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1.
Effects of dual-task interference on swallowing in healthy aging adults.
Krishnamurthy, R, Philip, R, Balasubramanium, RK, Rangarathnam, B
PloS one. 2021;(6):e0253550
Abstract
A wide body of literature has demonstrated that the neural representation of healthy swallowing is mostly bilateral, with one hemisphere dominant over the other. While several studies have demonstrated the presence of laterality for swallowing related functions among young adults, the data on older adults are still growing. The purpose of this paper is to investigate potential changes in hemispheric dominance in healthy aging adults for swallowing related tasks using a behavioral dual-task paradigm. A modified dual-task paradigm was designed to investigate the potential reduction in hemispherical specialization for swallowing function. Eighty healthy right-handed participants in the study were divided into two groups [Group 1: young adults (18-40 years) and Group 2: older adults (65 and above)]. All the participants performed a timed water swallow test at baseline and with two interference conditions (silent word repetition, and facial recognition). The results of the study revealed the following 1) a statistically significant effect of age on swallow performance; 2) statistically significant effect of each of the interference tasks on two of the swallow measures (VPS and VPT) in younger adults; and 3) no significant effect of the interference tasks on the swallowing performance of older adults. These findings suggest that aging substantially affects swallowing in older individuals, and this potentially accompanies a reduction in the hemispheric specialization for swallowing related tasks.
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Lipoic acid supplementation associated with neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy.
Spain, RI, Andeen, NK, Gibson, PC, Samuels, MH, Morris, CD, Solomon, AJ, Solomon, R, Waslo, C, Avasare, RS
Kidney international. 2021;(6):1208-1213
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Abstract
Lipoic acid (alpha lipoic acid, thioctic acid) is a popular over-the-counter antioxidant and insulin-mimetic supplement under investigation in a variety of conditions including multiple sclerosis, diabetes, and schizophrenia. Unfortunately, high-grade proteinuria was an unexpected adverse event specific to the treatment arm of our clinical trial investigating lipoic acid supplementation in patients with multiple sclerosis. This observation led to detection of similar patients in our nephrology practice. Here, we describe four biopsy-proven cases of neural epidermal growth factor-like 1 (NELL1)-associated membranous nephropathy following lipoic acid supplementation and a fifth suspected case. Discontinuation of lipoic acid and supportive therapy resulted in remission.
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A ketogenic diet consumed during radiotherapy improves several aspects of quality of life and metabolic health in women with breast cancer.
Klement, RJ, Weigel, MM, Sweeney, RA
Clinical nutrition (Edinburgh, Scotland). 2021;(6):4267-4274
Abstract
BACKGROUND & AIMS Ketogenic diets (KDs) have been proposed as complementary nutritional treatments for cancer patients. Because it is important to gain knowledge about the safety of KDs adopted during cancer therapy, we studied the effects of KDs on quality of life and blood parameters in women with early-stage breast cancer undergoing radiotherapy. METHODS A total of 29 patients consuming a KD were compared to 30 patients consuming their standard diet (SD) with respect to EORTC-QLQ30 questionnaire scores and different metabolic and hormonal blood parameters that were obtained prior to, in the middle of and at the end of radiotherapy. Baseline-to-end differences were assessed using Wilcoxon tests, and longitudinal changes were analyzed using linear mixed effects models. RESULTS Compared to the SD, women consuming a KD experienced significant improvements in emotional functioning, social functioning, sleep quality, future perspectives and systemic therapy side effects (all p-values <0.01). While breast symptoms increased significantly in both groups, the increase was less pronounced in the KD group. There was no hint of a detrimental effect of the KDs on either liver or kidney function; in contrast, biomarkers of metabolic health (gamma-glutamyl-transpeptidase, creatinine, triglycerides, IGF-1, free T3) significantly improved in the KD, but not the SD group. CONCLUSIONS These data support the hypothesis that consuming a KD during radiotherapy is safe for women with breast cancer and has the potential to improve quality of life and metabolic health. CLINICALTRIALS. GOV IDENTIFIER NCT02516501.
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Avelumab for platinum-ineligible/refractory recurrent and/or metastatic squamous cell carcinoma of the head and neck: phase Ib results from the JAVELIN Solid Tumor trial.
Guigay, J, Lee, KW, Patel, MR, Daste, A, Wong, DJ, Goel, S, Gordon, MS, Gutierrez, M, Balmanoukian, A, Le Tourneau, C, et al
Journal for immunotherapy of cancer. 2021;(10)
Abstract
BACKGROUND Recurrent and/or metastatic (R/M) disease develops in approximately 65% of patients with squamous cell carcinoma of the head and neck (SCCHN) and is associated with a poor prognosis. Immune checkpoint inhibitors have proven effective in multiple tumor types, including R/M SCCHN. We report the efficacy and safety of avelumab (antiprogrammed death ligand 1 antibody) in an expansion cohort of patients with platinum-refractory/ineligible R/M SCCHN enrolled in the phase I JAVELIN Solid Tumor trial (NCT01772004). METHODS Eligible patients with R/M SCCHN were aged ≥18 years and had received ≥1 line of platinum-based chemotherapy with disease progression or recurrence within 6 months of the last dose or were ineligible for platinum-based chemotherapy. All patients received avelumab 10 mg/kg every 2 weeks. Tumor assessments were carried out by a blinded independent review committee (IRC) and investigators according to Response Evaluation Criteria in Solid Tumors V.1.1 (RECIST 1.1). Key endpoints included best overall response, duration of response (DOR) and progression-free survival (PFS) assessed by IRC and investigator per RECIST 1.1, overall survival (OS), and safety. RESULTS Between April 24, 2015, and November 13, 2015, 153 patients were enrolled. Patients had a median of two prior lines of therapy for metastatic or locally advanced disease (range 0-6); 12 patients (7.8%) were not eligible for platinum-based chemotherapy. At data cut-off (December 31, 2017), the confirmed objective response rate was 9.2% (95% CI 5.1% to 14.9%) assessed by IRC and 13.1% (95% CI 8.2% to 19.5%) assessed by investigator. Median DOR was not reached (95% CI 4.2 to not estimable) based on IRC assessment. Median PFS was 1.4 months (95% CI 1.4 to 2.6) assessed by IRC and 1.8 months (95% CI 1.4 to 2.7) assessed by investigator; median OS was 8.0 months (95% CI 6.5 to 10.2). Any-grade treatment-related adverse events (TRAEs) occurred in 83 patients (54.2%) and were grade ≥3 in 10 patients (6.5%). The most common TRAEs were fatigue (n=19, 12.4%), fever (n=14, 9.2%), pruritus (n=12, 7.8%), and chills (n=11, 7.2%), and there were no treatment-related deaths. CONCLUSION Avelumab showed clinical activity and was associated with a low rate of grade ≥3 TRAEs in heavily pretreated patients with platinum-refractory/ineligible R/M SCCHN.
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SLC7A11 Is a Superior Determinant of APR-246 (Eprenetapopt) Response than TP53 Mutation Status.
Fujihara, KM, Corrales Benitez, M, Cabalag, CS, Zhang, BZ, Ko, HS, Liu, DS, Simpson, KJ, Haupt, Y, Lipton, L, Haupt, S, et al
Molecular cancer therapeutics. 2021;(10):1858-1867
Abstract
APR-246 (eprenetapopt) is in clinical development with a focus on hematologic malignancies and is promoted as a mutant-p53 reactivation therapy. Currently, the detection of at least one TP53 mutation is an inclusion criterion for patient selection into most APR-246 clinical trials. Preliminary results from our phase Ib/II clinical trial investigating APR-246 combined with doublet chemotherapy [cisplatin and 5-fluorouracil (5-FU)] in metastatic esophageal cancer, together with previous preclinical studies, indicate that TP53 mutation status alone may not be a sufficient biomarker for APR-246 response. This study aims to identify a robust biomarker for response to APR-246. Correlation analysis of the PRIMA-1 activity (lead compound to APR-246) with mutational status, gene expression, protein expression, and metabolite abundance across over 700 cancer cell lines (CCL) was performed. Functional validation and a boutique siRNA screen of over 850 redox-related genes were also conducted. TP53 mutation status was not consistently predictive of response to APR-246. The expression of SLC7A11, the cystine/glutamate transporter, was identified as a superior determinant of response to APR-246. Genetic regulators of SLC7A11, including ATF4, MDM2, wild-type p53, and c-Myc, were confirmed to also regulate cancer-cell sensitivity to APR-246. In conclusion, SLC7A11 expression is a broadly applicable determinant of sensitivity to APR-246 across cancer and should be utilized as the key predictive biomarker to stratify patients for future clinical investigation of APR-246.
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Gene therapy for aromatic L-amino acid decarboxylase deficiency by MR-guided direct delivery of AAV2-AADC to midbrain dopaminergic neurons.
Pearson, TS, Gupta, N, San Sebastian, W, Imamura-Ching, J, Viehoever, A, Grijalvo-Perez, A, Fay, AJ, Seth, N, Lundy, SM, Seo, Y, et al
Nature communications. 2021;(1):4251
Abstract
Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare genetic disorder characterized by deficient synthesis of dopamine and serotonin. It presents in early infancy, and causes severe developmental disability and lifelong motor, behavioral, and autonomic symptoms including oculogyric crises (OGC), sleep disorder, and mood disturbance. We investigated the safety and efficacy of delivery of a viral vector expressing AADC (AAV2-hAADC) to the midbrain in children with AADC deficiency (ClinicalTrials.gov Identifier NCT02852213). Seven (7) children, aged 4-9 years underwent convection-enhanced delivery (CED) of AAV2-hAADC to the bilateral substantia nigra (SN) and ventral tegmental area (VTA) (total infusion volume: 80 µL per hemisphere) in 2 dose cohorts: 1.3 × 1011 vg (n = 3), and 4.2 × 1011 vg (n = 4). Primary aims were to demonstrate the safety of the procedure and document biomarker evidence of restoration of brain AADC activity. Secondary aims were to assess clinical improvement in symptoms and motor function. Direct bilateral infusion of AAV2-hAADC was safe, well-tolerated and achieved target coverage of 98% and 70% of the SN and VTA, respectively. Dopamine metabolism was increased in all subjects and FDOPA uptake was enhanced within the midbrain and the striatum. OGC resolved completely in 6 of 7 subjects by Month 3 post-surgery. Twelve (12) months after surgery, 6/7 subjects gained normal head control and 4/7 could sit independently. At 18 months, 2 subjects could walk with 2-hand support. Both the primary and secondary endpoints of the study were met. Midbrain gene delivery in children with AADC deficiency is feasible and safe, and leads to clinical improvements in symptoms and motor function.
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Brain functions and cognition on transient insulin deprivation in type 1 diabetes.
Creo, AL, Cortes, TM, Jo, HJ, Huebner, AR, Dasari, S, Tillema, JM, Lteif, AN, Klaus, KA, Ruegsegger, GN, Kudva, YC, et al
JCI insight. 2021;(5)
Abstract
BACKGROUNDType 1 diabetes (T1D) is a risk factor for dementia and structural brain changes. It remains to be determined whether transient insulin deprivation that frequently occurs in insulin-treated individuals with T1D alters brain function.METHODSWe therefore performed functional and structural magnetic resonance imaging, magnetic resonance spectroscopy, and neuropsychological testing at baseline and following 5.4 ± 0.6 hours of insulin deprivation in 14 individuals with T1D and compared results with those from 14 age-, sex-, and BMI-matched nondiabetic (ND) participants with no interventions.RESULTSInsulin deprivation in T1D increased blood glucose, and β-hydroxybutyrate, while reducing bicarbonate levels. Participants with T1D showed lower baseline brain N-acetyl aspartate and myo-inositol levels but higher cortical fractional anisotropy, suggesting unhealthy neurons and brain microstructure. Although cognitive functions did not differ between participants with T1D and ND participants at baseline, significant changes in fine motor speed as well as attention and short-term memory occurred following insulin deprivation in participants with T1D. Insulin deprivation also reduced brain adenosine triphosphate levels and altered the phosphocreatine/adenosine triphosphate ratio. Baseline differences in functional connectivity in brain regions between participants with T1D and ND participants were noted, and on insulin deprivation further alterations in functional connectivity between regions, especially cortical and hippocampus-caudate regions, were observed. These alterations in functional connectivity correlated to brain metabolites and to changes in cognition.CONCLUSIONTransient insulin deprivation therefore caused alterations in executive aspects of cognitive function concurrent with functional connectivity between memory regions and the sensory cortex. These findings have important clinical implications, as many patients with T1D inadvertently have periods of transient insulin deprivation.TRIAL REGISTRATIONClinicalTrials.gov NCT03392441.FUNDINGClinical and Translational Science Award (UL1 TR002377) from the National Center for Advancing Translational Science; NIH grants (R21 AG60139 and R01 AG62859); the Mayo Foundation.
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Longitudinal Weight Gain and Related Risk Behaviors during the COVID-19 Pandemic in Adults in the US.
Bhutani, S, vanDellen, MR, Cooper, JA
Nutrients. 2021;13(2)
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The Covid-19 pandemic has altered health behaviours of many individuals resulting in weight gain. This cross-sectional study of 1779 individuals aimed to determine the long-term impact of Covid-19 on health behaviours and weight gain over 5 months. The results showed that most participants (40%) body weight increased alongside increased processed food intake and snacking. 33% of the individuals who gained weight continued to gain weight and 28% maintained their higher weight after lockdown measures were lifted. Take-away meals, processed food intake and stress levels remained high post-lockdown in those who gained weight. It was concluded that lockdown measures may have impacted daily life resulting in weight gain which may perpetuate long-term. This study could be used by healthcare professionals to understand that lockdown measures may have altered eating behaviours resulting in weight gain and that these may need to be uncovered to aid long-term weight loss.
Abstract
Cross-sectional analyses have shown increased obesogenic behaviors and a potential for weight gain during COVID-19 related peak-lockdown (March-May 2020), but longitudinal data are lacking. This study assessed longitudinal changes in body weight and lifestyle behaviors in the US adults during the pandemic. METHODS We used Qualtrics survey to collect self-reported data on body weight, dietary, physical activity, and psychological variables (n = 727) during the peak-lockdown (April/May) and at post-lockdown (September/October). Peak-lockdown weight data were categorized based on the magnitude of weight gained, maintained, or lost, and behavioral differences were examined between categories at two time points. RESULTS Body weight increased (+0.62 kg; p < 0.05) at the post-lockdown period. The body mass index also increased (26.38 ± 5.98 kg/m2 vs. 26.12 ± 5.81 kg/m2; p < 0.01) at the post-lockdown period vs. peak-lockdown period. Close to 40% of participants reported gaining either 1-4 lbs or >5 lbs of body weight during the peak-lockdown, while 18.2% lost weight. Weight-gainers engaged in riskier dietary behaviors such as frequent ultra-processed food intake (p < 0.01) and snacking (p < 0.001), were less active, and reported high stress and less craving control during peak-lockdown. Of those gaining >5 lbs, 33% continued to gain weight after the lockdown eased, while 28% maintain higher body weight. In weight-gainers, takeout meal frequency increased, and high ultra-processed food intake and stress, and low craving control continued to persist after the lockdown eased. CONCLUSION We show that the COVID-19 lockdown periods disrupted weight management among many Americans and that associated health effects are likely to persist.
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High-Protein Plant-Based Diet Versus a Protein-Matched Omnivorous Diet to Support Resistance Training Adaptations: A Comparison Between Habitual Vegans and Omnivores.
Hevia-Larraín, V, Gualano, B, Longobardi, I, Gil, S, Fernandes, AL, Costa, LAR, Pereira, RMR, Artioli, GG, Phillips, SM, Roschel, H
Sports medicine (Auckland, N.Z.). 2021;51(6):1317-1330
Abstract
BACKGROUND Acute protein turnover studies suggest lower anabolic response after ingestion of plant vs. animal proteins. However, the effects of an exclusively plant-based protein diet on resistance training-induced adaptations are under investigation. OBJECTIVE To investigate the effects of dietary protein source [exclusively plant-based vs. mixed diet] on changes in muscle mass and strength in healthy young men undertaking resistance training. METHODS Nineteen young men who were habitual vegans (VEG 26 ± 5 years; 72.7 ± 7.1 kg, 22.9 ± 2.3 kg/m2) and nineteen young men who were omnivores (OMN 26 ± 4 years; 73.3 ± 7.8 kg, 23.6 ± 2.3 kg/m2) undertook a 12-week, twice weekly, supervised resistance training program. Habitual protein intake was assessed at baseline and adjusted to 1.6 g kg-1 day-1 via supplemental protein (soy for VEG or whey for OMN). Dietary intake was monitored every four weeks during the intervention. Leg lean mass, whole muscle, and muscle fiber cross-sectional area (CSA), as well as leg-press 1RM were assessed before (PRE) and after the intervention (POST). RESULTS Both groups showed significant (all p < 0.05) PRE-to-POST increases in leg lean mass (VEG: 1.2 ± 1.0 kg; OMN: 1.2 ± 0.8 kg), rectus femoris CSA (VEG: 1.0 ± 0.6 cm2; OMN: 0.9 ± 0.5 cm2), vastus lateralis CSA (VEG: 2.2 ± 1.1 cm2; OMN: 2.8 ± 1.0 cm2), vastus lateralis muscle fiber type I (VEG: 741 ± 323 µm2; OMN: 677 ± 617 µm2) and type II CSA (VEG: 921 ± 458 µm2; OMN: 844 ± 638 µm2), and leg-press 1RM (VEG: 97 ± 38 kg; OMN: 117 ± 35 kg), with no between-group differences for any of the variables (all p > 0.05). CONCLUSION A high-protein (~ 1.6 g kg-1 day-1), exclusively plant-based diet (plant-based whole foods + soy protein isolate supplementation) is not different than a protein-matched mixed diet (mixed whole foods + whey protein supplementation) in supporting muscle strength and mass accrual, suggesting that protein source does not affect resistance training-induced adaptations in untrained young men consuming adequate amounts of protein. CLINICAL TRIAL REGISTRATION NCT03907059. April 8, 2019. Retrospectively registered.
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Genome-Wide Transcriptomic Analysis of Intestinal Mucosa in Celiac Disease Patients on a Gluten-Free Diet and Postgluten Challenge.
Dotsenko, V, Oittinen, M, Taavela, J, Popp, A, Peräaho, M, Staff, S, Sarin, J, Leon, F, Isola, J, Mäki, M, et al
Cellular and molecular gastroenterology and hepatology. 2021;(1):13-32
Abstract
BACKGROUND & AIMS Gluten challenge studies are instrumental in understanding the pathophysiology of celiac disease. Our aims in this study were to reveal early gluten-induced transcriptomic changes in duodenal biopsies and to find tools for clinics. METHODS Duodenal biopsies were collected from 15 celiac disease patients on a strict long-term gluten-free diet (GFD) prior to and post a gluten challenge (PGC) and from 6 healthy control individuals (DC). Biopsy RNA was subjected to genome-wide 3' RNA-Seq. Sequencing data was used to determine the differences between the three groups and was compared to sequencing data from the public repositories. The biopsies underwent morphometric analyses. RESULTS In DC vs. GFD group comparisons, 167 differentially expressed genes were identified with 117 genes downregulated and 50 genes upregulated. In PGC vs. GFD group comparisons, 417 differentially expressed genes were identified with 195 genes downregulated and 222 genes upregulated. Celiac disease patients on a GFD were not "healthy". In particular, genes encoding proteins for transporting small molecules were expressed less. In addition to the activation of immune response genes, a gluten challenge induced hyperactive intestinal wnt-signaling and consequent immature crypt gene expression resulting in less differentiated epithelium. Biopsy gene expression in response to a gluten challenge correlated with the extent of the histological damage. Regression models using only four gene transcripts described 97.2% of the mucosal morphology and 98.0% of the inflammatory changes observed. CONCLUSIONS Our gluten challenge trial design provided an opportunity to study the transition from health to disease. The results show that even on a strict GFD, despite being deemed healthy, patients reveal patterns of ongoing disease. Here, a transcriptomic regression model estimating the extent of gluten-induced duodenal mucosal injury is presented.