Citations

Abstract Background The Global Leadership Initiative on Malnutrition (GLIM) approach to malnutrition diagnosis is based on assessment of three phenotypic (weight loss, low body mass index, and reduced skeletal muscle mass) and two etiologic (reduced food intake/assimilation and disease burden/inflammation) criteria, with diagnosis confirmed by fulfillment of any combination of at least one phenotypic and at least one etiologic criterion. The original GLIM description provided limited guidance regarding assessment of inflammation, and this has been a factor impeding further implementation of the GLIM criteria. We now seek to provide practical guidance for assessment of inflammation. Methods A GLIM‐constituted working group with 36 participants developed consensus‐based guidance through a modified Delphi review. A multiround review and revision process served to develop seven guidance statements. Results The final round of review was highly favorable, with 99% overall “agree” or “strongly agree” responses. The presence of acute or chronic disease, infection, or injury that is usually associated with inflammatory activity may be used to fulfill the GLIM disease burden/inflammation criterion, without the need for laboratory confirmation. However, we recommend that recognition of underlying medical conditions commonly associated with inflammation be supported by C‐reactive protein (CRP) measurements when the contribution of inflammatory components is uncertain. Interpretation of CRP requires that consideration be given to the method, reference values, and units (milligrams per deciliter or milligram per liter) for the clinical laboratory that is being used. Conclusion Confirmation of inflammation should be guided by clinical judgment based on underlying diagnosis or condition, clinical signs, or CRP.

Background: The Schnur scale used body surface area (BSA) to determine the amount of breast tissue resection in reduction mammaplasty, resulting in a greater requirement of breast weight removal in patients with larger BSA. The authors aimed to demonstrate BSA variance among women with similar mastectomy weights and the range of mastectomy weights among women with comparable BSAs. Methods: A retrospective chart review of patients who underwent mastectomy from October of 2021 to June of 2022 was performed. Patients were included if they underwent skin-sparing or nipple-sparing mastectomy with a minimum specimen weight of 700 g. Patient’s BSA, body mass index (BMI), mastectomy weight, and Schnur weight requirement (SWR) were collected. Results: A total of 130 patients (194 breasts) were included. There was significant variance in mean BSA, BMI, SWR, and SWR-to–mastectomy weight ratio among women with similar mastectomy weights. BSA varied by as much as 0.82 units, BMI varied by as much as 32 kg/m2, and SWR varied by as much as 1365 g within the same mastectomy weight group. There was also significant variance in mastectomy weights among women with comparable BSA, especially in BSA groups greater than 2.20, with the greatest range in mastectomy weights being 1684 g. Conclusions: Analysis of mastectomy patients showed no predictable relationship between BSA and breast weight. There was significant variance in the BSA of patients with similar breast weights, and conversely in breast weights of patients with comparable BSA. Therefore, strict adherence to the Schnur weight requirement can prevent patients with macromastia from receiving breast reductions.

AbstractBackgroundStructural variants range from simple loss or gain of genetic material to complex events that restructure entire chromosomes. This heterogeneity coupled with variant size greater than sequencing read‐length makes structural variant mapping from short‐read sequencing data difficult and error‐prone. Consequently, the role of structural variants is poorly explored in many phenotypes, including dementia.MethodWe used the GATK‐SV pipeline that combines four external structural variant mapping algorithms with machine‐learning to build high‐quality consensus structural variant calls. We applied GATK‐SV to short‐read whole‐genome sequencing data of 2,601 frontotemporal dementia‐amyotrophic lateral sclerosis spectrum (FTD/ALS) patients, 2,612 Lewy body dementia (LBD) patients, and 4,132 neurologically unaffected participants.ResultAfter stringent quality‐control, we performed genome‐wide association studies on 2,307 ALS/FTD patients versus 3,677 controls with 4,699 common structural variants and 2,355 LBD patients versus 3,700 controls with 4,889 common structural variants. In the FTD/ALS cohort, we identified well‐known risk variants at the C9orf72 (p‐value = 4.99×10‐18, OR = 14.47, 95% CI = 7.90–26.49) and MAPT loci (p‐value = 3.48×10‐6, OR = 0.77, 95% CI = 0.68–0.86) corroborating the ability of our pipeline to identify disease‐associated structural variants. Moreover, we discovered, replicated, and validated TPCN1 as a novel risk locus for LBD (p‐value = 9.18×10‐6, OR = 1.43, 95% CI = 1.22–1.67). Further, we identified rare exonic variants with known pathogenic or likely pathogenic effects, such as an SNCA gene duplication in LBD and a deletion of exons 1 and 2 in CHCHD10 in FTD/ALS. We additionally observed structural variants in regulatory regions, e.g. a deletion of a key PSEN2 enhancer, which resulted in an approximate 0.70 fold‐change in PSEN2 expression in LBD. Finally, we built an interactive web app where structural variants can be visualized and explored (https://ndru-ndrs-lng-nih.shinyapps.io/non_ad_dementias_sv_app/).ConclusionCommon and rare structural variants play a role in LBD and FTD/ALS. Our structural variant resource is publicly available and can be used to further explore the role of structural variants in LBD and FTD/ALS.

AbstractBackgroundContext‐specific networks can capture functionally important genes that may not be differentially expressed. Leveraging seven different gene expression datasets of Alzheimer’s disease (AD) and healthy control brains, we constructed a novel pipeline that includes such network analysis, augmented by in vivo validations and in silico drug repurposing to facilitate prioritization of AD therapeutic targets.MethodWe utilized publicly available gene expression data from 733 AD and 454 control brains across 7 datasets and the NetDecoder (PMID: 26975659) network biology platform to build context‐specific networks. Based on the known protein‐protein interaction and gene expression correlations, information flow from the top differentially expressed genes (DEG) to transcriptional regulator genes was calculated using a process‐guided flow algorithm. Genes with the greatest informational flow changes across AD cohorts were systematically prioritized. We next validated these genes in a medium‐throughput screen of a tau‐transgenic Drosophila model (PMID: 11408621). Further, we identified existing small‐molecule drugs to target the candidate genes utilizing curated databases.ResultsA total of 14 context‐specific networks were constructed across 7 datasets. We found AD‐related genes, such as APP, to have high flow differences between AD and control networks and high connectivity. Notably, many such genes were not DEGs between AD and control, suggesting that the information flow captures novel aspects of AD pathophysiology. We nominated 224 unique genes with the greatest flow differences for functional validation. We screened 111 of the 224 candidate genes with readily available, high‐confidence orthologs in Drosophila. We identified genes that suppress (N = 68) or enhance (N = 27) tau‐related neurodegeneration in this model. We confirmed the effects of previously nominated genes, such as HDAC1, which enhances tau‐neurodegeneration if overexpressed and suppresses it if knocked down. We also identified and validated additional therapeutic targets. Lastly, we applied a network‐proximity‐based algorithm and identified small molecule drugs for the candidate genes.ConclusionWe present a novel pipeline that integrates analytic approaches, experimental validation, and drug repurposing to facilitate therapeutic discovery in AD. We applied this pipeline and nominated previously known and novel genes implicated in AD pathogenesis. Our pipeline demonstrates a cross‐species, systems‐level approach to therapeutic nomination in AD and related neurodegenerative diseases.

Abstract The Heidenhain variant of Creutzfeld-Jakob disease (CJD) is a rare form that initially presents with visual disturbances. In early stages, the presentation can mimic neuromyelitis optica spectrum disorders (NMOSD) and lead to unnecessary treatment modalities. Herein, we describe a case of a 66-year-old man who presented with bilateral vision loss and retro-orbital discomfort. In addition to immunosuppressive therapy, he received 4 rounds of therapeutic plasma exchange after his preliminary diagnosis of NMOSD. We were surprised to note that his condition did not show improvement but deteriorated, with severe neurocognitive symptoms. Eventually, CJD was suspected, and real-time quaking-induced conversion (RT-QuIC) was performed. By the time the diagnosis of Heidenhain variant of CJD was confirmed, the patient was discharged to hospice care and died shortly after.

Background: Clinically significant tricuspid regurgitation (TR) is an important contributor to morbidity and mortality. The Tricuspid Regurgitation Impact on Outcomes (TRIO) score based on 8 parameters (age, gender, chronic heart failure, chronic lung disease, heart rate, creatinine, aspartate transaminase level, and TR severity) is used for risk stratification. The performance of the TRIO score in patients with TR secondary to severe pulmonary hypertension (PH) is unknown. Research Questions: To evaluate whether the TRIO score can be applied in patients with TR and pulmonary hypertension (PH), and to identify other predictors of mortality. Methods: Retrospective study including patients with TR ≥ moderate. Severe PH was defined as right ventricular systolic pressure (RVSP) ≥50 mmHg. The impact of clinical, echocardiographic and laboratory variables on mortality was evaluated with the Cox proportional hazard method. Results: A total of 13,482 patients from the TRIO population were included; severe PH was present in 6,530 (48.4%); mean age 73.4 + 13.3, 55.7% females. TRIO score performance was modest (AUC 0.62) in risk stratification (Figure A). PH patients had significantly higher mortality than those without PH at all levels of TRIO score (Figure B); differences were progressively lower with increasing TRIO scores. At multivariate analysis, only TRIO score [HR = 1.54 (1.35-1.77) per unit change], presence of an elevated NT-proBNP [HR = 1.02 (1.02-1.03) per 1000 pg/ml change], RVSP (HR = 1.08 (1.02-1.16) per 10 mmHg change], presence of RV dysfunction [HR = 1.15, (1.05-1.26)] and pulmonary artery pulsatility index (PAPi) ≤ 4 [HR = 1.34 (1.07-1.67)] were significant predictors of mortality (model AUC 0.65). Conclusions: TRIO score allows risk stratification in PH patients, but performance is modest; incorporating additional factors marginally increased model performance. PH patients have higher mortality at all levels of TRIO score, more so at low scores.

Introduction: Tricuspid regurgitation is a common echocardiographic finding leading to excess morbidity and mortality in adult population. Hypothesis: Racial and ethnic disparities have been observed in various cardiovascular disorders’ prevalence and natural course, including valvular lesions. However, little is known about the epidemiology and clinical correlations of TR among non-Hispanic Black adults. Methods: To examine risk factors and clinical outcomes in non-Hispanic Black adults with moderate or more severe TR, 685 patients (7%) self-identified as non-Hispanic Black and 9127 (93%) self-identified as non-Hispanic White with a first echocardiographic report of moderate or more severe TR between 2005-2016 were studied. Results: Non-Hispanic Black patients had more severe TR when compared to white patients (25% vs. 20%, p<0.001). After adjusting for age and sex, non-Hispanic Black patients had significantly higher 10-year all-cause mortality (HR=1.34 (1.18, 1.52), p<0.001). Black race remained a risk factor for all-cause mortality even after adjustment for comorbidities like CHF, COPD, DM, CKD, hypertension, and ischemic heart disease (HR=1.23 (1.08, 1.40), p=0.002). Conclusions: Significant racial disparities exist in demographic, clinical and echocardiographic characteristics between non-Hispanic Black and White patients with moderate or more severe TR. Black race is a potential disease modifier leading to excess mortality.