Publications by authors named "Jennifer Davis"

523 Publications

The potential of school-based WASH programming to support children as agents of change in rural Zambian households.

BMC Public Health 2021 Oct 8;21(1):1812. Epub 2021 Oct 8.

Department of Civil and Environmental Engineering, Stanford University, Yang and Yamazaki Environment and Energy Building, 473 Via Ortega, Office 161, Stanford, CA, 94305, USA.

Background: Water, sanitation, and hygiene (WASH) interventions frequently assume that students who learn positive WASH behaviors will disseminate this information to their families. This is most prominent in school-based programs, which rely on students to act as "agents of change" to translate impact from school to home. However, there is little evidence to support or contradict this assumption.

Methods: We conducted a quasi-experimental, prospective cohort study in 12 schools in rural, southern Zambia to measure the impact of WASH UP!, a school-based WASH program designed by the creators of Sesame Street. WASH UP! is an educational program that uses stories and interactive games to teach students in grades 1-4 about healthy behaviors, such as washing hands and using the latrine. We completed in-person interviews with grade 1 and 4 students (N = 392 and 369, respectively), their teachers (N = 24) and caregivers (N = 729) using structured surveys containing both open- and closed-ended questions. We measured changes in knowledge and whether students reported sharing WASH-related messages learned in school with their caregivers at home.

Results: Student knowledge increased significantly, but primarily among students in grade 1. Overall rates of students reporting that they shared messages from the curriculum with their caregivers rose from 7 to 23% (p <  0.001). Students in grade 4 were 5.2 times as likely as those in grade 1 to report sharing a WASH-related message with their caregivers (ARR = 5.2, 95% C.I. = (2.3, 8.9); p <  0.001).

Conclusions: Although we measured only modest levels of student dissemination of WASH UP! messages from the school to the home, students in grade 4 showed significantly more promise as agents of change than those in grade 1. Future work should prioritize developing curricula that reflect the variability in needs, capabilities and support in the home and community among primary school students rather than a single approach for a wide range of ages and contexts.
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http://dx.doi.org/10.1186/s12889-021-11824-3DOI Listing
October 2021

Preventing the '24-hour Babel': the need for a consensus on a consistent terminology scheme for physical activity, sedentary behaviour and sleep.

Br J Sports Med 2021 Sep 23. Epub 2021 Sep 23.

Physical Therapy, The University of British Columbia, Vancouver, British Columbia, Canada

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http://dx.doi.org/10.1136/bjsports-2021-104487DOI Listing
September 2021

Breast cancer-derived GM-CSF regulates arginase 1 in myeloid cells to promote an immunosuppressive microenvironment.

J Clin Invest 2021 Oct;131(20)

Department of Medicine.

Tumor-infiltrating myeloid cells contribute to the development of the immunosuppressive tumor microenvironment. Myeloid cell expression of arginase 1 (ARG1) promotes a protumor phenotype by inhibiting T cell function and depleting extracellular l-arginine, but the mechanism underlying this expression, especially in breast cancer, is poorly understood. In breast cancer clinical samples and in our mouse models, we identified tumor-derived GM-CSF as the primary regulator of myeloid cell ARG1 expression and local immune suppression through a gene-KO screen of breast tumor cell-produced factors. The induction of myeloid cell ARG1 required GM-CSF and a low pH environment. GM-CSF signaling through STAT3 and p38 MAPK and acid signaling through cAMP were required to activate myeloid cell ARG1 expression in a STAT6-independent manner. Importantly, breast tumor cell-derived GM-CSF promoted tumor progression by inhibiting host antitumor immunity, driving a significant accumulation of ARG1-expressing myeloid cells compared with lung and melanoma tumors with minimal GM-CSF expression. Blockade of tumoral GM-CSF enhanced the efficacy of tumor-specific adoptive T cell therapy and immune checkpoint blockade. Taken together, we show that breast tumor cell-derived GM-CSF contributes to the development of the immunosuppressive breast cancer microenvironment by regulating myeloid cell ARG1 expression and can be targeted to enhance breast cancer immunotherapy.
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http://dx.doi.org/10.1172/JCI145296DOI Listing
October 2021

Patient-Directed Discharges Among Persons Who Use Drugs Hospitalized with Invasive S. aureus Infections: Opportunities for Improvement.

Am J Med 2021 Sep 8. Epub 2021 Sep 8.

Division of HIV, Infectious Diseases & Global Medicine, San Francisco General Hospital, University of California, San Francisco (UCSF), San Francisco, CA, USA.

Background: Despite the high burden of Staphylococcus aureus infections among persons who use drugs, limited data exist comparing outcomes of patient-directed discharge (also known as "against medical advice") vs. standard discharge among persons who use drugs hospitalized with S. aureus infection.

Methods: We conducted a retrospective study of hospitalizations among adults with S. aureus bacteremia, endocarditis, epidural abscess, and/or vertebral osteomyelitis at two San Francisco hospitals between 2013-2018. We compared odds of one-year readmission for infection persistence/recurrence and one-year mortality via multivariable logistic regression models adjusting for age, sex, Charlson comorbidity index and homelessness.

Results: Overall, 80/340 (24%) of hospitalizations for invasive S. aureus infections among persons who use drugs involved patient-directed discharge. Over half of patient-directed discharges 41/80 (51%) required readmission for persistent/recurrent S. aureus infection vs. 54/260 (21%) patients without patient-directed discharge (adjusted odds ratio 3.8 [95% CI 2.2-6.7]). One-year cumulative mortality was 15% after PDD vs. 11% after standard discharge (p=0.02); however, this difference was not significant after adjustment for mortality risk factors. More than half of deaths in the patient-directed discharge group (7/12, 58%) were due to drug overdose; none was due to S. aureus infection.

Conclusions: Among persons who use drugs hospitalized with invasive S. aureus infection, odds of hospital readmission for infection were almost 4-fold higher following patient-directed discharge compared to standard discharge. All-cause one-year mortality was similarly high in both groups, and drug overdose was a common cause of death in patient-directed discharge group.
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http://dx.doi.org/10.1016/j.amjmed.2021.08.007DOI Listing
September 2021

Effective Demand for In-Line Chlorination Bundled with Rental Housing in Dhaka, Bangladesh.

Environ Sci Technol 2021 09 9;55(18):12471-12482. Epub 2021 Sep 9.

Department of Civil & Environmental Engineering, Stanford University, Y2E2 Building, 473 Via Ortega, Stanford, California 94305, United States.

Delivering safe water in cities of lower- and middle-income countries remains elusive even where there is a piped supply. Passive, in-line chlorination upstream of the point of water collection reduces child diarrhea without the behavior change required for point-of-use water treatment products or manual chlorine dispensers. We conducted a price experiment to measure effective demand (willingness and ability to pay) for an in-line chlorination service using tablet chlorinators among 196 landlords of rental housing properties in Dhaka, Bangladesh. We offered a 12-month subscription using Becker-DeGroot-Marschak auctions with real money payments. The service consistently delivered chlorinated water and satisfied tenants. Landlords' effective demand for in-line chlorination was similar to or greater than that for point-of-use treatment products and manual chlorine dispensers previously documented among Dhaka households. Over the service period, landlords renting to low-income households had lower effective demand than those renting to middle-income households despite similar initial rates of payment across both groups. Making in-line chlorination financially viable for the lowest-income consumers would likely require service cost reductions, subsidies, or both. Our findings suggest that even revealed preference experiments may overestimate the effective demand needed to sustain water supply improvements, especially in low-income populations, if they only measure demand once.
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http://dx.doi.org/10.1021/acs.est.1c01308DOI Listing
September 2021

Improved Cardiovascular Tolerance to Hemorrhage after Oral Resveratrol Pretreatment in Dogs.

Vet Sci 2021 Jul 12;8(7). Epub 2021 Jul 12.

School of Veterinary Science, Murdoch University, Murdoch, WA 6150, Australia.

Resveratrol has been shown to preserve organ function and improve survival in hemorrhagic shock rat models. This study investigated whether seven days of oral resveratrol could improve hemodynamic response to hemorrhage and confer benefits on risk of acute kidney injury (AKI) without inducing coagulopathy in a canine model. Twelve greyhound dogs were randomly allocated to receive oral resveratrol (1000 mg/day) or placebo for seven days prior to inducing hemorrhage until a targeted mean blood pressure of ≤40 mmHg was achieved. AKI biomarkers and coagulation parameters were measured before, immediately following, and two hours after hemorrhage. Dogs were euthanized, and renal tissues were examined at the end of the experiment. All investigators were blinded to the treatment allocation. A linear mixed model was used to assess effect of resveratrol on AKI biomarkers and coagulation parameters while adjusting for volume of blood loss. A significant larger volume of blood loss was required to achieve the hypotension target in the resveratrol group compared to placebo group (median 64 vs. 55 mL/kg respectively, = 0.041). Although histological evidence of AKI was evident in all dogs, the renal tubular injury scores were not significantly different between the two groups, neither were the AKI biomarkers. Baseline (pre-hemorrhage) maximum clot firmness on the Rotational Thromboelastometry (ROTEM) was stronger in the resveratrol group than the placebo group (median 54 vs. 43 mm respectively, = 0.009). In summary, seven days of oral resveratrol did not appear to induce increased bleeding risk and could improve greyhound dogs' blood pressure tolerance to severe hemorrhage. Renal protective effect of resveratrol was, however, not observed.
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http://dx.doi.org/10.3390/vetsci8070129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8310360PMC
July 2021

Dysregulated clock gene expression and abnormal diurnal regulation of hippocampal inhibitory transmission and spatial memory in amyloid precursor protein transgenic mice.

Neurobiol Dis 2021 10 30;158:105454. Epub 2021 Jul 30.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address:

Patients with Alzheimer's disease (AD) often have fragmentation of sleep/wake cycles and disrupted 24-h (circadian) activity. Despite this, little work has investigated the potential underlying day/night disruptions in cognition and neuronal physiology in the hippocampus. The molecular clock, an intrinsic transcription-translation feedback loop that regulates circadian behavior, may also regulate hippocampal neurophysiological activity. We hypothesized that disrupted diurnal variation in clock gene expression in the hippocampus corresponds with loss of normal day/night differences in membrane excitability, synaptic physiology, and cognition. We previously reported disrupted circadian locomotor rhythms and neurophysiological output of the suprachiasmatic nucleus (the primary circadian clock) in Tg-SwDI mice with human amyloid-beta precursor protein mutations. Here, we report that Tg-SwDI mice failed to show day/night differences in a spatial working memory task, unlike wild-type controls that exhibited enhanced spatial working memory at night. Moreover, Tg-SwDI mice had lower levels of Per2, one of the core components of the molecular clock, at both mRNA and protein levels when compared to age-matched controls. Interestingly, we discovered neurophysiological impairments in area CA1 of the Tg-SwDI hippocampus. In controls, spontaneous inhibitory post-synaptic currents (sIPSCs) in pyramidal cells showed greater amplitude and lower inter-event interval during the day than the night. However, the normal day/night differences in sIPSCs were absent (amplitude) or reversed (inter-event interval) in pyramidal cells from Tg-SwDI mice. In control mice, current injection into CA1 pyramidal cells produced more firing during the night than during the day, but no day/night difference in excitability was observed in Tg-SwDI mice. The normal day/night difference in excitability in controls was blocked by GABA receptor inhibition. Together, these results demonstrate that the normal diurnal regulation of inhibitory transmission in the hippocampus is diminished in a mouse model of AD, leading to decreased daytime inhibition onto hippocampal CA1 pyramidal cells. Uncovering disrupted day/night differences in circadian gene regulation, hippocampal physiology, and memory in AD mouse models may provide insight into possible chronotherapeutic strategies to ameliorate Alzheimer's disease symptoms or delay pathological onset.
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http://dx.doi.org/10.1016/j.nbd.2021.105454DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8477442PMC
October 2021

Development and Application of an Interactive Physiologically Based Pharmacokinetic (iPBPK) Model to Predict Oxytetracycline Tissue Distribution and Withdrawal Intervals in Market-Age Sheep and Goats.

Toxicol Sci 2021 Sep;183(2):253-268

Institute of Computational Comparative Medicine (ICCM), Department of Anatomy and Physiology, College of Veterinary Medicine, Kansas State University, Manhattan, Kansas 66506, USA.

Oxytetracycline (OTC) is a widely used antibiotic in food-producing animals. Extralabel use of OTC is common and may lead to violative residues in edible tissues. It is important to have a quantitative tool to predict scientifically based withdrawal intervals (WDIs) after extralabel use in food animals to ensure human food safety. This study focuses on developing a physiologically based pharmacokinetic (PBPK) model for OTC in sheep and goats. The model included 7 compartments: plasma, lung, liver, kidneys, muscle, fat, and rest of the body. The model was calibrated with serum and tissue (liver, muscle, kidney, and fat) concentration data following a single intramuscular (IM, 20 mg/kg) and/or intravenous (IV, 10 mg/kg) administration of a long-acting formulation in sheep and goats. The model was evaluated with independent datasets from Food Animal Residue Avoidance Databank (FARAD). Results showed that the model adequately simulated the calibration datasets with an overall estimated coefficient of determination (R2) of 0.95 and 0.92, respectively, for sheep and goat models and had acceptable accuracy for the evaluation datasets. Monte Carlo sampling technique was applied to predict the time needed for drug concentrations in edible tissues to fall below tolerances for the 99th percentiles of the population. The model was converted to a web-based interactive PBPK (iPBPK) interface to facilitate model applications. This iPBPK model provides a useful tool to estimate WDIs for OTC after extralabel use in small ruminants to ensure food safety and serves as a basis for extrapolation to other tetracycline drugs and other food animals.
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http://dx.doi.org/10.1093/toxsci/kfab095DOI Listing
September 2021

Constitutive activation of NF-κB inducing kinase (NIK) in the mesenchymal lineage using Osterix (Sp7)- or Fibroblast-specific protein 1 (S100a4)-Cre drives spontaneous soft tissue sarcoma.

PLoS One 2021 22;16(7):e0254426. Epub 2021 Jul 22.

Musculoskeletal Research Center, Washington University School of Medicine, St. Louis, MO, United States of America.

Aberrant NF-κB signaling fuels tumor growth in multiple human cancer types including both hematologic and solid malignancies. Chronic elevated alternative NF-κB signaling can be modeled in transgenic mice upon activation of a conditional NF-κB-inducing kinase (NIK) allele lacking the regulatory TRAF3 binding domain (NT3). Here, we report that expression of NT3 in the mesenchymal lineage with Osterix (Osx/Sp7)-Cre or Fibroblast-Specific Protein 1 (FSP1)-Cre caused subcutaneous, soft tissue tumors. These tumors displayed significantly shorter latency and a greater multiple incidence rate in Fsp1-Cre;NT3 compared to Osx-Cre;NT3 mice, regardless of sex. Histological assessment revealed poorly differentiated solid tumors with some spindled patterns, as well as robust RelB immunostaining, confirming activation of alternative NF-κB. Even though NT3 expression also occurs in the osteolineage in Osx-Cre;NT3 mice, we observed no bony lesions. The staining profiles and pattern of Cre expression in the two lines pointed to a mesenchymal tumor origin. Immunohistochemistry revealed that these tumors stain strongly for alpha-smooth muscle actin (αSMA), although vimentin staining was uniform only in Osx-Cre;NT3 tumors. Negative CD45 and S100 immunostains precluded hematopoietic and melanocytic origins, respectively, while positive staining for cytokeratin 19 (CK19), typically associated with epithelia, was found in subpopulations of both tumors. Principal component, differential expression, and gene ontology analyses revealed that NT3 tumors are distinct from normal mesenchymal tissues and are enriched for NF-κB related biological processes. We conclude that constitutive activation of the alternative NF-κB pathway in the mesenchymal lineage drives spontaneous sarcoma and provides a novel mouse model for NF-κB related sarcomas.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0254426PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8297882PMC
July 2021

Analytical validation and reference intervals for a commercial multiplex assay to measure five novel biomarkers for acute kidney injury in canine urine.

Res Vet Sci 2021 Oct 7;139:78-86. Epub 2021 Jul 7.

Centre for Animal Production and Health, Murdoch University, Murdoch, Western Australia, Australia.

Novel urinary biomarkers are increasingly utilized for the diagnosis of acute kidney injury (AKI) in dogs. Magnetic-bead based immunoassays for the simultaneous measurement of multiple biomarkers represent a potentially efficient and cost effective tool for investigators; however there is limited data to support their reliable use in dogs. Analytical validation of a commercial multiplex assay for the measurement of five AKI biomarkers: clusterin, cystatin C, kidney-injury molecule 1 (KIM-1), monocyte chemoattractant protein 1 and neutrophil gelatinase-associated lipocalin (NGAL) in canine urine was performed. The effect of pre-analytical factors including potential interfering substances and sample storage methods were investigated. Urine from 110 healthy dogs was used to determine reference intervals for each biomarker measured, according to American Society of Veterinary Clinical Pathology guidelines. Additionally, urine from 21 dogs with pyuria was used to evaluate the impact of pyuria on biomarker concentration. The assay performed with acceptable accuracy and precision for the measurement of NGAL only. Clinically relevant urine concentrations of bilirubin, haemoglobin, and synthetic colloid solutions led to interference (mean percentage difference > +/- 15% compared to control) with measurement of all or some of the biomarkers. All biomarkers were stable in urine stored at 20-22 °C for 2 h, 4 °C for 12 h, or -20 °C for 6 months. Reference intervals could not be established for KIM-1 due to unacceptable measurement imprecision (intra- and inter assay coefficient of variation 45% and 20% respectively). Urine NGAL concentration was significantly elevated in pyuria (P < 0.001).
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http://dx.doi.org/10.1016/j.rvsc.2021.07.009DOI Listing
October 2021

Pharmacokinetics of dipyrone in horses: A multi-dose, dose escalation study.

J Vet Pharmacol Ther 2021 Jul 6. Epub 2021 Jul 6.

Biomedical Sciences and Pathobiology, Virginia-Maryland College of Veterinary Medicine, Blacksburg, VA, USA.

Dipyrone is a non-opioid, nonsteroidal anti-inflammatory drug with antipyretic and analgesic properties commonly used in horses. Dipyrone is rapidly hydrolyzed to the primary active metabolite 4-methylaminoantipyrine (4-MAA). The purpose of this study was to determine the pharmacokinetic profile of 4-MAA following repeated and escalating doses of intravenously administered dipyrone. Twenty-six horses were randomly allocated to five treatment groups (one placebo group and four dipyrone groups [30 mg/kg q8h, 30 mg/kg q12h, 60 mg/kg q8h, and 90 mg/kg q12h]) and treated for nine consecutive days. Blood was collected at predetermined timepoints, and plasma was analyzed for 4-MAA concentrations with a validated LC/MS/MS method. Following a single dose, there was a linear correlation to the maximum concentration (C ) achieved. There was a disproportionate increase in the minimum concentration (C ) of 4-MAA with accumulation occurring at higher doses or more frequent dosing intervals. Significant differences were noted in 4-MAA C , half-life, and area under the curve during the dosing interval (AUC ) when dipyrone was administered at 30 mg/kg q12h versus q8h. Adverse effects attributed to drug administration were not noted.
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http://dx.doi.org/10.1111/jvp.12996DOI Listing
July 2021

Sex Differences in Subsequent Falls and Falls Risk: A Prospective Cohort Study in Older Adults.

Gerontology 2021 Jun 29:1-8. Epub 2021 Jun 29.

Department of Physical Therapy, Aging, Mobility and Cognitive Neuroscience Laboratory, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.

Background: Sex differences for subsequent falls and falls risk factors in community-dwelling older adults who have fallen are unknown. Our aim was to: (1) compare the number of falls between sexes, (2) identify modifiable falls risk factors, and (3) explore the interaction of sex on falls risk factors in older adults who fall.

Methods: Four hundred sixty-two community dwellers seeking medical attention after an index fall were recruited from the Vancouver Falls Prevention Clinic and participated in this 12-month prospective cohort study. Ninety-six participants were part of a randomized controlled trial of exercise. Falls were tracked with monthly falls calendars. Demographics, falls risk measures, and the number of subsequent falls were compared between sexes. A principal component analysis (PCA) was employed to reduce the falls risk measures to a smaller set of factors. The PCA factors were used in negative binomial regression models to predict the number of subsequent falls. Age, exposure time (i.e., number of falls monitoring days), and prescribed exercise (yes/no) were used as covariates, and sex (male/female) and PCA factors were used as main effects. The interaction of sex by PCA factor was then included.

Results: Males fell more over 12 months (males: 2.80 ± 6.86 falls; females: 1.25 ± 2.63 falls) than females, and poorer executive function predicted falls in males. Four PCA factors were defined - impaired cognition and mobility, low mood and self-efficacy, mobility resilience, and perceived poor health - each predicted the number of falls. The sex by mobility resilience interaction suggested that mobility resilience was less protective of falls in males.

Conclusion: Modifiable risk factors related to cognition, physical function, psychological wellbeing, and health status predicted subsequent falls. In males, better mobility was not as protective of falls compared with females. This may be due to males' poorer executive function, contributing to decreased judgement or slowed decision-making during mobility. These results may inform efficacious sex-specific falls prevention strategies.
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http://dx.doi.org/10.1159/000516260DOI Listing
June 2021

Immunogenomic profiling and pathological response results from a clinical trial of docetaxel and carboplatin in triple-negative breast cancer.

Breast Cancer Res Treat 2021 Aug 26;189(1):187-202. Epub 2021 Jun 26.

Lester & Sue Smith Breast Center and Dan L. Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.

Purpose: Patients with triple-negative breast cancer (TNBC) who do not achieve pathological complete response (pCR) following neoadjuvant chemotherapy have a high risk of recurrence and death. Molecular characterization may identify patients unlikely to achieve pCR. This neoadjuvant trial was conducted to determine the pCR rate with docetaxel and carboplatin and to identify molecular alterations and/or immune gene signatures predicting pCR.

Experimental Design: Patients with clinical stages II/III TNBC received 6 cycles of docetaxel and carboplatin. The primary objective was to determine if neoadjuvant docetaxel and carboplatin would increase the pCR rate in TNBC compared to historical expectations. We performed whole-exome sequencing (WES) and immune profiling on pre-treatment tumor samples to identify alterations that may predict pCR. Thirteen matching on-treatment samples were also analyzed to assess changes in molecular profiles.

Results: Fifty-eight of 127 (45.7%) patients achieved pCR. There was a non-significant trend toward higher mutation burden for patients with residual cancer burden (RCB) 0/I versus RCB II/III (median 80 versus 68 variants, p 0.88). TP53 was the most frequently mutated gene, observed in 85.7% of tumors. EGFR, RB1, RAD51AP2, SDK2, L1CAM, KPRP, PCDHA1, CACNA1S, CFAP58, COL22A1, and COL4A5 mutations were observed almost exclusively in pre-treatment samples from patients who achieved pCR. Seven mutations in PCDHA1 were observed in pre-treatment samples from patients who did not achieve pCR. Several immune gene signatures including IDO1, PD-L1, interferon gamma signaling, CTLA4, cytotoxicity, tumor inflammation signature, inflammatory chemokines, cytotoxic cells, lymphoid, PD-L2, exhausted CD8, Tregs, and immunoproteasome were upregulated in pre-treatment samples from patients who achieved pCR.

Conclusion: Neoadjuvant docetaxel and carboplatin resulted in a pCR of 45.7%. WES and immune profiling differentiated patients with and without pCR.

Trial Registration: Clinical trial information: NCT02124902, Registered 24 April 2014 & NCT02547987, Registered 10 September 2015.
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http://dx.doi.org/10.1007/s10549-021-06307-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8443324PMC
August 2021

Time-restricted feeding rescues high-fat-diet-induced hippocampal impairment.

iScience 2021 Jun 11;24(6):102532. Epub 2021 May 11.

Department of Psychiatry and Behavioral Neurobiology, University of Alabama at Birmingham, 1720 7th Avenue S., Birmingham, AL 35294, USA.

Feeding rodents a high-fat diet (HFD) disrupts normal behavioral rhythms, particularly meal timing. Within the brain, mistimed feeding shifts molecular rhythms in the hippocampus and impairs memory. We hypothesize that altered meal timing induced by an HFD leads to cognitive impairment and that restricting HFD access to the "active period" (i.e., night) rescues the normal hippocampal function. In male mice, access to an HFD for 20 weeks increased body weight and fat mass, increased daytime meal consumption, reduced hippocampal long-term potentiation (LTP), and eliminated day/night differences in spatial working memory. Importantly, two weeks of time-restricted feeding (TRF) at the end of the chronic HFD protocol rescued spatial working memory and restored LTP magnitude, even though there was no change in body composition and total daily caloric intake. These findings suggest that short-term TRF is an effective mechanism for rescuing HFD-induced impaired cognition and hippocampal function.
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http://dx.doi.org/10.1016/j.isci.2021.102532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8188491PMC
June 2021

Verbal memory is associated with adherence to COVID-19 protective behaviors in community dwelling older adults.

Aging Clin Exp Res 2021 Jul 15;33(7):2043-2051. Epub 2021 Jun 15.

Department of Psychiatry and Human Behavior, Alpert Medical School of Brown University, Box G-BH, Providence, RI, 02912, USA.

Background: Adherence to protective behaviors is central to limiting the spread of COVID-19 and associated risk of serious illness and mortality in older populations. Whether cognition predicts adherence to protective behaviors has not been examined in older adults.

Aims: To examine whether specific cognitive abilities predict adherence to COVID-19 protective behaviors in older adults, independent of other relevant factors.

Methods: Data from 431 older adults (i.e., ≥ 65 years) who took part in the COVID-19 module of the Health and Retirement Study were included in the present study. Separate binary logistic regression models were used to examine whether performance on measures of immediate and delayed recall and working memory predicted adherence to COVID-19 protective behaviors, controlling for demographics, level of COVID-19 concern, depressive symptoms, and medical conditions.

Results: For every unit increase in immediate and delayed recall, the probability of adhering to COVID-19 protective behaviors increased by 47% and 69%, respectively. There was no association between the measure of working memory and adherence.

Discussion: It is of public interest to understand the factors that reduce adherence to protective behaviors so that we can better protect those most vulnerable and limit community spread. Our findings demonstrate that reduced memory predicts non-adherence to COVID-19 protective behaviors, independent of virus concern, and other relevant demographic and health factors.

Conclusions: Public health strategies aimed at increasing adherence to COVID-19 protective behaviors in community dwelling older adults, should account for the role of reduced cognitive function in limiting adherence.
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http://dx.doi.org/10.1007/s40520-021-01905-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8204921PMC
July 2021

Methylation-eQTL Analysis in Cancer Research.

Bioinformatics 2021 Jun 12. Epub 2021 Jun 12.

Department of Biostatistics, Epidemiology and Informatics, The University of Pennsylvania, Philadelphia, PA 19104-6021, USA.

Motivation: DNA methylation is a key epigenetic factor regulating gene expression. While promoter methylation has been well studied, recent publications have revealed that functionally important methylation also occurs in intergenic and distal regions, and varies across genes and tissue types. Given the growing importance of inter-platform integrative genomic analyses, there is an urgent need to develop methods to discover and characterize gene-level relationships between methylation and expression.

Results: We introduce a novel sequential penalized regression approach to identify methylation-expression quantitative trait loci (methyl-eQTLs), a term that we have coined to represent, for each gene and tissue type, a sparse set of CpG loci best explaining gene expression and accompanying weights indicating direction and strength of association. Using TCGA and MD Anderson colorectal cohorts to build and validate our models, we demonstrate our strategy better explains expression variability than current commonly used gene-level methylation summaries. The methyl-eQTLs identified by our approach can be used to construct gene-level methylation summaries that are maximally correlated with gene expression for use in integrative models, and produce a tissue-specific summary of which genes appear to be strongly regulated by methylation. Our results introduce an important resource to the biomedical community for integrative genomics analyses involving DNA methylation.

Availability And Implementation: We produce an R Shiny app (https://rstudio-prd-c1.pmacs.upenn.edu/methyl-eQTL/) that interactively presents methyl-eQTL results for colorectal, breast, and pancreatic cancer. The source R code for this work is provided in the supplement.

Supplementary Information: Supplementary data are available at Bioinformatics online.
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http://dx.doi.org/10.1093/bioinformatics/btab443DOI Listing
June 2021

Outcomes from an extended scope of practice speech-language pathology service for low risk ENT outpatients: A 5-year service review.

Int J Speech Lang Pathol 2021 Jun 2:1-9. Epub 2021 Jun 2.

Department of Otolaryngology Head and Neck Surgery, Division of Surgery, Integrated Specialist Ear Nose and Throat Service, Logan Hospital, Metro South Hospital and Health Service, Queensland Health, Queensland, Australia.

: Early evidence supports the safety and efficiency of extended scope speech-language pathology (SLP) clinics designed to manage low risk ear nose and throat (ENT) outpatient referrals, however long-term data is lacking. The aim of this study was to complete a 5-year audit of clinical outcomes, including rates of re-referral, for a SLP Allied Health Practitioner (SLP AHP) led dysphagia and dysphonia service within an Integrated Specialist ENT Service.: A retrospective audit was undertaken of all patients referred with non-urgent dysphonia and/or dysphagia symptoms over a 5-year period since establishment of the SLP AHP service. Clinical outcomes, rates and reasons for re-referral to the specialist ENT waiting list were investigated.: Of 616 patient referrals, 462 patients were seen by the SLP AHP service. Most (72%,  = 333) received all required management through the clinical model, with only 28% ( = 129) requiring additional ENT intervention, consistent with previously published data. Only 36 of the 616 (6%) were re-referred/re-presented within 12 months of first presentation, of which only 12 were referred for same condition as initial referral. No adverse outcomes were recorded on the clinical database during this 5-year period.: Results provide further evidence that the SLP AHP service is a safe and efficient method for managing low risk ENT outpatient referrals.
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http://dx.doi.org/10.1080/17549507.2021.1916592DOI Listing
June 2021

Chromatin state dynamics confers specific therapeutic strategies in enhancer subtypes of colorectal cancer.

Gut 2021 May 31. Epub 2021 May 31.

Department of Genomic Medicine, University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Objective: Enhancer aberrations are beginning to emerge as a key epigenetic feature of colorectal cancers (CRC), however, a comprehensive knowledge of chromatin state patterns in tumour progression, heterogeneity of these patterns and imparted therapeutic opportunities remain poorly described.

Design: We performed comprehensive epigenomic characterisation by mapping 222 chromatin profiles from 69 samples (33 colorectal adenocarcinomas, 4 adenomas, 21 matched normal tissues and 11 colon cancer cell lines) for six histone modification marks: H3K4me3 for Pol II-bound and CpG-rich promoters, H3K4me1 for poised enhancers, H3K27ac for enhancers and transcriptionally active promoters, H3K79me2 for transcribed regions, H3K27me3 for polycomb repressed regions and H3K9me3 for heterochromatin.

Results: We demonstrate that H3K27ac-marked active enhancer state could distinguish between different stages of CRC progression. By epigenomic editing, we present evidence that gains of tumour-specific enhancers for crucial oncogenes, such as and was required for excessive proliferation. Consistently, combination of MEK plus bromodomain inhibition was found to have synergistic effects in CRC patient-derived xenograft models. Probing intertumour heterogeneity, we identified four distinct enhancer subtypes (EPIgenome-based Classification, EpiC), three of which correlate well with previously defined transcriptomic subtypes (consensus molecular subtypes, CMSs). Importantly, CMS2 can be divided into two EpiC subgroups with significant survival differences. Leveraging such correlation, we devised a combinatorial therapeutic strategy of enhancer-blocking bromodomain inhibitors with pathway-specific inhibitors (PARPi, EGFRi, TGFβi, mTORi and SRCi) for EpiC groups.

Conclusion: Our data suggest that the dynamics of active enhancer underlies CRC progression and the patient-specific enhancer patterns can be leveraged for precision combination therapy.
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http://dx.doi.org/10.1136/gutjnl-2020-322835DOI Listing
May 2021

Hyperpolarized MRI with silicon micro and nanoparticles: Principles and applications.

Wiley Interdiscip Rev Nanomed Nanobiotechnol 2021 Nov 13;13(6):e1722. Epub 2021 May 13.

Department of Cancer Systems Imaging, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Silicon-based micro and nanoparticles are ideally suited for use as biomedical imaging agents because of their biocompatibility, biodegradability, and simple surface chemistry that facilitates drug loading and targeting. A method to hyperpolarize silicon particles using dynamic nuclear polarization (DNP), which increases magnetic resonance (MR) imaging signals by several orders-of-magnitude through enhanced nuclear spin alignment, was developed to allow silicon particles to function as contrast agents for in vivo magnetic resonance imaging. In this review, we describe the application of the DNP technique to silicon particles and nanoparticles for background-free real-time molecular MR imaging. This review provides a summary of the state-of-the-science in silicon particle hyperpolarization with a detailed protocol for hyperpolarizing silicon particles. This information will foster awareness and spur interest in this emerging area of nanoimaging and provide a path to new developments and discoveries to further advance the field. This article is categorized under: Diagnostic Tools > In Vivo Nanodiagnostics and Imaging Therapeutic Approaches and Drug Discovery > Nanomedicine for Oncologic Disease Therapeutic Approaches and Drug Discovery > Emerging Technologies.
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http://dx.doi.org/10.1002/wnan.1722DOI Listing
November 2021

A Pooled Case-only Analysis of Reproductive Risk Factors and Breast Cancer Subtype Among Black Women in the Southeastern United States.

Cancer Epidemiol Biomarkers Prev 2021 Jul 4;30(7):1416-1423. Epub 2021 May 4.

Vanderbilt-Ingram Cancer Center, Nashville, Tennessee.

Background: We investigated the association between reproductive risk factors and breast cancer subtype in Black women. On the basis of the previous literature, we hypothesized that the relative prevalence of specific breast cancer subtypes might differ according to reproductive factors.

Methods: We conducted a pooled analysis of 2,188 (591 premenopausal, 1,597 postmenopausal) Black women with a primary diagnosis of breast cancer from four studies in the southeastern United States. Breast cancers were classified by clinical subtype. Case-only polytomous logistic regression models were used to estimate ORs and 95% confidence intervals (CI) for HER2 and triple-negative breast cancer (TNBC) status in relation to estrogen receptor-positive (ER)/HER2 status (referent) for reproductive risk factors.

Results: Relative to women who had ER/HER2 tumors, women who were age 19-24 years at first birth (OR, 1.78; 95% CI, 1.22-2.59) were more likely to have TNBC. Parous women were less likely to be diagnosed with HER2 breast cancer and more likely to be diagnosed with TNBC relative to ER/HER2 breast cancer. Postmenopausal parous women who breastfed were less likely to have TNBC [OR, 0.65 (95% CI, 0.43-0.99)].

Conclusions: This large pooled study of Black women with breast cancer revealed etiologic heterogeneity among breast cancer subtypes.

Impact: Black parous women who do not breastfeed are more likely to be diagnosed with TNBC, which has a worse prognosis, than with ER/HER2 breast cancer.
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http://dx.doi.org/10.1158/1055-9965.EPI-20-1784DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8254754PMC
July 2021

Comparative one-year outcomes of invasive Staphylococcus aureus infections among persons with and without drug use: an observational cohort study.

Clin Infect Dis 2021 Apr 27. Epub 2021 Apr 27.

University of California San Francisco, San Francisco, CA, USA.

Background: Persons who use drugs (PWUD) face substantial risk of Staphylococcus aureus infections. Limited data exist describing clinical and substance use characteristics of PWUD with invasive S. aureus infections or comparing treatment and mortality outcomes in PWUD vs. non-PWUD. These are needed to inform optimal care for this marginalized population.

Methods: We identified adults hospitalized from 2013-2018 at 2 medical centers in San Francisco with S. aureus bacteremia or ICD-coded diagnoses of endocarditis, epidural abscess, or vertebral osteomyelitis with compatible culture. In addition to demographic and clinical characteristic comparison, we constructed multivariate Cox proportional hazards models for one-year infection-related readmission and mortality, adjusted for age, race/ethnicity, housing, comorbidities, and MRSA.

Results: Of 963 hospitalizations for S. aureus infections in 946 patients, 372/963 (39%) occurred in PWUD. Among PWUD, heroin (198/372, 53%) and methamphetamine use (185/372, 50%) were common. Among 214 individuals using opioids, 98/214 (46%) did not receive methadone or buprenorphine. PWUD had lower antibiotic completion than non-PWUD (70% vs. 87%; p<0.001). While drug use was not associated with increased mortality, one-year readmission for ongoing or recurrent infection was double in PWUD vs. non-PWUD (28% vs. 14%; aHR 2.0 [95% CI:1.3-2.9). MRSA was independently associated with one-year readmission for infection (aHR 1.5 [95% CI 1.1-2.2]).

Conclusion: Compared to non-PWUD, PWUD with invasive S. aureus infections had lower rates of antibiotic completion and twice the risk of infection persistence/recurrence at one year. Among PWUD, both opioid and stimulant use were common. Models for combined treatment of substance use disorders and infections, particularly MRSA, are needed.
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http://dx.doi.org/10.1093/cid/ciab367DOI Listing
April 2021

Engrafted Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes Undergo Clonal Expansion In Vivo.

Circulation 2021 Apr 19;143(16):1635-1638. Epub 2021 Apr 19.

Department of Laboratory Medicine and Pathology (D.E.-N., D.B., A.M.M., C.E.M., N.J.S., J.D.), University of Washington, Seattle.

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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044974DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8059012PMC
April 2021

A 'case-mix' approach to understand adherence trajectories for a falls prevention exercise intervention: A longitudinal cohort study.

Maturitas 2021 May 22;147:1-6. Epub 2021 Feb 22.

Center for Hip Health and Mobility, Vancouver Coastal Health Research Institute, University of British Columbia, Vancouver, British Columbia, Canada; Aging, Mobility, and Cognitive Neuroscience Lab, Department of Physical Therapy, Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Djavad Mowafaghian Centre for Brain Health, University of British Columbia, Vancouver, British Columbia, Canada.

Objective: We identified adherence-based case-mixes from participants' longitudinal adherence to falls prevention exercise interventions over 12 months. Second, we identified modifiable baseline predictors (cognition, mobility and functional status) based on participants' case-mix adherence trajectories.

Study Design And Outcome Measures: This study was a 12-month longitudinal secondary analysis of data from 172 participants who received the Otago Exercise Program (OEP) in a randomized controlled trial. Adherence to the OEP was ascertained monthly via self-report. Case-mixes, groups of individuals who followed similar adherence trajectories, were visually defined using 12-month longitudinal trajectories; we used latent class growth modeling. Baseline predictors of adherence were examined for the following categories: 1) cognition, 2) mobility and 3) functional status.

Results: Four distinct case-mixes were identified. The "non-adherent" case-mix (18 %) was distinguished by a non-adherent and decreasing adherence trajectory over time. The "low adherence" case-mix (45 %) did not have complete adherence or consistent adherence over the 12-month follow-up. The "moderate adherence" case-mix (27 %) was characterized by a stable (i.e., non-variable) adherence trajectory with a slightly increasing pattern at midpoint. The "high adherence" case-mix (10 %) demonstrated consistent and high adherence over the 12-month follow-up. For individuals with "moderate adherence", the Digit Symbol Substitution Test (DSST) significantly predicted adherence (relative risk ratio (RRR) = 1.12 (0.95 CI: 1.0-1.26); p = 0.049). For individuals with "high adherence", the Digits Forward minus Digits Backward (RRR = 0.43 (0.95 CI: 0.23-0.79); p = 0.002) and Instrumental Activities of Daily Living (RRR = 0.36 (0.95 CI: 0.16-0.81); p = 0.01) significantly predicted adherence.

Conclusions: Cognitive profile and activities of daily living at baseline may predict the longitudinal pattern of adherence.
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http://dx.doi.org/10.1016/j.maturitas.2021.02.004DOI Listing
May 2021

Adding cognition to AT(N) models improves prediction of cognitive and functional decline.

Alzheimers Dement (Amst) 2021 31;13(1):e12174. Epub 2021 Mar 31.

Department of Psychiatry and Human Behavior Alpert Medical School of Brown University Providence Rhode Island USA.

Introduction: This study sought to determine whether adding cognition to a model with Alzheimer's disease biomarkers based on the amyloid, tau, and neurodegeneration/neuronal injury-AT(N)-biomarker framework predicts rates of cognitive and functional decline in older adults without dementia.

Methods: The study included 465 participants who completed amyloid positron emission tomography, cerebrospinal fluid phosphorylated tau, structural magnetic resonance imaging, and serial neuropsychological testing. Using the AT(N) framework and a newly validated cognitive metric as the independent variables, we used linear mixed effects models to examine a 4-year rate of change in cognitive and functional measures.

Results: The inclusion of baseline cognitive status improved model fit in predicting rate of decline in outcomes above and beyond biomarker variables. Specifically, those with worse cognitive functioning at baseline had faster rates of memory and functional decline over a 4-year period, even when accounting for AT(N).

Discussion: Including a newly validated measure of baseline cognition may improve clinical prognosis in non-demented older adults beyond the use of AT(N) biomarkers alone.
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http://dx.doi.org/10.1002/dad2.12174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012408PMC
March 2021

Osteolineage depletion of mitofusin2 enhances cortical bone formation in female mice.

Bone 2021 07 1;148:115941. Epub 2021 Apr 1.

Musculoskeletal Research Center, Division of Bone and Mineral Disease, Washington University School of Medicine, St. Louis, MO 63110, USA; Shriners Hospitals for Children, St. Louis, MO 63110, USA; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Mitochondria are essential organelles that form highly complex, interconnected dynamic networks inside cells. The GTPase mitofusin 2 (MFN2) is a highly conserved outer mitochondrial membrane protein involved in the regulation of mitochondrial morphology, which can affect various metabolic and signaling functions. The role of mitochondria in bone formation remains unclear. Since MFN2 levels increase during osteoblast (OB) differentiation, we investigated the role of MFN2 in the osteolineage by crossing mice bearing floxed Mfn2 alleles with those bearing Prx-cre to generate cohorts of conditional knock out (cKO) animals. By ex vivo microCT, cKO female mice, but not males, display an increase in cortical thickness at 8, 18, and 30 weeks, compared to wild-type (WT) littermate controls. However, the cortical anabolic response to mechanical loading was not different between genotypes. To address how Mfn2 deficiency affects OB differentiation, bone marrow-derived mesenchymal stromal cells (MSCs) from both wild-type and cKO mice were cultured in osteogenic media with different levels of β-glycerophosphate. cKO MSCs show increased mineralization and expression of multiple markers of OB differentiation only at the lower dose. Interestingly, despite showing the expected mitochondrial rounding and fragmentation due to loss of MFN2, cKO MSCs have an increase in oxygen consumption during the first 7 days of OB differentiation. Thus, in the early phases of osteogenesis, MFN2 restrains oxygen consumption thereby limiting differentiation and cortical bone accrual during homeostasis in vivo.
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http://dx.doi.org/10.1016/j.bone.2021.115941DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8162829PMC
July 2021

Targeted Therapy to β3 Integrin Reduces Chemoresistance in Breast Cancer Bone Metastases.

Mol Cancer Ther 2021 06 30;20(6):1183-1198. Epub 2021 Mar 30.

Department of Medicine, Division of Molecular Oncology, Washington University School of Medicine, St. Louis, Missouri.

Breast cancer bone metastases are common and incurable. Tumoral integrin β3 (β3) expression is induced through interaction with the bone microenvironment. Although β3 is known to promote bone colonization, its functional role during therapy of established bone metastases is not known. We found increased numbers of β3 tumor cells in murine bone metastases after docetaxel chemotherapy. β3 tumor cells were present in 97% of post-neoadjuvant chemotherapy triple-negative breast cancer patient samples ( = 38). High tumoral β3 expression was associated with worse outcomes in both pre- and postchemotherapy triple-negative breast cancer groups. Genetic deletion of tumoral β3 had minimal effect , but significantly enhanced docetaxel activity, particularly in the bone. Rescue experiments confirmed that this effect required intact β3 signaling. Ultrastructural, transcriptomic, and functional analyses revealed an alternative metabolic response to chemotherapy in β3-expressing cells characterized by enhanced oxygen consumption, reactive oxygen species generation, and protein production. We identified mTORC1 as a candidate for therapeutic targeting of this β3-mediated, chemotherapy-induced metabolic response. mTORC1 inhibition in combination with docetaxel synergistically attenuated murine bone metastases. Furthermore, micelle nanoparticle delivery of mTORC1 inhibitor to cells expressing activated αvβ3 integrins enhanced docetaxel efficacy in bone metastases. Taken together, we show that β3 integrin induction by the bone microenvironment promotes resistance to chemotherapy through an altered metabolic response that can be defused by combination with αvβ3-targeted mTORC1 inhibitor nanotherapy. Our work demonstrates the importance of the metastatic microenvironment when designing treatments and presents new, bone-specific strategies for enhancing chemotherapeutic efficacy.
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http://dx.doi.org/10.1158/1535-7163.MCT-20-0931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8442608PMC
June 2021

Evaluating the Influence of the Complete Health Improvement Program (CHIP) on Blood Glucose, Blood Pressure, and Weight.

J Lifestyle Med 2021 Jan;11(1):33-37

Partial Fulfillment of the Requirements for the Degree of Doctor of Nursing Practice, Department of Graduate Nursing, Clarke University, Dubuque, IA, USA.

Background: Diabetes, hypertension, and obesity are vastly prevalent in the United States. Lifestyle modification programs can aid in controlling chronic disease. The aim of the study was to evaluate the health outcomes of the Complete Health Improvement Program (CHIP) concerning blood glucose, blood pressure, and weight. CHIP is a lifestyle medicine education program involving diet modification and increased physical activity.

Methods: A quantitative, summative program evaluation was performed to measure the outcomes of CHIP. Pre and post data sets were collected on 73 individuals who completed the 12-week CHIP program. Pre and post program blood glucose levels, blood pressure readings, and weight measurements were analyzed using a paired t-test with a 95% confidence level. Analysis determined influence of the intervention on the biomarkers.

Results: The post-intervention group means showed decreases in blood glucose, blood pressure, and weight. Statistical analysis revealed significant decreases in blood glucose (p = 0.008) and weight (p = 0.000). Blood pressure readings did not have statistically significant decreases (p = 0.403); however, the pre-intervention blood pressure readings were in the normotensive range.

Conclusion: Results indicated that the Complete Health Improvement Program decreased participants' blood glucose levels, blood pressure readings, and weight measurements. Statistically significant decreases in blood glucose and weight suggest enhanced control of diabetes and obesity through utilization of CHIP.
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http://dx.doi.org/10.15280/jlm.2021.11.1.33DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957043PMC
January 2021

Reshaping the path of vascular cognitive impairment with resistance training: a study protocol for a randomized controlled trial.

Trials 2021 Mar 18;22(1):217. Epub 2021 Mar 18.

Djavad Mowafaghian Centre for Brain Health, Vancouver, British Columbia, Canada.

Background: Subcortical ischemic vascular cognitive impairment (SIVCI) is the most common form of vascular cognitive impairment. Importantly, SIVCI is considered the most treatable form of cognitive impairment in older adults, due to its modifiable risk factors such as hypertension, diabetes mellitus, and hypercholesterolemia. Exercise training is a promising intervention to delay the progression of SIVCI, as it actively targets these cardiometabolic risk factors. Despite the demonstrated benefits of resistance training on cognitive function and emerging evidence suggesting resistance training may reduce the progression of white matter hyperintensities (WMHs), research on SIVCI has predominantly focused on the use of aerobic exercise. Thus, the primary aim of this proof-of-concept randomized controlled trial is to investigate the efficacy of a 12-month, twice-weekly progressive resistance training program on cognitive function and WMH progression in adults with SIVCI. We will also assess the efficiency of the intervention.

Methods: Eighty-eight community-dwelling adults, aged > 55 years, with SIVCI from metropolitan Vancouver will be recruited to participate in this study. SIVCI will be determined by the presence of cognitive impairment (Montreal Cognitive Assessment < 26) and cerebral small vessel disease using computed tomography or magnetic resonance imaging. Participants will be randomly allocated to a twice-weekly exercise program of (1) progressive resistance training or (2) balance and tone training (i.e., active control). The primary outcomes are cognitive function measured by the Alzheimer's Disease Assessment Scale-Cognitive-Plus (ADAS-Cog-13 with additional cognitive tests) and WMH progression.

Discussion: The burden of SIVCI is immense, and to our knowledge, this will be the first study to quantify the effect of progressive resistance training on cognitive function and WMH progression among adults with SIVCI. Slowing the rate of cognitive decline and WMH progression could preserve functional independence and quality of life. This could lead to reduced health care costs and avoidance of early institutional care.

Trial Registration: ClinicalTrials.gov NCT02669394 . Registered on February 1, 2016.
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http://dx.doi.org/10.1186/s13063-021-05156-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7971404PMC
March 2021

Process Development of Sj-p80: A Low-Cost Transmission-Blocking Veterinary Vaccine for Asiatic Schistosomiasis.

Front Immunol 2020 23;11:578715. Epub 2021 Feb 23.

Center for Tropical Medicine and Infectious Diseases, School of Medicine, Texas Tech University Health Sciences Center, Lubbock, TX, United States.

Asiatic schistosomiasis caused by is a neglected tropical disease resulting in significant morbidity to both humans and animals - particularly bovines - in endemic areas. Infection with this parasite leads to less healthy herds, causing problems in communities which rely on bovines for farming, milk and meat production. Additionally, excretion of parasite eggs in feces perpetuates the life cycle and can lead to human infection. We endeavored to develop a minimally purified, inexpensive, and effective vaccine based on the 80 kDa large subunit of the calcium activated neutral protease (calpain) from (Sj-p80). Here we describe the production of veterinary vaccine-grade Sj-p80 at four levels of purity and demonstrate in a pilot study that minimally purified antigen provides protection against infection in mice when paired with a low-cost veterinary adjuvant, Montanide™ ISA61 VG. Preliminary data demonstrate that the vaccine is immunogenic with robust antibody titers following immunization, and vaccination resulted in a reduction of parasite eggs being deposited in the liver (23.4-51.4%) and intestines (1.9-55.1%) depending on antigen purity as well as reducing the ability of these eggs to hatch into miracidia by up to 31.6%. We therefore present Sj-p80 as a candidate vaccine antigen for Asiatic schistosomiasis which is now primed for continued development and testing in bovines in endemic areas. A successful bovine vaccine could play a major role in reducing pathogen transmission to humans by interrupting the parasitic life cycle and improving quality of life for people living in endemic countries.
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http://dx.doi.org/10.3389/fimmu.2020.578715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7959798PMC
June 2021
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