Childhood obesity and its adverse health consequences have risen worldwide, with low socioeconomic status increasing the risk in high-income countries like the US. Understanding the interplay between childhood obesity, cognition, socioeconomic factors, and the brain is crucial for prevention and treatment. Using data from the ABCD study, we investigated how body mass index (BMI) relates to brain structural and functional connectivity metrics. Obese/overweight children (n = 2,356) were more likely to live in poverty and exhibited lower cognitive performance compared to normal weight children (n = 4,754). Higher BMI was associated with multiple brain measures that were strongest for lower longitudinal diffusivity in corpus callosum, increased activity in cerebellum, insula, and somatomotor cortex, and decreased functional connectivity in multimodal brain areas, with effects more pronounced among children from low-income families. Notably, nearly 80% of the association of low income and 70% of the association of impaired cognition on BMI were mediated by higher brain activity in somatomotor areas. Increased resting activity in somatomotor areas and decreased structural and functional connectivity likely contribute to the higher risk of overweight/obesity among children from low-income families. Supporting low-income families and implementing educational interventions to improve cognition may promote healthy brain function and reduce the risk of obesity.
Dardo Tomasi, Nora D. Volkow
We evaluated the safety and viral rebound, after analytical treatment interruption (ATI), of vedolizumab and ART in recent HIV-1 infection. We used this model to analyze the impact of α4β7 on the HIV-1 reservoir size. Participants started ART with monthly Vedolizumab infusions and ATI was performed at week 24. Biopsies were obtained from ileum and caecum at baseline and week 24. Vedolizumab levels, HIV-1 reservoir, flow cytometry and cell-sorting and antibody competition experiments were assayed. Vedolizumab was safe and well-tolerated. No participant achieved undetectable viremia off ART 24 weeks after ATI. Only a modest effect on the time to achieve >1000 HIV-RNA copies/mL and the proportion of participants off ART was observed, being higher compared to historical controls. Just before ATI, α4β7 expression was associated with HIV-1 DNA and RNA in peripheral blood and with PD1 and TIGIT levels. Importantly, a complete blocking of α4β7 was observed on peripheral CD4+ T-cells but not in gut (ileum and caecum), where α4β7 blockade and vedolizumab levels were inversely associated with HIV-1 DNA. Our findings support α4β7 as an important determinant in HIV-1 reservoir size, suggesting the complete α4β7 blockade in tissue as a promising tool for HIV-cure combination strategies.
Maria Reyes Jimenez-Leon, Carmen Gasca-Capote, Cristina Roca-Oporto, Nuria Espinosa, Salvador Sobrino, Maria Fontillon-Alberdi, Ce Gao, Isabelle Roseto, Gregory Gladkov, Inmaculada Rivas-Jeremias, Karin Neukam, Jose German Sanchez-Hernandez, Raul Rigo-Bonnin, Antonio J. Cervera-Barajas, Rosario Mesones, Federico García, Ana Isabel Alvarez-Rios, Sara Bachiller, Joana Vitalle, Alberto Perez-Gomez, María Inés Camacho-Sojo, Isabel Gallego, Christian Brander, Ian McGowan, Beatriz Mothe, Pompeyo Viciana, Xu Yu, Mathias Lichterfeld, Luis F. Lopez-Cortes, Ezequiel Ruiz-Mateos
Background Glycogen storage disease type IV (GSD IV) is an ultrarare autosomal recessive disorder that causes deficiency of functional glycogen branching enzyme and formation of abnormally structured glycogen termed polyglucosan. GSD IV has traditionally been categorized based on primary hepatic or neuromuscular involvement, with hepatic GSD IV subclassified as discrete subtypes: classic (progressive) and nonprogressive.Methods To better understand the progression of liver disease in GSD IV, we present clinical and histopathology data from 23 patients from around the world and characterized the liver involvement in the Gbe1ys/ys knockin mouse model.Results We propose an alternative to the established subtype-based terminology for characterizing liver disease in GSD IV and recognize 3 tiers of disease severity: (i) “severe progressive” liver disease, (ii) “intermediate progressive” liver disease, and (iii) “attenuated” liver disease. Analysis of liver pathology revealed that risk for liver failure cannot be predicted from liver biopsy findings alone in individuals affected by GSD IV. Moreover, analysis of postmortem liver pathology from an individual who died over 40 years after being diagnosed with nonprogressive hepatic GSD IV in childhood verified that liver fibrosis did not regress. Last, characterization of the liver involvement in a mouse model known to recapitulate the adult-onset neurodegenerative form of GSD IV (Gbe1ys/ys mouse model) demonstrated hepatic disease.Conclusion Our findings challenge the established subtype-based view of GSD IV and suggest that liver disease severity among patients with GSD IV represents a disease continuum.Trial registration ClinicalTrials.gov NCT02683512Funding None
Rebecca L. Koch, Bridget T. Kiely, Su Jin Choi, William R. Jeck, Leticia S. Flores, Vikrant Sood, Seema Alam, Gilda Porta, Katy LaVecchio, Claudia Soler-Alfonso, Priya S. Kishnani
BACKGROUND. Identifying patients with acute kidney injury (AKI) who are at higher risk of chronic kidney disease (CKD) progression at time of AKI diagnosis remains a major challenge in clinical practice. METHODS. Kidney transcriptome sequencing was applied to identify the top up-regulated genes in mice with AKI. The product of the top-ranked gene was identified in the tubular cells and urine both in mouse and human AKI. Data from two cohorts of patients with a prehospitalization estimated glomerular filtration rate (eGFR) ≥ 45 ml/min/1.73m2 who survived for at least 90 days after AKI were used to derive and validate multivariable prediction models. AKI to CKD progression was defined as a persistent eGFR < 60 ml/min/1.73m2 and with a minimum 25% reduction from baseline eGFR 90 days after AKI in patients with prehospitalization eGFR ≥ 60 ml/min/1.73m2. AKI to advanced CKD was defined by a sustained reduction of eGFR < 30 ml/min/1.73m2 90 days after AKI in those with prehospitalization eGFR 45–60 ml/min/1.73m2. RESULTS. Kidney cytokeratin 20 (CK20) was up-regulated in injured proximal tubular cells and detectable in urine within 7 days after AKI. High concentrations of urinary CK20 (uCK20) were independently associated with the severity of histological AKI and the risk of AKI to CKD or advanced CKD progression. In Test set, the AUC of uCK20 for predicting AKI to CKD or advanced CKD was 0.80, outperformed currently used biomarkers for detecting kidney tubular injury. Addition of uCK20 to an established clinical model improved the ability for predicting AKI-CKD progression with an AUC of 0.90, and largely improved the risk reclassification. CONCLUSION. This finding highlighted uCK20 as a useful predictor for AKI to CKD progression, and may provide a tool to early identify patients at high risk of CKD following AKI. FUNDING. The National Natural Science Foundation of China (Key Program).
Rui Ma, Han Ouyang, Shihong Meng, Jun Liu, Jianwei Tian, Nan Jia, Youhua Liu, Xin Xu, Xiaobing Yang, Fan Fan Hou
BACKGROUND Persistent cough and dyspnea are prominent features of post-acute sequelae of SARS-CoV-2 (also termed ’Long COVID’); however, physiologic measures and clinical features associated with these pulmonary symptoms remain poorly defined. Using longitudinal pulmonary function testing (PFTs) and CT imaging, this study aimed to identify the characteristics and determinants of pulmonary Long COVID. METHODS This single-center retrospective study included 1,097 patients with clinically defined Long COVID characterized by persistent pulmonary symptoms (dyspnea, cough, and chest discomfort) lasting for ≥1 month after resolution of primary COVID infection. RESULTS After exclusion, a total of 929 patients with post-COVID pulmonary symptoms and PFTs were stratified diffusion impairment and restriction as measured by percent predicted diffusion capacity for carbon monoxide (DLCO) and total lung capacity (TLC). Dyspnea was the predominant symptom in the cohort (78%) and had similar prevalence regardless of degree of diffusion impairment or restriction. Longitudinal evaluation revealed diffusion impairment (DLCO ≤80%) and pulmonary restriction (TLC ≤80%) in 51% of the cohort overall (n=479). In multivariable logistic regression analysis (adjusted odds ratio; aOR, 95% confidence interval [CI]), invasive mechanical ventilation during primary infection conferred the greatest increased odds of developing pulmonary Long COVID with diffusion impairment and restriction (aOR=10.9 [4.09-28.6]). Finally, a sub-analysis of CT imaging identified radiographic evidence of fibrosis in this patient population. CONCLUSIONS Longitudinal PFT measurements in patients with prolonged pulmonary symptoms after SARS-CoV-2 infection revealed persistent diffusion impaired restriction as a key feature of pulmonary Long COVID. These results emphasize the importance of incorporating PFTs into routine clinical practice for evaluation of patients with prolonged pulmonary symptoms after resolution of SARS-CoV-2. Subsequent clinical trials should leverage combined symptomatic and quantitative PFT measurements for more targeted enrollment of pulmonary Long COVID patients. FUNDING This work was supported by the National Institute of Allergy and Infectious Diseases (AI156898, K08AI129705), the National Heart, Lung, and Blood Institute (HL153113, OTA21-015E, HL149944), and the COVID-19 Urgent Research Response Fund established by the Hugh Kaul Precision Medicine Network at the University of Alabama at Birmingham.
Michael John Patton, Donald Benson, Sarah W. Robison, Dhaval Raval, Morgan L. Locy, Kinner Patel, Scott Grumley, Emily B. Levitan, Peter Morris, Matthew Might, Amit Gaggar, Nathaniel Erdmann
Background. Disease of the aorta varies from atherosclerosis to aneurysms with complications including rupture, dissection, and poorly characterized limited tears. We studied limited tears without any mural hematoma, termed intimomedial tears to gain insight into aortic vulnerability to excessive wall stresses. Our premise is that minimal injuries in aortas with sufficient medial resilience to prevent tear progression correspond to initial mechanisms leading to complete structural failure in aortas with significantly compromised medial resilience. Methods. Intimomedial tears were macroscopically identified in 9 of 108 ascending aortas after surgery and analyzed by histology and immunofluorescence confocal microscopy. Results. Non-hemorrhagic, non atheromatous tears correlated with advanced aneurysmal disease and most lacked distinctive symptoms or radiological signs. Tears traversed the intima and part of the subjacent media, while the resultant defects were partially or completely filled with neointima characterized by differentiated smooth muscle cells, scattered leukocytes, dense fibrosis, and absent elastic laminae despite tropoelastin synthesis. Healed lesions contained organized fibrin at tear edges without evidence of plasma and erythrocyte extravasation or lipid accumulation. Conclusion. These findings suggest a multiphasic model of aortic wall failure in which primary lesions of intimomedial tears either heal if the media is sufficiently resilient or progress as dissection or rupture by medial delamination and tear completion, respectively. Moreover, mural incorporation of thrombus and cellular responses to injury, two historically important concepts in atheroma pathogenesis, contribute to vessel wall repair with adequate conduit function but even together are not sufficient to induce atherosclerosis. Funding. R01-HL146723, R01-HL168473, and Yale Department of Surgery.
Abdulrahman H.M. Hassab, David J. Hur, Prashanth Vallabhajosyula, George Tellides, Roland Assi
BACKGROUND Differentiating malignant from nonmalignant body fluids remains a clinical challenge because of the unsatisfying performance of conventional cytology. We aimed to improve the sensitivity and ubiquity of cancer cell detection by assaying universal cancer–only methylation (UCOM) markers in supernatant cell-free DNA (cfDNA).METHODS An observational prospective cohort including 1,321 nonmalignant and malignant body fluids of multiple cancers was used to develop and validate a cfDNA UCOM methylation diagnostic assay. All samples were divided into 2 portions for cytology and supernatant cfDNA methylation analysis.RESULTS The significant hypermethylation of a potentially novel UCOM marker, TAGMe, together with the formerly reported PCDHGB7, was identified in the cfDNA of malignant body fluid samples. The combined model, cell-free cancer-universal methylation (CUE), was developed and validated in a prospective multicancer cohort with markedly elevated sensitivity and specificity, and was further verified in a set containing additional types of malignant body fluids and metastases. In addition, it remained hypersensitive in detecting cancer cells in cytologically negative malignant samples.CONCLUSION cfDNA methylation markers are robust in detecting tumor cells and are applicable to diverse body fluids and tumor types, providing a feasible complement to current cytology-based diagnostic analyses.TRIAL REGISTRATION This study was registered at Chictr.org.cn (ChiCTR2200060532).FUNDING National Natural Science Foundation of China (32270645, 31872814, 32000505, 82170088), the National Key R&D Program of Ningxia Hui Autonomous region (2022BEG01003), Shanghai Municipal Key Clinical Specialty (shslczdzk02201), Science and Technology Commission of Shanghai Municipality (20DZ2261200, 20DZ2254400), and Major Special Projects of Basic Research of Shanghai Science and Technology Commission (18JC1411101).
Zhanrui Mao, Shihua Dong, Yu Yan, Chengyang Wang, Wei Li, Lu Wang, Chengchen Qian, Yuanlin Song, Lin Tong, Wenqiang Yu
BACKGROUND Intrinsic molecular subtypes define distinct biological breast cancers and can be used to further improve diagnosis and risk allocation.METHODS The Copenhagen Breast Cancer Genomics Study (CBCGS) prospectively included women diagnosed with breast cancer at Rigshospitalet from 2014 to 2021. Eligible patients were females with a primary invasive breast cancer (T1c, if N0M0; otherwise, any T, any N, or any M stage) and no prior malignancy. All patients underwent molecular profiling with the CIT256 and PAM50 molecular profile.RESULTS In the study period, 2,816 patients were included in the CBCGS. Molecular subtyping showed an increase in nonluminal (molecular-apocrine, luminal C, and Basal-like) as compared with luminal (luminal A, luminal B, and Normal-like) subtypes with increasing stage from I to IV. Across all stages, we found a significant difference in survival among subtypes; 91% of patients with LumA were alive at 5 years compared with 91% for LumB, 84% for LumC, 82% for mApo, and 80% for Basal-like. We identified 442 tumors (16%) that were discordant in subtype between CIT256 and IHC. Discordant subtype proved to be a risk factor of death among patients with IHC luminal breast cancer (hazard ratio [HR], 2.08; 95% CI, 1.51–2.86) in a multivariable Cox regression analysis. Discordance occurred more often among patients with N3, stage IV, or grade III disease.CONCLUSION Our findings indicate that molecular subtypes are a predominant classification for survival. Assessment is particularly crucial for patients with IHC luminal breast cancer with known high-risk factors, since they are at an increased risk of harboring an aggressive molecular subtype.
Tobias Berg, Maj-Britt Jensen, Alan Celik, Maj-Lis Talman, Maria Anna Misiakou, Ann Søegaard Knoop, Finn Cilius Nielsen, Bent Ejlertsen, Maria Rossing
BACKGROUND Diagnosis of PMM2-CDG, the most common congenital disorder of glycosylation (CDG), relies on measuring carbohydrate-deficient transferrin (CDT) and genetic testing. CDT tests have false negatives and may normalize with age. Site-specific changes in protein N-glycosylation have not been reported in sera in PMM2-CDG.METHODS Using multistep mass spectrometry–based N-glycoproteomics, we analyzed sera from 72 individuals to discover and validate glycopeptide alterations. We performed comprehensive tandem mass tag–based discovery experiments in well-characterized patients and controls. Next, we developed a method for rapid profiling of additional samples. Finally, targeted mass spectrometry was used for validation in an independent set of samples in a blinded fashion.RESULTS Of the 3,342 N-glycopeptides identified, patients exhibited decrease in complex-type N-glycans and increase in truncated, mannose-rich, and hybrid species. We identified a glycopeptide from complement C4 carrying the glycan Man5GlcNAc2, which was not detected in controls, in 5 patients with normal CDT results, including 1 after liver transplant and 2 with a known genetic variant associated with mild disease, indicating greater sensitivity than CDT. It was detected by targeted analysis in 2 individuals with variants of uncertain significance in PMM2.CONCLUSION Complement C4–derived Man5GlcNAc2 glycopeptide could be a biomarker for accurate diagnosis and therapeutic monitoring of patients with PMM2-CDG and other CDGs.FUNDING U54NS115198 (Frontiers in Congenital Disorders of Glycosylation: NINDS; NCATS; Eunice Kennedy Shriver NICHD; Rare Disorders Consortium Disease Network); K08NS118119 (NINDS); Minnesota Partnership for Biotechnology and Medical Genomics; Rocket Fund; R01DK099551 (NIDDK); Mayo Clinic DERIVE Office; Mayo Clinic Center for Biomedical Discovery; IA/CRC/20/1/600002 (Center for Rare Disease Diagnosis, Research and Training; DBT/Wellcome Trust India Alliance)
Kishore Garapati, Rohit Budhraja, Mayank Saraswat, Jinyong Kim, Neha Joshi, Gunveen S. Sachdeva, Anu Jain, Anna N. Ligezka, Silvia Radenkovic, Madan Gopal Ramarajan, Savita Udainiya, Kimiyo Raymond, Miao He, Christina Lam, Austin Larson, Andrew C. Edmondson, Kyriakie Sarafoglou, Nicholas B. Larson, Hudson H. Freeze, Matthew J. Schultz, Tamas Kozicz, Eva Morava, Akhilesh Pandey
BACKGROUND Broadly neutralizing monoclonal antibodies (bNAbs) represent a promising strategy for HIV-1 immunoprophylaxis and treatment. 10E8VLS and VRC07-523LS are bNAbs that target the highly conserved membrane-proximal external region (MPER) and the CD4-binding site of the HIV-1 viral envelope glycoprotein, respectively.METHODS In this phase 1, open-label trial, we evaluated the safety and pharmacokinetics of 5 mg/kg 10E8VLS administered alone, or concurrently with 5 mg/kg VRC07-523LS, via s.c. injection to healthy non–HIV-infected individuals.RESULTS Eight participants received either 10E8VLS alone (n = 6) or 10E8VLS and VRC07-523LS in combination (n = 2). Five (n = 5 of 8, 62.5%) participants who received 10E8VLS experienced moderate local reactogenicity, and 1 participant (n = 1/8, 12.5%) experienced severe local reactogenicity. Further trial enrollment was stopped, and no participant received repeat dosing. All local reactogenicity resolved without sequelae. 10E8VLS retained its neutralizing capacity, and no functional anti-drug antibodies were detected; however, a serum t1/2 of 8.1 days was shorter than expected. Therefore, the trial was voluntarily stopped per sponsor decision (Vaccine Research Center, National Institute of Allergy and Infectious Diseases [NIAID], NIH). Mechanistic studies performed to investigate the underlying reason for the reactogenicity suggest that multiple mechanisms may have contributed, including antibody aggregation and upregulation of local inflammatory markers.CONCLUSION 10E8VLS resulted in unexpected reactogenicity and a shorter t1/2 in comparison with previously tested bNAbs. These studies may facilitate identification of nonreactogenic second-generation MPER-targeting bNAbs, which could be an effective strategy for HIV-1 immunoprophylaxis and treatment.TRIAL REGISTRATION Clinicaltrials.gov, accession no. NCT03565315.FUNDING Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH.
Seemal F. Awan, Amarendra Pegu, Larisa Strom, Cristina A. Carter, Cynthia S. Hendel, LaSonji A. Holman, Pamela J. Costner, Olga Trofymenko, Renunda Dyer, Ingelise J. Gordon, Ro Shauna S. Rothwell, Somia P. Hickman, Michelle Conan-Cibotti, Nicole A. Doria-Rose, Bob C. Lin, Sarah O’Connell, Sandeep R. Narpala, Cassandra G. Almasri, Cuiping Liu, Sungyoul Ko, Young D. Kwon, Aryan M. Namboodiri, Janardan P. Pandey, Frank J. Arnold, Kevin Carlton, Jason G. Gall, Peter D. Kwong, Edmund V. Capparelli, Robert T. Bailer, Adrian B. McDermott, Grace L. Chen, Richard A. Koup, John R. Mascola, Emily E. Coates, Julie E. Ledgerwood, Martin R. Gaudinski, the VRC 610 study team
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