“Ozempic Face”: Construct, Consequence, or Clinical Entity?

IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.

Background: Self-reported racial classification is often used as a proxy for phenotypic differences among clinical populations. We demonstrate an approach to identify differences between Black and White individuals using clinical notes among patients hospitalized with heart failure (HF). Methods: We identified HF hospitalizations for patients at Yale and developed a word frequency embedding (TF-IDF)-based natural language processing (NLP) model on clinical notes to classify “tokens” or words from notes of Black and White individuals based on their frequency. We manually classified these tokens into clinical and non-clinical entities. We evaluated the frequency of clinical tokens successfully identified in ICD diagnosis codes and qualitatively assessed non-clinical tokens for stigmatizing language across Black and White patients. Results: There were 8798 patients (mean age 81±13y, 50% female) with a total of 14,655 unique patient encounters. Of these, 4293 were for Black patients. The NLP-based model determined Black vs White race of patients based only on notes with an AUROC of 0.92 after removing all explicit mentions of race. Of the top 80 tokens that identified Black vs White patients from notes, 53 (66%) were identified as clinical entities. The clinical tokens were underrepresented in structured ICD diagnosis for both Black and White, with a median 88% (IQR=27%, Q1=66%, Q3=94%) of Black-identifying tokens defining clinical conditions and 72% (IQR=45%, Q1=43%, Q3=89%) for White-identifying tokens. Among non-clinical tokens, there was a greater occurrence of stigmatizing words in the notes of Black patients (40% vs 32% in White). Conclusion: We demonstrate that an NLP-based approach can better define clinical differences between Black and White patients, and can be used to screen for stigmatizing language against Black and other minority groups.

Acute drug-induced hypertension, sympathomimetic toxicity, and other hyperadrenergic states can be caused by both xenobiotic toxicity and withdrawal. This manuscript is a selective review of the recent literature regarding pharmacologic causes of hypertensive emergencies and other hyperadrenergic states. We will discuss designer stimulants, alpha2 and baclofen agonist withdrawal, and the clinical entity known as posterior reversible encephalopathy syndrome (PRES). Additionally, we examine the controversial "unopposed alpha" phenomenon which may result from use of beta-adrenergic antagonist in the presence of stimulant toxicity. These topics encompass clinical situations and disease entities that are increasingly encountered and are often either unanticipated or under-recognized.

Pottier C, Mateiu L, Baker MC, et al. Shared brain transcriptomic signature in TDP-43 type A FTLD patients with or without GRN mutations. Brain 2022;145(7):2472–2485. doi: 10.1093/brain/awab437. The clinical disorders caused by frontotemporal lobar degeneration pathologies (FTLD) are highly heterogeneous in their pathology and phenotypes. Patients are typically diagnosed as having one of several clinical entities defined by specific clinical criteria, including behavioral variant frontotemporal dementia, primary progressive aphasia, progressive supranuclear palsy or corticobasal syndrome.1 The clinicopathological correlations of these syndromes are often imprecise.2 The main pathology observed in FTLD patients is FTLD-TDP, named after the TDP-43 protein aggregates found in the brain. According to the type and localization of TDP-43 aggregates in the cortical layers, FTLD-TDP is classified into five pathological subtypes A to E, with A to C being the most common. A wide range of clinical phenotypes has been associated with FTLD-TDP-A pathology.3 Patients harboring mutations in the gene encoding progranulin (GRN) invariably present with FTLD-TDP-A pathology. However, the majority of FTLD-TDP-A patients does not carry GRN mutations and remain genetically unexplained. Recently, Pottier et al explored transcriptional changes underlying FTLD-TDP, performing RNA-sequencing on 66 genetically unexplained FTLD-TDP patients (including 24 FTLD-TDP-A, 20 FTLD-TDP-B and 22 FTLD-TDP-C), 24 FTLD-TDP patients with GRN mutations and 24 control participants.4 Using an unbiased approach, the authors showed that GRN mutation carriers and FTLD-TDP-A patients without a known mutation shared a common transcriptional signature that was independent of GRN loss-of-function. Lumping both such groups and comparing them to the control group showed they presented a distinct alteration of processes related to immune response, synaptic transmission, RNA metabolism, angiogenesis and vesicle-mediated transport. FTLD-TDP-A and GRN mutation carriers also presented common frontal cortex cellular composition as well as similar GABAergic, GDNF and sphingolipid pathways. Finally, the authors reported increased GRN expression in frontal cortex of FTLD-TDP-A compared to GRN mutation carriers suggesting that the shared transcriptomic profile is independent and likely downstream of loss of GRN.4 In spite of some limitations, including a limited sample size and the focus on a single affected brain region, still this study reports for the first time a shared transcriptional signature in the frontal cortex of FTLD-TDP-A patients with and without GRN mutations providing new avenues for research and suggesting potentially new therapeutic targets. Furthermore, such findings may have implications for other common neurodegenerative disorders, as TDP-43 pathology is present in late-onset Alzheimer's disease. Recent studies using a transdiagnostic approach to the spectrum of FTLD identified overlapping clinical features and patterns of covarying brain atrophy across the discrete diagnostic entities.1 Complementary, applying a genetic screening to patients with a syndromic characterization beyond the boundaries of clinical entities can expand the phenotypic spectrum associated to several known disease-genes.5 Expanding previous evidence, Pottier et al showed shared alterations in FTLD-TDP-A and GRN mutation carriers in different pathways potentially common to other neurodegenerative diseases. Within the deconvoluted microglia the authors highlighted the GDNF signaling pathway, crucial for microglial activation in several neurological disorders including Parkinson's disease.4 Similarly, NSF and S1PR3 play significant roles within the GABAergic and sphingolipids pathways respectively.4 Disclosing new common druggable pathways across different clinical and genetic entities may foster the implementation of new drugs within the framework of basket trials and represent the way forward the discovery of disease-modifying treatments for neurodegenerative diseases. (1) Research project: A. Conception, B. Organization, C. Execution; (2) Statistical Analysis: A. Design, B. Execution, C. Review and Critique; (3) Manuscript Preparation: A. Writing of the first draft, B. Review and Critique. M.P.: 1A, 1B, 1C, 3A. P.B.: 3B. Ethical Compliance Statement: We confirm that we have read the Journal's position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Neither patient consent nor IRB approval was required for this work. Funding Sources and Conflicts of Interest: There are no specific funding sources for the present report. The authors declare that there are no conflicts of interest relevant to this work. Financial Disclosures for the Previous 12 Months: Dr Marina Picillo is supported by the Michael J. Fox Foundation for Parkinson's research; Prof Paolo Barone received consultancies as a member of the advisory board for Zambon, Lundbeck, UCB, Chiesi, Abbvie and Acorda.

Renal Artery Stenosis Due To Entrapment

Background: In a study that has been done five years ago, it was reported that too few of healthcare workers were aware of abdominal obesity and metabolic syndrome (MetS) as a clinical entity. The aim of this study was to evaluate if any difference in abdominal obesity and MetS awareness in healthcare staff working in the same hospitals was occurred in the past 5 years. Methods : A total of 731 healthcare workers (physicians: 262, nurses: 199, other healthcare staff: 270, mean age: 32.17 ± 8.0) were enrolled. Demographic, anthropometric, and biochemical data were recorded. International Diabetes Federation (IDF) criteria were used for abdominal obesity and MetS assessment. Results : The frequency of abdominal obesity and awareness of abdominal obesity was 32.5% (36.6% in women, 29.7% in men, P = 0.050) and 16.7% (18.7% in physicians, 9.6% in nurses, 3.8% in other healthcare staff, P = 0.001) respectively. The awareness of MetS as a clinical entity was 31.3% (78.6% in physicians, 11.1% in nurses, 0.4% in other healthcare staff, P = 0.001). The frequency of MetS was 6.1% (3.7% in women, 10% in men, P = 0.015). Conclusions: In this research, it has been found out that for the past five years, still very few of the healthcare workers are aware of the MetS and abdominal obesity as a clinical entity. J Endocrinol Metab. 2013;3(3):57-61 doi: https://doi.org/10.4021/jem176w

Clinical notes make a large part of Electronic Health Records (EHR). While applying large and automated analysis on unstructured clinical notes can be much more complex than on structured data, it can potentially provide better support and information for medical decision-making. In this paper, we propose a methodology to identify clinical entities and their associations that are widely exist across multiple types of clinical notes. The focus of this research is to discover patterns of significant relationships amongst clinical entities, such as treatments, tests, and diagnoses, particularly in clinical notes within EHR. Extracting clinical entities associations from clinical notes is a crucial task for many applications in clinical and public health informatics. We utilize population-level data to discover knowledge sets which can help health providers during their assessments for patients. We incorporate Natural Language Processing, text mining, and weighted association rule mining techniques in building a pipeline to transform clinical notes into knowledge set. Our preliminary results with proposed weighted clinical transactional itemset representation show promising results in identifying strongly related clinical entities. We evaluated our results with labeled data from a healthcare professional with an accuracy of 98.3% on the relevancy task and 54.4% of rules are labeled as interesting and worth further clinical investigation. We discovered patterns of patients developing secondary problems during their length of stay at a hospital.

Background12q14 microdeletion syndrome is characterized by low birth weight and failure to thrive, proportionate short stature and developmental delay. The opposite syndrome (microduplication) has not yet been characterized. Our main objective is the recognition of a new clinical entity - 12q14 microduplication syndrome. - as well as confirming the role of HMGA2 gene in growth regulation.Case presentationArray Comparative Genomic Hybridization (CGH), Karyotype, Fluorescence in situ Hybridization, Quantitative-PCR analysis and Whole exome sequencing (WES) were performed in a girl presenting overgrowth and obesity. Array CGH identified a 1.5 Mb 12q14.3 microduplication involving HMGA2, GRIP1, IRAK3, MSRB3 and TMBIM4 genes. Karyotype and FISH showed that duplication was a de novo insertion of 12q14.3 region on chromosome 9p resulting in an interstitial microduplication. Q-PCR confirmed the duplication only in the proband. WES revealed no pathogenic variants.ConclusionsPhenotypic comparison with patients with 12q14 microdeletion syndrome showed a reciprocal presentation, suggesting a phenotypically recognizable 12q14 microduplication syndrome as well as confirming the role of HMGA2 gene in growth regulation. It is also indicative that other genes, such as IRAK3 and MSRB3 might have of role in weight gain and obesity.

Myalgic encephalomyelitis (ME), described in the medical literature since 1938, is characterized by distinctive muscular symptoms, neurological symptoms, and signs of circulatory impairment. The only mandatory feature of chronic fatigue syndrome (CFS), introduced in 1988 and redefined in 1994, is chronic fatigue, which should be accompanied by at least four or more out of eight “additional” symptoms. The use of the abstract, polythetic criteria of CFS, which define a heterogeneous patient population, and self-report has hampered both scientific progress and accurate diagnosis. To resolve the “diagnostic impasse” the Institute of Medicine proposes that a new clinical entity, systemic exercise intolerance disease (SEID), should replace the clinical entities ME and CFS. However, adopting SEID and its defining symptoms, does not resolve methodological and diagnostic issues. Firstly, a new diagnostic entity cannot replace two distinct, partially overlapping, clinical entities such as ME and CFS. Secondly, due to the nature of the diagnostic criteria, the employment of self-report, and the lack of criteria to exclude patients with other conditions, the SEID criteria seem to select an even more heterogeneous patient population, causing additional diagnostic confusion. This article discusses methodological and diagnostic issues related to SEID and proposes a methodological solution for the current “diagnostic impasse”.

Chromosomal rearrangements in the short arm of chromosome 4 can result in 2 different clinical entities: Wolf-Hirschhorn syndrome (WHS), characterized by severe growth delay, mental retardation, microcephaly, ‘Greek helmet’ facies, and closure defects, or partial 4p trisomy, associated with multiple congenital anomalies, mental retardation, and facial dysmorphisms. We present clinical and laboratory findings in a patient who showed a small duplication in 4p16.3 associated with a subtle terminal deletion in the same chromosomal region. GTG-banding analyses, multiplex ligation-dependent probe amplification analyses, and studies by array-based comparative genomic hybridization were performed. The results of the analyses revealed a de novo 1.3 Mb deletion of the terminal 4p and a 1.1 Mb duplication in our patient, encompassing the WHS critical region. Interestingly, this unusual duplication/deletion rearrangement results in an intermediate phenotype that shares characteristics of the WHS and the 4p trisomy syndrome. The use of novel technologies in the genetic diagnosis leads to the description of new clinical syndromes; there is a growing list of microduplication syndromes. Therefore, we propose that overexpression of candidate genes in WHS (WHSC1, WHSC2 and LETM1) due to a duplication causes a clinical entity different to both the WHS and 4p trisomy syndrome.

Takotsubo cardiomyopathy: a hidden enemy of the hypovolemic patient?

A New Classification of Pulmonary Hypertension

To obtain detailed information on current prescribing rates of antibiotics for respiratory tract infections (RTIs) in Dutch general practice and its relation with age and respiratory tract clinical entities. We assessed the mean proportion of antibiotics prescribed for RTIs per age group, contact-based and population-based using all patient contacts concerning RTIs in the year 2000 selected from the IPCI database, containing information on general practice consultations of 235,290 patients. In one-third of all contacts concerning RTIs, antibiotics were prescribed, with much variation between age groups and clinical entities. For children (0-15 years) and the elderly (over 75 years), the lowest contact-based percentages of prescribed antibiotics for RTIs were found, while population-based, children of age 0-5 years received far more antibiotics for RTIs. High prescribing rates were seen in patients with sinusitis-like complaints (67%) or pneumonia (78%), whereas low rates were found for patients with upper RTIs (16%). Potential over-prescribing of antibiotics for RTIs occurs in the age group 31-65 years, not in children and the elderly, and in patients with upper RTIs, sinusitis and most likely acute bronchitis (contact-based). The management of these subgroups of patients should be addressed in quality assurance programmes. Children and the elderly visit the GP much more often than adults, which can be explained by more frequent (children) or more severe (elderly) RTI morbidity, but in proportion they do not receive more antibiotics.

BackgroundClinical entity recognition as a fundamental task of clinical text processing has been attracted a great deal of attention during the last decade. However, most studies focus on clinical text in English rather than other languages. Recently, a few researchers have began to study entity recognition in Chinese clinical text.MethodsIn this paper, a novel deep neural network, called attention-based CNN-LSTM-CRF, is proposed to recognize entities in Chinese clinical text. Attention-based CNN-LSTM-CRF is an extension of LSTM-CRF by introducing a CNN (convolutional neural network) layer after the input layer to capture local context information of words of interest and an attention layer before the CRF layer to select relevant words in the same sentence.ResultsIn order to evaluate the proposed method, we compare it with other two currently popular methods, CRF (conditional random field) and LSTM-CRF, on two benchmark datasets. One of the datasets is publically available and only contains contiguous clinical entities, and the other one is constructed by us and contains contiguous and discontiguous clinical entities. Experimental results show that attention-based CNN-LSTM-CRF outperforms CRF and LSTM-CRF.ConclusionsCNN and attention mechanism are individually beneficial to LSTM-CRF-based Chinese clinical entity recognition system, no matter whether contiguous clinical entities are considered. The conribution of attention mechanism is greater than CNN.

Administrative databases are increasingly being used to construct health care report cards. We analyzed information from one of the original report cards, the Medicare Hospital Information Project. Assessment of mortality statistics for three clinical entities--coronary artery bypass surgery, hip reconstruction, and treatment of sepsis--demonstrated widespread outcome variances that reflected imperfect definitions rather than performance issues in clinical care. The use of administrative data sets to design report cards requires clinical expertise to ensure validity of the data. Designers of report card measures should share preliminary data with providers to enable feedback in methods and uncover definitional and validity concerns before widespread dissemination.