFpEF is linked to LA function improvement in paroxysmal atrial fibrillation (pxAF) patients post-ablation. Purpose To investigate whether the improvement of LA function after ablation in patients with pxAF combined with HFpEF is better than that in patients without HFpEF. Methods 147 patients with pxAF were enrolled and HFpEF was ascertained based on the H2FPEF score. All patients underwent transthoracic echocardiography (TTE) at baseline and 3 months after ablation. Left atrial volume index (LAVI), left atrial ejection fraction (LAEF) and left atrial peak reservoir strain (LA RS) were measured. Improvement of left atrial function is defined as the difference in the above 3 indicators at baseline and 3 months after ablation. The change of the above atrial functional parameters was compared between patients with high-probability of HFpEF [hp-HFpEF] and medium/low-probability of HFpEF [lp-HFpEF]) in univariate and multivariate analysis. Statistical analyses were conducted using independent samples t-tests, Mann-Whitney U tests, and ANCOVA. Results 147 patients were included (30 hp-HFpEF, 117 lp-HFpEF, mean age 62.6 years, 63.3% men, mean BMI 25.54kg/㎡, mean disease course 28.2 months, mean CHA2DS2-VASc score 1.97). In the univariate analysis, the following factors were significantly different between hp-HFpEF and lp-HFpEF, including BMI (26.95±3.71 vs. 25.18±3.00, p=0.007), CHA2DS2-VASc score (3[3-4] vs. 2[1-2], p＜0.001), LA function at baseline including LAVI (41.59±11.38 vs. 32.57[27.68-41.10], p=0.003), LAEF (45.97±10.26 vs. 57.23±9.08, p＜0.001), LA RS (26.43±10.68 vs. 34.43±10.60, p＜0.001), and difference at baseline and 3 months after ablation in LA function including LAVI (4.92±1.08 vs. 3.33±1.18, p＜0.001), LAEF (13.41±9.71 vs. 2.98±9.69, p＜0.001), LA RS (23.61±10.23 vs. 7.29±6.91, p＜0.001), and in left ventricular (LV) TTE indicators including E/e’ (3.10±2.30 vs. -0.32±2.68, p＜0.001), LV ejection fraction (10.5[7.0-16.5] vs. 2.0[-5.0-6.0], p＜0.001), LV global longitudinal strain (14.94±4.27 vs. 5.15[2.63-8.30], p＜0.001) and LV mass (17.79±28.67 vs 1.50[-8.75-17.00], p=0.006). After adjusted for BMI, CHA2DS2-VASc score, LA function at baseline and difference at baseline and 3 months after ablation in LV TTE indicators, the improvement of LA function 3 months after ablation in patients with hp-HFpEF is better than that in patients with lp-HFpEF: LAVI significantly decreased (4.24±0.21 vs. 3.46± 0.09, p＜0.001), LAEF significantly increased (12.90±2.13 vs. 3.09±0.86, p＜0.001) and LA RS significantly increased (21.44±1.81 vs. 8.02±0.76, p＜0.001) in hp-HFpEF compared with lp-HFpEF. Conclusion Patients with pxAF with hp-HFpEF showed better improvement in LA function after ablation than those with Ip-HFpEF.

Lipid-associated GWAS loci as important markers of the risk, severity, and clinical course of peripheral artery disease

ABSTRACT Background This study investigated the relationship between lipid-associated loci identified through genome-wide association studies (GWAS) and the risk of peripheral artery disease (PAD), its severity, as well as clinical and laboratory features. Research design and methods A study included 1263 unrelated Russian subjects, consisting of 620 patients diagnosed with PAD and 643 healthy controls. Thirteen single nucleotide polymorphisms (SNP) were genotyped using the MassArray-4 system. Results Polymorphisms rs1689800, rs55730499 and rs881844 were found to be associated with an increased risk of PAD, whereas SNPs rs1883025, rs3136441, rs3764261 and rs6065906 showed protective effects against disease (Pperm ≤ 0.05). SNPs rs1689800, rs217406, rs1883025, and rs3136441 exhibited combined effects with cigarette smoking on the PAD risk (Pperm ≤ 0.05). Polymorphisms rs55730499 (beta = 0.124, Pperm = 0.04), rs9987289 (beta = 0.558, Pperm = 0.03), and rs881844 beta = −0.171, Pperm = 0.03) correlated with the ankle-brachial index. Multiple associations have been found between the SNPs and clinically significant characteristics, including disease severity, risk of gangrene, early disease onset, plasma procoagulant and atherogenic lipid changes (Pperm ≤ 0.05). Conclusions We identified novel genetic markers associated with PAD susceptibility and disease-related clinical and laboratory features. The identified biomarkers enhance the potential for predictive genetic testing related to the risk and progression of PAD, facilitating the integration of molecular diagnostics into clinical decision-making processes.

Updates in Immunotherapy for Pancreatic Cancer.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with limited effective therapeutic options. Due to a variety of cancer cell-intrinsic factors, including KRAS mutations, chemokine production, and other mechanisms that elicit a dysregulated host immune response, PDAC is often characterized by poor immune infiltration and an immune-privileged fibrotic stroma. As understanding of the tumor microenvironment (TME) evolves, novel therapies are being developed to target immunosuppressive mechanisms. Immune checkpoint inhibitors have limited efficacy when used alone or with radiation. Combinations of immune therapies, along with chemotherapy or chemoradiation, have demonstrated promise in preclinical and early clinical trials. Despite dismal response rates for immunotherapy for metastatic PDAC, response rates with neoadjuvant immunotherapy are somewhat encouraging, suggesting that incorporation of immunotherapy in the treatment of PDAC should be earlier in the disease course. Precision therapy for PDAC may be informed by advances in transcriptomic sequencing that can identify immunophenotypes, allowing for more appropriate treatment selection for each individual patient. Personalized and antigen-specific therapies are an increasing topic of interest, including adjuvant immunotherapy using personalized mRNA vaccines to prevent recurrence. Further development of personalized immune therapies will need to balance precision with generalizability and cost.

Bibliometric and Content Analysis of Articles on Artificial Intelligence in Healthcare

The use of artificial intelligence in the healthcare sector is becoming widespread for reasons such as analyzing digital patient data, including it in decision-making processes, improving the quality of healthcare services, and providing cost, time, and access advantages. This study aims to evaluate published articles on bibliometric indicators and the use of artificial intelligence in the healthcare sector and examine the content of the most cited articles. Articles about artificial intelligence in the health sector in the Web of Science database were included in the study using the criteria of “keyword, publication year, and publication language”. The research covers 2,680 articles published in English by 14,195 authors from 106 countries in 1084 journals between 2020-2024. 4,671 different keywords were used in the published articles. The country that published the most was “USA”, the journal was “Journal of Medical Internet Research”, the author was “Meng Ji”, and the most cited author was “Weihua Li”. The 55 most cited (≥50) articles focused on themes related to “diagnosis of COVID-19 disease”, “diagnosis of diseases”, “detection and classification of cancerous cells”, “identification of disease risk factors and disease prediction”, “prediction of treatment outcomes”, “prediction of disease course”, “personalized treatment recommendations”, “decision-making processes”, “ethical considerations, risks, and responsibilities”. With the COVID-19 pandemic, it is seen that the number of articles on artificial intelligence in the healthcare sector has increased exponentially. In the research, articles related to artificial intelligence in the health sector were examined, and a framework was created for researchers by revealing the most publishing countries, journals, authors, most cited authors, and keywords that were used the most.