Different Phenotypes Of Patients Research Articles

#614 Identifying distinct patient phenotypes in patients with chronic kidney disease

Abstract Background and Aims Patients with chronic kidney disease (CKD) are heterogeneous in terms of age, causes of CKD, and comorbidities. Although individual risk factors greatly influence patients’ risk of clinical outcomes, this heterogeneity is rarely used to guide clinical decision-making. In this study we aimed to derive phenotypes in patients with CKD based on characteristics commonly available in routine clinical practice and evaluated whether these phenotypes were associated with clinical outcomes. Method Patients from the Utrecht Patient Oriented Database (UPOD) who were 18 years or older with CKD (defined as an eGFR <60 ml/min/1.73 m2 or an UACR > 3 mg/mmol present for >3 months) and visited one of the cardiovascular outpatient clinics of the University Medical Center Utrecht between 2012 and 2019 were included. Patient phenotypes were derived with latent class analyses based on age, sex, CKD stage, cause of kidney disease, and (cardiovascular) comorbidities. The incidence rate/100 person years (IR/100PY) for all-cause mortality and kidney failure (defined as initiation of kidney replacement therapy or a sustained eGFR <15) and 95% confidence interval (95% CI) was calculated for each phenotype. Results Overall 9005 patients were included (mean age 65 ± 14 years, 42% women, mean estimated glomerular filtration rate (eGFR) 49 ± 17 ml/min/1.73 m2). The median follow-up was 3.8 years [interquartile range 1.8–6.4]. Latent class analysis identified 7 phenotypes with the following characteristics: phenotype 1 were young patients with primary kidney disease (10%); phenotype 2 were patients with diabetes and a preserved eGFR (9%); phenotype 3 were patients with low comorbidity and inflammation (28%); phenotype 4 were older patients with a history of cardiovascular disease (27%); phenotype 5 were older patients with a history of cardiovascular disease and severe CKD (16%); phenotype 6 were younger patients with a kidney transplant and low comorbidity (6%); and phenotype 7 were older patients with a kidney transplant and cardiovascular disease (6%). The risk of all-cause mortality and kidney failure differed significantly between the identified phenotypes. The phenotypes of younger kidney transplant recipients, younger patients with primary kidney disease, and diabetes with preserved eGFR had the lowest risk for all-cause mortality (for all, IR/100 PY <5) (Fig. 1). The phenotypes with an intermediate incidence rate for all-cause mortality were the low comorbidity and inflammation phenotype (IR/100PY 7.4, 95% CI 6.9–8.0), the phenotype of older patients with cardiovascular disease (IR/100PY 7.2, 95% CI 6.7–7.8), and the phenotype of older patients with a kidney transplant and cardiovascular disease (IR/100PY 6.5, 95% CI 5.5–7.6). The phenotypes with highest incidence rate for all-cause mortality was the phenotype of older patients with cardiovascular disease and severe CKD (IR/100PY 12.5, 95% CI11.5–13.4). The phenotypes with the lowest risk for kidney failure were the diabetes phenotype, the low comorbidity and inflammation phenotype, and the phenotype of older patients with cardiovascular disease (all IR/100 PY <1). The phenotype of older patients with cardiovascular disease and severe CKD also had the highest risk to develop kidney failure (IR/100PY 5.8, 95% CI 5.1–6.6), followed by the phenotype of patients with primary kidney disease (IR/100PY 4.4, 95% CI 3.7 −5.5). Conclusion We identified 7 different phenotypes of patients with CKD including 2 phenotypes of patients with a kidney transplant with different clinical characteristics and prognosis. The differences in risk of all-cause mortality and kidney failure warrants a different monitoring and follow-up across the different phenotypes within the setting of CKD. Future studies should invest In evaluating the implementation of our identified phenotypes in routine clinical practice or clinical trial design with respect to differences in treatments.

Comparing biomechanics and neurophysiology between different phenotypes of patients with oropharyngeal dysphagia.

The pathophysiology of oropharyngeal dysphagia (OD) across patient phenotypes may differ. The aim of this study was to compare the biomechanics and neurophysiology of swallowing between healthy volunteers (HVs) and patients with dysphagia as a consequence of aging (OOD), post-stroke (PSOD), Parkinson's disease (POD), or dementia (DOD). A retrospective study including 35 HVs and 109 OOD, 195 PSOD, 78 POD, and 143 DOD patients was performed. Videofluoroscopic data of signs of impaired efficacy and safety, penetration-aspiration scale (PAS) score, and the biomechanics of laryngeal vestibule closure (LVC) and opening (LVO) and of upper esophageal sphincter opening (UESO) were collected. Neurophysiology was assessed with pharyngeal sensory evoked potentials and neurotopography maps. All OD phenotypes showed signs of impaired efficacy and safety of swallowing, increased PAS score (p < 0.001), and delayed time to LVC (p < 0.0001). OOD (p < 0.0001), PSOD (p < 0.0001), and POD (p = 0.0065) patients also had delayed time to LVO, and OOD (p = 0.0062) and DOD (p = 0.0016) patients to UESO. Regarding neurophysiology, all phenotypes presented impaired pharyngeal sensitivity, a significant reduction in cortical activation, and impaired sensory input integration. Additionally, only PSOD was associated with impaired conduction of sensory stimuli. In conclusion, we found common but also specific pathophysiological elements. These results improve our understanding of OD pathophysiology and may help pave the way for phenotype-specific treatments.

Unsupervised cluster analysis reveals different phenotypes in patients after transcatheter aortic valve replacement.

The aim of this study was to identify phenotypes with potential prognostic significance in aortic stenosis (AS) patients after transcatheter aortic valve replacement (TAVR) through a clustering approach. This multi-centre retrospective study included 1365 patients with severe AS who underwent TAVR between January 2015 and March 2019. Among demographics, laboratory, and echocardiography parameters, 20 variables were selected through dimension reduction and used for unsupervised clustering. Phenotypes and outcomes were compared between clusters. Patients were randomly divided into a derivation cohort (n = 1092: 80%) and a validation cohort (n = 273: 20%). Three clusters with markedly different features were identified. Cluster 1 was associated predominantly with elderly age, a high aortic valve gradient, and left ventricular (LV) hypertrophy; Cluster 2 consisted of preserved LV ejection fraction, larger aortic valve area, and high blood pressure; and Cluster 3 demonstrated tachycardia and low flow/low gradient AS. Adverse outcomes differed significantly among clusters during a median of 2.2 years of follow-up (P < 0.001). After adjustment for clinical and echocardiographic data in a Cox proportional hazards model, Cluster 3 (hazard ratio, 4.18; 95% confidence interval, 1.76-9.94; P = 0.001) was associated with increased risk of adverse outcomes. In sequential Cox models, a model based on clinical data and echocardiographic variables (χ2 = 18.4) was improved by Cluster 3 (χ2 = 31.5; P = 0.001) in the validation cohort. Unsupervised cluster analysis of patients after TAVR revealed three different groups for assessment of prognosis. This provides a new perspective in the categorization of patients after TAVR that considers comorbidities and extravalvular cardiac dysfunction.

Phenotyping of heart failure with preserved ejection faction using electronic health records and echocardiography.

Patients presenting symptoms of heart failure with preserved ejection fraction (HFpEF) are not a homogenous population. Different phenotypes can differ in prognosis and optimal management strategies. We sought to identify phenotypes of HFpEF by using the medical information database from a large university hospital centre using machine learning. We explored the use of clinical variables from electronic health records in addition to echocardiography to identify different phenotypes of patients with HFpEF. The proposed methodology identifies four phenotypic clusters based on both clinical and echocardiographic characteristics, which have differing prognoses (death and cardiovascular hospitalization). This work demonstrated that artificial intelligence-derived phenotypes could be used as a tool for physicians to assess risk and to target therapies that may improve outcomes.

Abstract 15376: Candidacy and Fate of Right Heart Failure Patients Undergoing Tricuspid Valve Surgery

Objective: There are no current guidelines for risks and benefits of cardiac surgery for patients with right heart failure (RHF). In this study, we analyzed pre-operative RHF variables aiming to assess candidacy for surgery and impact of tricuspid intervention. Methods: We retrospectively identified 522 patients with severe (+3 or more) tricuspid regurgitation (TR) who underwent cardiac surgery between 01/2007 and 01/2014 . The mean follow up was 4.7 years (± 4.3 years). Cluster analysis was performed using preoperative RHF clinical and hemodynamics variables, and outcomes after surgery were assessed. Results: Cluster analysis divided the cohort into three distinct clusters representing different phenotypes of patients with RHF-associated TR (cluster 1: 220 patient, cluster 2: 224 patients, cluster 3: 78 patients). Cluster I had highest concomitant left-sided valve procedure (72% mitral valve surgery, p&lt;.0001) with best RV function (fractional area change % 35 ± 13, p=.0002). Cluster II had highest MELD score (14 ± 4, p&lt;.0001), creatinine (1.4 ± 0.6, p&lt;.0001), and worst RV function (fractional area change % 30 ± 12, p=.0002). Cluster III had the most dilated right heart with right atrial area of 42 ± 14 mm, p&lt;.0001 and RV area in diastole 42 ± 10 mm, p&lt;.0001. Survival was best in Cluster I followed by Cluster III while worst in Cluster II (70%, 59%, and 29% at 8-years, respectively), Figure 1. Recurrent TR was highest in Cluster III, followed by Cluster II while least in Cluster I at 10-years (9%, 8%, and 5%, respectively). Conclusions: Cluster analysis of RHF identified three distinct groups of patients presenting for cardiac surgery. Pre-operative RV dysfunction was associated with worse clinical outcomes and need careful assessment before surgery. Pre-operative right heart dilation was associated with recurrent TR for which more aggressive tricuspid repair or even replacement might be considered.

Phenotyping of Heart Failure with preserved ejection faction using electronic health records and echocardiography

Abstract Funding Acknowledgements Type of funding sources: Public hospital(s). Main funding source(s): CHU de Rennes Aims Patients presenting heart failure (HF) symptoms with preserved left ventricular ejection fraction (HFpEF) are not a homogenous population. Different phenotypes can differ in prognosis and optimal management strategies. We sought to identify phenotypes of HFpEF by using the medical information database from a large University Hospital Center using machine learning. Methods and results We explored the use of clinical variables from electronic health records (EHR) in addition to echocardiography to identify different phenotypes of patients with heart failure and preserved ejection fraction. The proposed methodology identifies 4 phenotypic clusters based on both clinical and echocardiographic characteristics which have differing prognoses (death and cardio-vascular hospitalization). Conclusion This work demonstrated that AI derived phenotypes could be used as a tool for physicians to assess risk and to target therapies that may improve outcomes.

Clinical Heterogeneity and Different Phenotypes in Patients with SETD2 Variants: 18 New Patients and Review of the Literature.

SETD2 belongs to the family of histone methyltransferase proteins and has been associated with three nosologically distinct entities with different clinical and molecular features: Luscan-Lumish syndrome (LLS), intellectual developmental disorder, autosomal dominant 70 (MRD70), and Rabin-Pappas syndrome (RAPAS). LLS [MIM #616831] is an overgrowth disorder with multisystem involvement including intellectual disability, speech delay, autism spectrum disorder (ASD), macrocephaly, tall stature, and motor delay. RAPAS [MIM #6201551] is a recently reported multisystemic disorder characterized by severely impaired global and intellectual development, hypotonia, feeding difficulties with failure to thrive, microcephaly, and dysmorphic facial features. Other neurologic findings may include seizures, hearing loss, ophthalmologic defects, and brain imaging abnormalities. There is variable involvement of other organ systems, including skeletal, genitourinary, cardiac, and potentially endocrine. Three patients who carried the missense variant p.Arg1740Gln in SETD2 were reported with a moderately impaired intellectual disability, speech difficulties, and behavioral abnormalities. More variable findings included hypotonia and dysmorphic features. Due to the differences with the two previous phenotypes, this association was then named intellectual developmental disorder, autosomal dominant 70 [MIM 620157]. These three disorders seem to be allelic and are caused either by loss-of-function, gain-of-function, or missense variants in the SETD2 gene. Here we describe 18 new patients with variants in SETD2, most of them with the LLS phenotype, and reviewed 33 additional patients with variants in SETD2 that have been previously reported in the scientific literature. This article offers an expansion of the number of reported individuals with LLS and highlights the clinical features and the similarities and differences among the three phenotypes associated with SETD2.

Identification and characterization of a new variation in DPM2 gene in two Chinese siblings with mild intellectual impairment.

Introduction: Congenital disorders of glycosylation (CDGs) are a genetically heterogeneous group of metabolic disorders caused by abnormal protein or lpid glycosylation. DPM2 is one subunit of a heterotrimeric complex for dolichol-phosphatemannose synthase (DPMS), a key enzyme in glycosylation, and only four patients with DPM2-CDG have been reported. Methods: Whole-exome sequencing (WES) was performed in a Chinese family having two siblings with a mild form of DPM2-CDG with developmental delay, mild intellectual disability, hypotonia, and increased serum creatine kinase. Sanger sequencing was used to validate the variants identified in the siblings and their parents. In vitro functional study was performed. Results: A homozygous mutation, c.197G>A (p.Gly66Glu) in exon 4 of DPM2 (NM_003863) was identified by whole exome sequencing (WES). In vitro functional analysis demonstrated that this variant increased the expression level of DPM2 protein and western blot revealed a significant decrease in ICAM1, a universal biomarker for hypoglycosylation in patients with CDG, suggesting abnormal N-linked glycosylation. We also reviewed the 4 previously reported patients carrying homozygous or compound heterozygous variants of DMP2 gene, and found that patients with variants within the region encoding the first domain had more severe clinical symptoms than those with variants within the second domain. However, the actual genotype-phenotype relationship needs more study. Discussion: Overall, our study broadens the variant spectrum of DPM2 gene, attempts to explain the different phenotypes in patients with different DPM2 variants, and emphasizes the need of further functional studies to understand the underlying pathophysiology of the phenotypic heterogeneity.

Study of Hematopoietic Stem Cells in Patients with Extensive Burns

Introduction. Assessment of tissue regeneration, including that at the cellular and subcellular levels, appears to be one of the important trends in the complex treatment of patients with extensive burns. It is known that hematopoietic stem cells (HSCs) contribute to tissue restoration and regeneration through paracrine effects or direct cell differentiation, being a central component of post-burn anemia recovery and capable of forming not only blood cells, but also other types of cells. Notably, the role of these cells in burn injury has not been studied yet.The aim of the study was to investigate in dynamics the content of hematopoietic stem cells of different phenotypes in patients with extensive burns in the process of complex treatment. Methods. Hematopoietic stem cells and their subpopulations in peripheral blood samples were analyzed on a FACSCalibur flow cytometer (Becton Dickinson, USA) using the CellQuest program and CD45/CD34/CD38 and CD45/CD34/CD133 monoclonal antibody panels (BD, USA). The results obtained were statistically processed using the GraphPad Prism 7.0 program (USA), results were considered statistically significant at p0.05.Results. Hematopoietic stem cells and their subpopulations were studied at different stages of the complex treatment in 25 patients with a large burn area, ​​more than 30% of the body surface. The comparison group consisted of 15 healthy volunteers. Upon admission to the Burn Center, a group of severely burned patients revealed a significant deep deficiency of both total HSCs CD45+34+ (p=0.0002) and their subpopulations CD45dim34+38+ (p=0.019), with predominantly early precursors of hematopoiesis CD45dim34+38- (p=0.0001) and CD45dim34+133+ (p=0.0002). In the course of the complex treatment, including surgical necrectomy and autodermoplasty of burn wounds, there was observed normalization of total HSCs CD45+34+ (0.050.012%, p=0.031) and a subpopulation of early HSCs CD45dim34+38- (0.0390.009%, p=0.016) in 20 days of treatment in the group of burn patients. There was a significant increase of mature CD45dim34+133- HSCs (p=0.0380) as a result of treatment, while the deficit of the more differentiated population of CD45dim34+38+ HSCs did not fully recover (p=0.272).Conclusion. The firstly detected modulations in the content of hematopoietic stem cells of different phenotypes in patients with extensive burns may reflect the state of compensatory-adaptive reactions of hematopoiesis in the course of the complex treatment. The data obtained may support the predictive use of HSC subcellular markers to assess the regenerative potential in burn wounds healing, including that during staged surgical treatment and autodermoplasty, and to predict the development of local and general complications of burn disease.

Expression of Serum Omentin, CTRP9, and Vaspin in Patients with Polycystic Ovary Syndrome.

Objective To explore the relationship between serum omentin, C1q/tumor necrosis factor-related protein-9 (CTRP9), and visceral fat-specific serine protease inhibitor (vaspin) levels in different phenotypes in patients with polycystic ovary syndrome (PCOS). Methods One hundred PCOS patients treated at our hospital's clinic of reproductive medicine were chosen and included into the research group, and 100 healthy women who came for physical examination during the same time period were included into the control group. According to the definition of obesity by the WHO (body mass index (BMI) ≥25 kg/m2), 100 patients with PCOS were equally divided into obese (study group A) and nonobese (study group B) groups. 100 healthy women were also divided into obese (control group A) and nonobese (control group B) groups with 50 patients each. Comparison among the 4 groups was performed in factors/indicators including the serum omentin, CTRP9, and vaspin levels and biochemical indexes (triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), fasting insulin (FINS), total testosterone, and homeostasis model assessment of insulin resistance (HOMA-IR) levels), and the correlation analysis was conducted with omentin, CTRP9, and vaspin. Results There was no significant difference in age, TG, TC, and LDL-C among the 4 groups (P > 0.05). The BMI, WHR, HDL-C, and omentin of the obese phenotype were significantly different from those of the nonobese phenotype (P < 0.05). Among the four groups, FINS, HOMA-IR, and vaspin in group A (obesity) was the highest, and the control group B (nonobese) was the lowest. There was no significant difference in the levels of study group B (nonobese) and control group A (obesity). The level of CTRP9 in the study group was significantly lower than that in the control group (P < 0.05). Taking serum omentin, CTRP9, and vaspin levels of patients in the study group as dependent variables, Pearson correlation analysis showed that the omentin level was negatively correlated with BMI, WHR, FINS, TG, TC, LDL-C, HOMA-IR, and TT levels (P < 0.05) and was positively correlated with the HDL-C level (P < 0.05); CTRP9 level was negatively correlated with BMI, TC, and HOMA-IR (P < 0.05) and was not correlated with age, WHR, FINS, TG, HDL-C, LDL-C, HOMA-IR, and TT levels. The vaspin level was positively correlated with BMI, WHR, FINS, TG, TC, LDL-C, HOMA-IR, and TT levels (P < 0.05) and negatively correlated with HDL-C levels (P < 0.05) and was not correlated with age. Conclusion When compared with healthy people, PCOS patients have higher serum vaspin levels and lower CTRP9 levels; BMI, TC, LDL-C, FINS, TG, total testosterone, HDL-C levels, waist-to-hip ratio, and HOMA-IR are all closely related to serum vaspin and CTRP9 levels; increasing serum CTRP9 levels and decreasing vaspin levels help to slow progress and promote prognosis of the disease. Serum omentin level is connected with the obesity index but not with PCOS.

Aspirin for Primary Prevention of Cardiovascular Diseases: "WALTZ" with the Evidence.

Purpose of ReviewIn this review article, a detailed analysis of the current literature is provided, along with a “glimpse” into what the future holds for aspirin in the context of primary prevention.Recent FindingsThe role of aspirin in primary prevention of cardiovascular diseases (CVD) has been extensively evaluated; however, the results provided over the years have been controversial. Identification of individual subgroups who may benefit from aspirin administration at an acceptable risk of bleeding complications is of paramount importance. Additionally, questions emerge at everyday clinical practice regarding the optimal use of aspirin in different phenotypes of patients due to age, sex, obesity status, frailty and diabetes mellitus.SummaryUntil further data become available, the effective management of the well-established CV risk factors constitutes the milestone in the primary prevention of CVD. Moreover, based on the available evidence, the beneficial addition of aspirin in the modern era of lifestyle and pharmacological interventions for primary CVD prevention remains largely undetermined and further research is needed.

Juvenile-Onset Kufs Disease in a Chinese Consanguineous Family due to CLN6 Mutation

Objective: The aim of this study was to identify the genetic cause of two cases of Kufs disease in the same family. The two affected individuals exhibited different levels of severity under magnetic resonance imaging (MRI). Methods: Whole-exome sequencing was performed on affected individuals, and the candidate gene was confirmed by Sanger sequencing. Western blot analysis was used to evaluate the level of expression of CLN6 protein in 239T cells. Results: We identified a novel homozygous mutation of the CLN6 gene (c.14G>T, p.Arg5Leu) in a consanguineous Chinese family in which two people had Kufs disease. Both patients exhibited seizures and progressive psychomotor decline and mental deterioration without visual impairment. They had different ages of onset, although they carried the same missense mutation. The affected female showed a pronounced abnormal MRI signal in the bilateral hippocampus, while her younger brother only showed a very slight abnormal signal. Further study showed that this missense mutation could decrease the level of expression of CLN6 protein. Conclusions: A novel homozygous mutation of the CLN6 gene was identified, and patients with the same mutation showed different ages of onset and different levels of severity under MRI. Significance: Our study established that the same CLN6 mutation could produce different phenotypes in patients, and it has expanded the mutational and phenotypical spectrum of the CLN6 gene.

Tongue+ protocol for the diagnosis of obstructive sleep apnoea in Quirónsalud Marbella hospital

Background: Myofunctional therapy has been shown to be effective in treating sleep-disordered breathing. The elaboration of this protocol arises with the purpose of establishing a complete and common evaluation of sleep respiratory disorders from the point of view of the anatomy and functionality of the upper airway to guarantee the long-term treatment of the different phenotypes of patients with obstructive sleep apnoea (OSA). Our multidisciplinary unit has an experience of more than 10 years in treating OSA patients and has numerous recent publications focused on the role of myofunctional therapy. Methods: The evaluation of the patient with obstructive sleep apnoea is carried out jointly by the medical team of Pulmonology and Otorhinolaryngology of the Sleep Unit. The patients undergo an anatomical and motor tone evaluation of the upper airway to find the cause of the collapse and a sleep study to confirm the diagnosis and its severity. Conclusions: With this protocol we want to present our clinical experience in the comprehensive diagnostic management of the patient with obstructive sleep apnea and provide the most correct treatment among the different therapeutic options available for sleep apnea.

Investigation of GALNS variants and genotype-phenotype correlations in a large cohort of patients with mucopolysaccharidosis type IVA.

Mucopolysaccharidosis type IVA (MPS IVA) is a rare autosomal recessive disorder resulting from the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS) caused by pathogenic variants in the GALNS gene. A systematic analysis for genotype-phenotype correlation is essential due to hundreds of variants generating different levels of residual GALNS activity and causing a wide degree of clinical manifestation effects. Here, we retrospectively analyzed clinical and genetic data of 108 unrelated patients with MPS IVA to investigate the variants spectrum of GALNS and assess their clinical effects. In this cohort, 82 patients were classified as severe, 14 as intermediate, and 12 as mild. One hundred and one GALNS variants were identified, of which 47 were novel. Most patients with at least one GALNS null variant were classified as severe phenotype (92%, 33/36). Missense variants mapped to different residues of GALNS protein resulted in different phenotypes in patients with MPS IVA. Ninety-two percent of patients with two missense variants mapped to buried residues were classified as severe (92%, 24/26), while at least one missense variant mapped to surface residues was identified in patients with biallelic missense variants presenting intermediate MPS IVA (78%, 7/9) and presenting mild MPS IVA (86%, 6/7). Our study contributes to a better understanding of the molecular spectrum of GALNS variants and their clinical implications. Based on the data herein reported, we generated a systematic flowchart correlating the GALNS variants to assist in phenotype prediction and classification of patients with MPS IVA.

Identification of Two Different Phenotypes of Patients with Amiodarone-Induced Thyrotoxicosis and Positive Thyrotropin Receptor Antibody Tests.

Introduction: Serum thyrotropin (TSH) receptor antibodies (TRAbs) are occasionally found in patients with amiodarone-induced thyrotoxicosis (AIT), and usually point to a diagnosis of type 1 AIT (AIT1) due to Graves' disease (GD). However, the TRAb role and function in AIT have not been clarified. Methods: A retrospective cohort study of 309 AIT patients followed at a single academic center over a 30-year period. AIT TRAb-positive patients (n = 21, 7% of all cases) constituted the study group; control groups consisted of type 2 AIT (AIT2) TRAb-negative patients (n = 233), and 100 non-AIT patients with GD. Clinical and biochemical data at diagnosis and during the course of disease were compared. Histological samples of patients who had total thyroidectomy were reviewed. Stored serum samples were used for a functional assay of TRAb class G immunoglobulins (IgGs) in Chinese hamster ovary (CHO) cells stably transfected with complementary DNA encoding for the TSH receptor. Results: TRAb-positive patients were grouped according to color flow Doppler sonography, radioactive iodine thyroid uptake, and duration of amiodarone therapy before thyrotoxicosis in type 1 (n = 9, 43%; TRAb1) or type 2 (n = 12, 57%; TRAb2) AIT. TRAb1 patients had clinical and biochemical features indistinguishable from GD controls, and were responsive to methimazole. Conversely, TRAb2 patients had clinical features similar to AIT2 controls, and were responsive to glucocorticoids, but not to methimazole. The CHO cell functional assay demonstrated that TRAb1 IgGs had a stimulatory effect on cyclic AMP production, which was absent in TRAb2 IgGs. Pathology in TRAb1 showed hyperplastic thyroid follicles and mild lymphocyte infiltration, reflecting thyroid stimulation. On the contrary, TRAb2 samples revealed follicle destruction, macrophage infiltration, and sometimes fibrosis, consistent with a destructive process. Conclusions: Almost 60% of TRAb-positive AIT patients had a destructive thyroiditis. TRAb-positive tests in AIT patients do thus not necessarily imply a diagnosis of GD and AIT1, and should be evaluated in the clinical and biochemical setting of each AIT patient and confirmed by measuring thyroid-stimulating immunoglobulins.

A Systematic and a Scoping Review on the Psychometrics and Clinical Utility of the Volume-Viscosity Swallow Test (V-VST) in the Clinical Screening and Assessment of Oropharyngeal Dysphagia.

(1) Background: The volume-viscosity swallow test (V-VST) is a clinical tool for screening and diagnosis of oropharyngeal dysphagia (OD). Our aims were to examine the clinical utility of the V-VST against videofluoroscopy (VFS) or fiberoptic endoscopic evaluation of swallow (FEES) and to map the V-VST usage with patients at risk of OD across the years since it was described for the first time, carrying a systematic and a scoping review. (2) Methods: We performed both a systematic review (SR) including studies that look at the diagnostic test accuracy, and a scoping review (ScR) with articles published from September 2008 to May 2020. Searches were done in different databases, including PubMed and EMBASE from September 2008 until May 2020, and no language restrictions were applied. A meta-analysis was done in the SR to assess the psychometric properties of the V-VST. Quality of studies was assessed by Dutch Cochrane, QUADAS, GRADE (SR), and STROBE (ScR) criteria. The SR protocol was registered on PROSPERO (registration: CRD42020136252). (3) Results: For the diagnostic accuracy SR: four studies were included. V-VST had a diagnostic sensitivity for OD of 93.17%, 81.39% specificity, and an inter-rater reliability Kappa = 0.77. Likelihood ratios (LHR) for OD were 0.08 (LHR–) and 5.01 (LHR+), and the diagnostic odds ratio for OD was 51.18. Quality of studies in SR was graded as high with low risk of bias. In the ScR: 34 studies were retrieved. They indicated that V-VST has been used internationally to assess OD’s prevalence and complications. (4) Conclusions: The V-VST has strong psychometric properties and valid endpoints for OD in different phenotypes of patients. Our results support its utility in the screening and clinical diagnosis and management of OD.

Characterizing respiratory parameters, settings, and adherence in real-world patients using adaptive servo ventilation therapy: big data analysis.

There is minimal guidance around how to optimize inspiratory positive airway pressure (IPAP) levels during use of adaptive servo ventilation (ASV) in clinical practice. This real-world data analysis investigated the effects of IPAP and minimum pressure support settings on respiratory parameters and adherence in ASV-treated patients. A United States-based telemonitoring database was queried for patients starting ASV between August 1, 2014 and November 30, 2019. Patients meeting the following criteria were included: United States-based patients aged ≥ 18 years; AirCurve 10 device (ResMed); and ≥ 1 session with usage of ≥ 1 hour in the first 90 days. Key outcomes were mask leak and residual apnea-hypopnea index at different IPAP settings, adherence and therapy termination rates, and respiratory parameters at different minimum pressure support settings. There were 63,996 patients included. Higher IPAP was associated with increased residual apnea-hypopnea index and mask leak but did not impact device usage per session (average > 6 h/day at all IPAP settings; 6.7 h/day at 95th percentile IPAP 25 cm H2O). There were no clinically relevant differences in respiratory rate, minute ventilation, leak, and residual apnea-hypopnea index across all possible minimum pressure support settings. Patients with a higher 95th percentile IPAP or with minimum pressure support of 3 cm H2O were most likely to remain on ASV therapy at 1 year. Our findings showed robust levels of longer-term adherence to ASV therapy in a large group of real-world patients. There were no clinically important differences in respiratory parameters across a range of pressure and pressure support settings. Future work should focus on the different phenotypes of patients using ASV therapy. Malhotra A, Benjafield AV, Cistulli PA, etal. Characterizing respiratory parameters, settings, and adherence in real-world patients using adaptive servo ventilation therapy: big data analysis. J Clin Sleep Med. 2021;17(12):2355-2362.

Identifying Clinical Phenotypes in Moderate to Severe Acute Respiratory Distress Syndrome Related to COVID-19: The COVADIS Study.

Objectives: Different phenotypes have been identified in acute respiratory distress syndrome (ARDS). Existence of several phenotypes in coronavirus disease (COVID-19) related acute respiratory distress syndrome is unknown. We sought to identify different phenotypes of patients with moderate to severe ARDS related to COVID-19.Methods: We conducted an observational study of 416 COVID-19 patients with moderate to severe ARDS at 21 intensive care units in Belgium and France. The primary outcome was day-28 ventilatory free days. Secondary outcomes were mortality on day 28, acute kidney injury, acute cardiac injury, pulmonary embolism, and deep venous thrombosis. Multiple factor analysis and hierarchical classification on principal components were performed to distinguish different clinical phenotypes.Results: We identified three different phenotypes in 150, 176, and 90 patients, respectively. Phenotype 3 was characterized by short evolution, severe hypoxemia, and old comorbid patients. Phenotype 1 was mainly characterized by the absence of comorbidities, relatively high compliance, and long duration of symptoms, whereas phenotype 2 was characterized female sex, and the presence of mild comorbidities such as uncomplicated diabetes or chronic hypertension. The compliance in phenotype 2 was lower than that in phenotype 1, with higher plateau and driving pressure. Phenotype 3 was associated with higher mortality compared to phenotypes 1 and 2.Conclusions: In COVID-19 patients with moderate to severe ARDS, we identified three clinical phenotypes. One of these included older people with comorbidities who had a fulminant course of disease with poor prognosis. Requirement of different treatments and ventilatory strategies for each phenotype needs further investigation.

Additional prognostic value of vasodilator stress CMR in patients with inconclusive stress test to detect coronary artery disease

Abstract Funding Acknowledgements Type of funding sources: None. BACKGROUND Guidelines recommend performing a non-invasive testing for ischemia to diagnose coronary artery disease (CAD). However, these tests are frequently inconclusive (25%). This population has been poorly studied because of its heterogeneity. In such cases, stress cardiac magnetic resonance (CMR) may be useful to improve diagnostic certainty. To date, no study has evaluated the prognostic value of stress CMR in these patients presenting with prior inconclusive test. PURPOSE To assess the additional prognostic value of vasodilator stress perfusion CMR in patients with a first inconclusive stress test to detect CAD. METHODS Between 2008 and 2018, consecutive patients with inconclusive stress test prospectively referred for vasodilator stress perfusion CMR with dipyridamole were followed for major adverse cardiovascular events (MACE) defined as cardiac death or myocardial infarction. Inconclusive stress test was defined by echocardiography or nuclear stress testing with uncertain conclusion about the diagnosis of CAD. To characterize this population, an unsupervised clustering analysis was performed using 18 variables. Univariable and multivariable Cox regressions were performed to determine the prognostic value of inducible ischemia by stress CMR in each cluster. RESULTS Of 1502 patients with inconclusive stress test (62 ± 12 years, 59% men), 1441 (96%) completed the CMR protocol and 1397(93%) completed the follow-up (median 5.5 ± 2.3 years). Stress CMR was well tolerated without occurrence of death or severe adverse event. The clustering analysis identified 3 clusters: Cluster 1 (n = 524, 35%) had the highest prevalence of previous percutaneous coronary intervention (PCI), the highest presence of myocardial scar on CMR, the lowest LVEF(35 ± 7%) and the highest degree of LV dilatation. Cluster 2 (n = 406, 27%) had the highest prevalence of previous coronary artery bypass grafting (CABG), preserved LVEF(54 ± 10%), absence of LV dilatation and rate of male(89%). Cluster 3 (n = 572, 38%) had the lowest rate of previous PCI/CABG and of myocardial scar. This cluster gathered the oldest patients (73 ± 11 years), predominantly female (60%), with the highest rate of atrial fibrillation and body mass index. Survival analysis found significant differences across clusters for the occurrence of MACE (p = 0.02). Moreover, inducible ischemia was significantly associated with the occurrence of MACE in each cluster (cluster 1, HR 2.28; [95%CI: 1.31-3.99]; p = 0.0028; cluster 2, HR 3.37; [95%CI, 1.97-5.75]; p &amp;lt; 0.0001; cluster 3, HR 2.73; [95%CI, 1.67-4.46]; p &amp;lt; 0.0001). In multivariable Cox regression, inducible ischemia was an independent predictor of a higher incidence of MACE in each cluster (p &amp;lt; 0.001). CONCLUSIONS Cluster analysis identified 3 different phenotypes of patients with inconclusive stress test that were associated with distinct clinical and prognostic profiles. Within these clusters, CMR stress has an additional prognostic value to predict the occurrence of MACE. Abstract Figure. Kaplan-Meier for MACE in each cluster

Clustering for identification of patients with inconclusive non-invasive testing for ischaemia to detect coronary artery disease

Guidelines recommend performing a non-invasive testing for ischemia to diagnose coronary artery disease (CAD). However, these tests are frequently inconclusive (20–30%) and can lead to uncertainty about the likelihood of CAD. This population has been poorly studied because it is a heterogeneous population difficult to characterise. To characterise a population of patients with inconclusive test using an unsupervised classification algorithm, then to compare the prognosis of each clusters identified. Between 2008 and 2018, consecutive patients with inconclusive stress test to detect CAD prospectively referred for a second stress test were followed for major adverse cardiovascular events (MACE) defined as cardiac death or non-fatal myocardial infarction (MI). Inconclusive stress test was defined by stress echocardiography or nuclear stress testing with uncertain conclusion. Data were analysed by a hierarchical clustering on principal components (HCPC) to perform this unsupervised classification algorithm. Among baseline, clinical and CMR characteristics, 18 variables were used for the clustering of patients. Of 1502 patients with inconclusive stress test (61.9 ± 11.8 years, 59% men), 1397 (93%) completed the follow-up (median 5.5 ± 2.3 years). An unsupervised clustering analysis of those patients identified 3 clusters of phenotypes: cluster 1 ( n = 524, 35%) had the highest prevalence of previous PCI (59%), the highest presence of a myocardial scar defined by CMR (58%), the lowest LVEF (35 ± 7%) and the highest degree of LV dilatation (LVEDVi = 124 ± 25 mL/m 2 ). Cluster 2 ( n = 406, 27%) had the highest prevalence of previous CABG (82%), preserved LVEF (54 ± 10%), absence of LV dilatation (LVEDVi = 82 ± 20 mL/m 2 ), and presence of myocardial scar defined by CMR (52%). This cluster comprised predominantly male patients (89%), with the highest rate of dyslipidemia (81%) or hypertension (71%). Cluster 3 ( n = 572, 38%) had the lowest rate of previous CABG or PCI (9%) and the lowest rate of myocardial scar in CMR (6%). This cluster gathered the oldest patients (73 ± 11 years) and was predominantly female (60%) with the highest rate of atrial fibrillation (51%) or body mass index (31 ± 7.8 kg/m 2 ). Survival analysis found significant differences across clusters for the occurrence of MACE ( P = 0.02) et cardiovascular mortality ( P < 0.0001) ( Fig. 1 ). Using Cox proportional hazards modelling, clusters 1 (hazard ratio: 0.72; 95% confidence interval: 0.50 to 1.04) and 3 (hazard ratio: 0.62; 95% confidence interval: 0.30 to 1.25) had a similar prognostic, which was better than cluster 2 (HR: 1.00 [reference]). Cluster analysis of clinical and CMR variables identified 3 different phenotypes of patients with inconclusive stress test to detect CAD that were associated with distinct clinical and prognostic profiles.