Publications by authors named "J Fisher"

5,311 Publications

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Photodynamic Therapy for Biomodulation and Disinfection in Implant Dentistry: Is It Feasible and Effective?

Photochem Photobiol 2021 Apr 19. Epub 2021 Apr 19.

Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, 20742, USA.

Dental implants are the most common rehabilitation and restorative treatment used to replace missing teeth. Biofilms adhere to implant surfaces to trigger implant-associated infection and inflammatory response. Clinically, the biofilm induces a local host response with the infiltration of phagocytic immune cells. The pro-inflammatory surroundings set off osteoclastogenesis, which leads to the septic loosening of the implant. The standard of dental care for implant-associated infection relies on a combination of surgery and antimicrobial therapy. Antibacterial photodynamic therapy is a non-invasive and photochemistry-based approach capable of reducing bacterial load and modulating inflammatory responses. In this review, we explore the photobiomodulation and disinfection outcomes promoted by photodynamic therapy for implant infections, highlighting the quality of evidence on the most up-to-date studies, and discuss the major challenges on the advance of these therapeutic strategies.
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http://dx.doi.org/10.1111/php.13434DOI Listing
April 2021

The Impact of Coronavirus (COVID-19) Related Public-Health Measures on Training Behaviours of Individuals Previously Participating in Resistance Training: A Cross-Sectional Survey Study.

Sports Med 2021 Apr 19. Epub 2021 Apr 19.

Solent University, Southampton, UK.

Introduction: Understanding the impact of lockdown upon resistance training (RT), and how people adapted their RT behaviours, has implications for strategies to maintain engagement in similar positive health behaviours. Further, doing so will provide a baseline for investigation of the long-term effects of these public health measures upon behaviours and perceptions, and facilitate future follow-up study.

Objectives: To determine how the onset of coronavirus (COVID-19), and associated 'lockdown', affected RT behaviours, in addition to motivation, perceived effectiveness, enjoyment, and intent to continue, in those who regularly performed RT prior to the pandemic.

Methods: We conducted an observational, cross-sectional study using online surveys in multiple languages (English, Danish, French, German, Italian, Portuguese, Slovakian, Swedish, and Japanese) distributed across social media platforms and through authors' professional and personal networks. Adults (n = 5389; median age = 31 years [interquartile range (IQR) = 25, 38]), previously engaged in RT prior to lockdown (median prior RT experience = 7 years [IQR = 4, 12]) participated. Outcomes were self-reported RT behaviours including: continuation of RT during lockdown, location of RT, purchase of specific equipment for RT, method of training, full-body or split routine, types of training, repetition ranges, exercise number, set volumes (per exercise and muscle group), weekly frequency of training, perception of effort, whether training was planned/recorded, time of day, and training goals. Secondary outcomes included motivation, perceived effectiveness, enjoyment, and intent to continue RT.

Results: A majority of individuals (82.8%) maintained participation in RT during-lockdown. Marginal probabilities from generalised linear models and generalised estimating equations for RT behaviours were largely similar from pre- to during-lockdown. There was reduced probability of training in privately owned gyms (~ 59% to ~ 7%) and increased probability of training at home (~ 18% to ~ 89%); greater probability of training using a full-body routine (~ 38% to ~ 51%); reduced probability of resistance machines (~ 66% to ~ 13%) and free weight use (~ 96% to ~ 81%), and increased probability of bodyweight training (~ 62% to ~ 82%); reduced probability of moderate repetition ranges (~ 62-82% to ~ 55-66%) and greater probability of higher repetition ranges (~ 27% to ~ 49%); and moderate reduction in the perception of effort experienced during-training (r = 0.31). Further, individuals were slightly less likely to plan or record training during lockdown and many changed their training goals. Additionally, perceived effectiveness, enjoyment, and likelihood of continuing current training were all lower during-lockdown.

Conclusions: Those engaged in RT prior to lockdown these behaviours with only slight adaptations in both location and types of training performed. However, people employed less effort, had lower motivation, and perceived training as less effective and enjoyable, reporting their likelihood of continuing current training was similar or lower than pre-lockdown. These results have implications for strategies to maintain engagement in positive health behaviours such as RT during-restrictive pandemic-related public health measures. PRE-REGISTRATION: https://osf.io/qcmpf .

Preprint: The preprint version of this work is available on SportRχiv: https://osf.io/preprints/sportrxiv/b8s7e/ .
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http://dx.doi.org/10.1007/s40279-021-01438-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8054258PMC
April 2021

Cerebrovascular Reactivity: Purpose, Optimizing Methods, and Limitations to Interpretation - A Personal 20-Year Odyssey of (Re)searching.

Front Physiol 2021 1;12:629651. Epub 2021 Apr 1.

Joint Department of Medical Imaging and the Functional Neuroimaging Lab, University Health Network, Toronto, ON, Canada.

The brain is a neurovascular organ. A stimulus-response approach is effective in interrogating the physiology of its vasculature. Ideally, the stimulus is standardized across patients, and in a single patient over time. We developed a standard stimulus and attempted to measure, classify, and interpret the many forms of responses. Over the past 20 years, our work has delivered nuanced insights into normal cerebral vascular physiology, as well as adaptive physiological responses in the presence of disease. The trajectory of our understanding did not follow a logical linear progression; rather, it emerged as a coalescence of new, old, and previously dismissed, ideas that had accumulated over time. In this essay, we review what we believe were our most valuable - and sometimes controversial insights during our two decades-long journey.
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http://dx.doi.org/10.3389/fphys.2021.629651DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8047146PMC
April 2021

Clinical Spectrum of Pediatric Heat Illness and Heatstroke in a North American Desert Climate.

Pediatr Emerg Care 2021 Apr 9. Epub 2021 Apr 9.

From the Department of Emergency Medicine, University of Nevada, Las Vegas School of Medicine, Las Vegas, NV.

The spectrum of historical features and clinical presentations of heat illness and heatstroke in the pediatric population has received limited focus in the emergency medicine literature. The majority of published cases involve children trapped in closed spaces and adolescent athletes undergoing high-intensity training regimens in geographical regions with moderately high ambient temperatures and high humidity. There has been less research on the potential impact of extreme temperatures and radiant heat that are the hallmarks of the US southwest region. We performed a retrospective review of pediatric heat illness at our facility located in a North American desert climate.
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http://dx.doi.org/10.1097/PEC.0000000000002438DOI Listing
April 2021

Pembrolizumab in Patients With Metastatic Breast Cancer With High Tumor Mutational Burden: Results From the Targeted Agent and Profiling Utilization Registry (TAPUR) Study.

J Clin Oncol 2021 Apr 12:JCO2002923. Epub 2021 Apr 12.

American Society of Clinical Oncology, Alexandria, VA.

Purpose: The TAPUR Study is a phase II basket trial that aims to identify signals of antitumor activity of commercially available targeted agents in patients with advanced cancers harboring genomic alterations known to be drug targets. Results in a cohort of patients with metastatic breast cancer (mBC) with high tumor mutational burden (HTMB) treated with pembrolizumab are reported.

Methods: Patients with advanced mBC received standard doses of either 2 mg/kg or 200 mg infusions of pembrolizumab every 3 weeks. Simon's two-stage design was used with a primary study end point of disease control (DC) defined as objective response or stable disease of at least 16 weeks duration. If two or more patients in stage I achieved DC, the cohort would enroll 18 additional patients in stage II. Secondary end points include progression-free survival (PFS), overall survival, and safety.

Results: Twenty-eight patients were enrolled from October 2016 to July 2018. All patients' tumors had HTMB ranging from 9 to 37 mutations/megabase. DC and objective response were noted in 37% (95% CI, 21 to 50) and 21% of patients (95% CI, 8 to 41), respectively. Median PFS was 10.6 weeks (95% CI, 7.7 to 21.1); median overall survival was 30.6 weeks (95% CI, 18.3 to 103.3). No relationship was observed between PFS and tumor mutational burden. Five patients experienced ≥ 1 serious adverse event or grade 3 adverse event at least possibly related to pembrolizumab consistent with the product label.

Conclusion: Pembrolizumab monotherapy has antitumor activity in heavily pretreated patients with mBC characterized by HTMB. Our findings support the recent US Food and Drug Administration approval of pembrolizumab for treatment of patients with unresectable or metastatic solid tumors with HTMB without alternative treatment options.
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http://dx.doi.org/10.1200/JCO.20.02923DOI Listing
April 2021

A role for GLUT3 in glioblastoma cell invasion that is not recapitulated by GLUT1.

Cell Adh Migr 2021 Dec;15(1):101-115

Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, USA.

The multifaceted roles of metabolism in invasion have been investigated across many cancers. The brain tumor glioblastoma (GBM) is a highly invasive and metabolically plastic tumor with an inevitable recurrence. The neuronal glucose transporter 3 (GLUT3) was previously reported to correlate with poor glioma patient survival and be upregulated in GBM cells to promote therapeutic resistance and survival under restricted glucose conditions. It has been suggested that the increased glucose uptake mediated by GLUT3 elevation promotes survival of circulating tumor cells to facilitate metastasis. Here we suggest a more direct role for GLUT3 in promoting invasion that is not dependent upon changes in cell survival or metabolism. Analysis of glioma datasets demonstrated that GLUT3, but not GLUT1, expression was elevated in invasive disease. In human xenograft derived GBM cells, GLUT3, but not GLUT1, elevation significantly increased invasion in transwell assays, but not growth or migration. Further, there were no changes in glycolytic metabolism that correlated with invasive phenotypes. We identified the GLUT3 C-terminus as mediating invasion: substituting the C-terminus of GLUT1 for that of GLUT3 reduced invasion. RNA-seq analysis indicated changes in extracellular matrix organization in GLUT3 overexpressing cells, including upregulation of osteopontin. Together, our data suggest a role for GLUT3 in increasing tumor cell invasion that is not recapitulated by GLUT1, is separate from its role in metabolism and survival as a glucose transporter, and is likely broadly applicable since GLUT3 expression correlates with metastasis in many solid tumors.
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http://dx.doi.org/10.1080/19336918.2021.1903684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043167PMC
December 2021

Biomedical Researchers' Perceptions of the NIH's Sex as a Biological Variable Policy for Animal Research: Results from a U.S. National Survey.

J Womens Health (Larchmt) 2021 Apr 8. Epub 2021 Apr 8.

Department of Social Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.

In 2015, the National Institutes of Health (NIH) established a policy on sex as a biological variable (SABV) in an effort to address the overrepresentation of men and male animals in biomedical research and the lack of attention to sex-based responses to medical treatments. However, questions remain regarding how U.S. biomedical researchers perceive the impact of the SABV policy on their own research and on translational science more broadly. A national survey of U.S. scientists who use vertebrate animals in their research was conducted. Respondents were asked how they select and use animal species as model organisms as well as how they perceive the impact of the SABV policy on their research practices. Almost all respondents reported that they had previously heard of the NIH SABV policy, and over one-third had altered their study designs to comply with the policy. There were robust differences in perceptions of the SABV policy based on researchers' primary species of model organism. However, there was no significant difference in the likelihood of researchers analyzing their results by sex based on whether they had received recent NIH funding. While many researchers report adhering to the SABV policy requirements, more work needs to be done to ensure that the policy is being evenly applied to researchers using all types of animal models and that researchers adhere to the policy after receiving NIH funding, particularly in terms of reporting on and analyzing SABV in their study findings for publication.
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http://dx.doi.org/10.1089/jwh.2020.8997DOI Listing
April 2021

Hospitalizations in Sarcoidosis: A Cohort Study of a Universal Health Care Population.

Ann Am Thorac Soc 2021 Apr 8. Epub 2021 Apr 8.

Mount Sinai Hospital, Toronto, Ontario, Canada.

Rationale: Population-based analyses of hospitalization rates from countries with universal health care systems are lacking for patients with sarcoidosis.

Objectives: We aimed to evaluate the long-term trends in hospitalization rates and risk factors for hospitalization in patients with sarcoidosis in Ontario, Canada.

Methods: We performed a cohort study using health administrative data from Ontario, Canada between 1996 and 2015. Sarcoidosis patients were identified by ≥ 2 physician visits using International Classification of Diseases codes. All-cause and sarcoidosis-related hospitalization rates were age- and sex-standardized. Hospitalization rates between groups were analyzed using Cochran-Armitage and Breslow-Day tests. Associations between patient characteristics and hospitalization rates were evaluated using multivariable Poisson regression.

Results: In total, 18,550 individuals with sarcoidosis experienced 33,516 all-cause and 1,725 sarcoidosis-related hospitalizations. Adjusted all-cause hospitalization rates decreased from 206.4 to 152.1 per 1000 cases between 1996 and 2015 (26% decrease, p<0.001). The largest decrease in all-cause hospitalization occurred in patients 18-25 years old (67% decrease, p<0.001). Adjusted sarcoidosis-related hospitalization rates decreased from 21.8 to 4.2 per 1000 cases between 1996 and 2015 (80% decrease, p<0.001). The decrease in sarcoidosis-related hospitalizations was largest in women compared with men (87% vs. 72%, p=0.004) and in those 26-35 years old (91% reduction, p<0.001). Lower income [RR 1.16 (1.10-1.23), p<0.001)] and rural residence [RR 1.16 (1.08-1.24), p<0.001] were associated with increased all-cause hospitalizations.

Conclusions: Hospitalization rates in sarcoidosis patients have decreased over the past 20 years, most substantially in patients of younger age. Important differences in the risk of hospitalization exists based on gender, socioeconomic and geographic factors in patients with sarcoidosis.
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http://dx.doi.org/10.1513/AnnalsATS.202009-1134OCDOI Listing
April 2021

Victorian healthcare experience survey 2016-2018; evaluation of interventions to improve the patient experience.

BMC Health Serv Res 2021 Apr 7;21(1):316. Epub 2021 Apr 7.

School of Public Health and Preventive Medicine, Monash University, Melbourne, Australia.

Background: Patient experience is recognised as a quality of care indicator and increasingly health services are working on achieving set targets and improving their performance. Interventions at the point of care targeting communication with patients, patient engagement in care processes and discharge planning are associated with better patient experience. However, their efficacy and application to different contexts are still unclear. The aims were to describe the interventions implemented by health services to improve patient experience, their impact on overall patient experiences and specific experiences in areas of communication, discharge planning, patient education on treatment/tests, the physical environment and access to care.

Methods: Secondary data analysis of the Victorian Healthcare Experience inpatient surveys reported in September 2016 and 2018 and content analysis of interventions published in the Victorian Quality Account for 2017 from 59 public health services in Victoria, Australia. The interventions were categorised using an adapted taxonomy of professional interventions by the Cochrane EPOC Review Group. Univariate tests and confirmatory factor analysis were conducted to test measure invariance across the 2016 and 2018 groups and examine the association between each of the intervention categories on overall patient experience measure and specific outcome measures.

Results: This study found that the overall patient experience was consistent (93%) between 2016 and 2018 samples. In comparing impact, a single intervention rather than none or multiple interventions in communication, respect and dignity and treatment and disease education areas were associated with a higher level of the overall patient experience. Interventions in waiting time, access to service, care continuity and emotional support categories were associated with a decrease in overall patient experience.

Conclusion: This study found that to improve the overall patient experience, more focus is needed on evidence-based interventions in dignity and respect and emotional support. Furthermore, the choice of interventions should be guided by evidence of their efficacy and prioritising implementing one intervention well, provides more gains.
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http://dx.doi.org/10.1186/s12913-021-06336-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8028773PMC
April 2021

Inter-rater reliability of care home staff's proxy judgements with residents' assessments of their own health-related quality of life: an analysis of the PATCH trial EQ-5D data.

Age Ageing 2021 Apr 5. Epub 2021 Apr 5.

Academic Unit for Ageing and Stroke Research, Bradford Teaching Hospitals NHS Foundation Trust, Bradford, UK.

Objectives: to compare care staff proxies with care home residents' self-assessment of their health-related quality of life (HRQoL).

Methods: we assessed the degree of inter-rater reliability between residents and care staff proxies for the EQ-5D-5L index, domains and EQ Visual Analogue Scale at baseline, 3 months and 6 months, collected as part of the PATCH trial. We calculated kappa scores. Interpreted as <0 no agreement, 0-0.2 slight, 0.21-0.60 fair to moderate and >0.6 substantial to almost perfect agreement. Qualitative interviews with care staff and researchers explored the challenges of completing these questions.

Results: over 50% of the HRQoL data from residents was missing at baseline compared with a 100% completion rate by care staff proxies. A fair-to-moderate level of agreement was found for the EQ-5D-5L index. A higher level of agreement was achieved for the EQ-5D-5L domains of mobility and pain. Resident 'non-completers' were more likely to: be older, have stayed a longer duration in the care home, have lower Barthel Index and Physical Activity and Mobility in Residential Care (PAM-RC) scores, a greater number of co-morbidities and have joined the trial through consultee agreement. Interviews with staff and researchers indicated that it was easier to rate residents' mobility levels than other domains, but in general it was difficult to obtain data from residents or to make an accurate proxy judgement for those with dementia.

Conclusions: whilst assessing HRQoL by care staff proxy completion provides a more complete dataset, uncertainty remains as to how representative these values are for different groups of residents within care homes.
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http://dx.doi.org/10.1093/ageing/afab053DOI Listing
April 2021

Heparin binding protein in severe COVID-19-A prospective observational cohort study.

PLoS One 2021 6;16(4):e0249570. Epub 2021 Apr 6.

Faculty of Medicine, Department of Clinical Sciences Lund, Division of Infection Medicine, Lund University, Lund, Sweden.

Background And Aims: Neutrophil-derived heparin binding protein (HBP; also known as azurocidin or CAP-37) is a key player in bacterial sepsis and a promising biomarker in severe infections. The aims of this study were to assess whether HBP is involved in the pathophysiology of COVID-19 and, if so, whether it can be used to predict severe disease preferably using a point-of-care test.

Methods: This was a prospective convenience sample study of biomarkers in patients admitted to Skåne University hospital in Sweden with a confirmed COVID-19 diagnosis. Plasma samples and clinical data were collected within 72h after admission, during hospital stay and at discharge. Plasma HBP concentrations samples were measured both with enzyme-linked immunosorbent assay (ELISA) and with a novel dry immunofluorescence analyzer (Joinstar) point-of-care test.

Results: Thirty-five COVID-19 patients were enrolled in the study. Twenty-nine patients had blood samples taken within 72h after admission. We compared the highest HBP value taken within 72h after admission in patients who eventually developed organ dysfunction (n = 23) compared to those who did not (n = 6), and found that HBP was significantly elevated in those who developed organ dysfunction (25.0 ng/mL (interquartile range (IQR) 16.6-48.5) vs 10.6 ng/mL (IQR 4.8-21.7 ng/mL), p = 0.03). Point-of-care test measurements correlated well with ELISA measurements (R = 0.83). HBP measured by the POC device predicted development of COVID-induced organ dysfunction with an AUC of 0.88 (95% confidence interval (CI) 0.70-1.0).

Conclusions: HBP is elevated prior to onset of organ dysfunction in patients with severe COVID-19 using a newly developed point-of-care test and hence HBP could be used in a clinical setting as a prognostic marker in COVID-19.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249570PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023466PMC
April 2021

Non-local Muscle Fatigue Effects on Muscle Strength, Power, and Endurance in Healthy Individuals: A Systematic Review with Meta-analysis.

Sports Med 2021 Apr 5. Epub 2021 Apr 5.

School of Sport, Health and Social Science, Solent University, Southampton, UK.

Background: The fatigue of a muscle or muscle group can produce global responses to a variety of systems (i.e., cardiovascular, endocrine, and others). There are also reported strength and endurance impairments of non-exercised muscles following the fatigue of another muscle; however, the literature is inconsistent.

Objective: To examine whether non-local muscle fatigue (NLMF) occurs following the performance of a fatiguing bout of exercise of a different muscle(s).

Design: Systematic review and meta-analysis.

Search And Inclusion: A systematic literature search using a Boolean search strategy was conducted with PubMed, SPORTDiscus, Web of Science, and Google Scholar in April 2020, and was supplemented with additional 'snowballing' searches up to September 2020. To be included in our analysis, studies had to include at least one intentional performance measure (i.e., strength, endurance, or power), which if reduced could be considered evidence of muscle fatigue, and also had to include the implementation of a fatiguing protocol to a location (i.e., limb or limbs) that differed to those for which performance was measured. We excluded studies that measured only mechanistic variables such as electromyographic activity, or spinal/supraspinal excitability. After search and screening, 52 studies were eligible for inclusion including 57 groups of participants (median sample = 11) and a total of 303 participants.

Results: The main multilevel meta-analysis model including all effects sizes (278 across 50 clusters [median = 4, range = 1 to 18 effects per cluster) revealed a trivial point estimate with high precision for the interval estimate [- 0.02 (95% CIs = - 0.14 to 0.09)], yet with substantial heterogeneity (Q = 642.3, p < 0.01), I = 67.4%). Subgroup and meta-regression analyses showed that NLMF effects were not moderated by study design (between vs. within-participant), homologous vs. heterologous effects, upper or lower body effects, participant training status, sex, age, the time of post-fatigue protocol measurement, or the severity of the fatigue protocol. However, there did appear to be an effect of type of outcome measure where both strength [0.11 (95% CIs = 0.01-0.21)] and power outcomes had trivial effects [- 0.01 (95% CIs = - 0.24 to 0.22)], whereas endurance outcomes showed moderate albeit imprecise effects [- 0.54 (95% CIs = - 0.95 to - 0.14)].

Conclusions: Overall, the findings do not support the existence of a general NLMF effect; however, when examining specific types of performance outcomes, there may be an effect specifically upon endurance-based outcomes (i.e., time to task failure). However, there are relatively fewer studies that have examined endurance effects or mechanisms explaining this possible effect, in addition to fewer studies including women or younger and older participants, and considering causal effects of prior training history through the use of longitudinal intervention study designs. Thus, it seems pertinent that future research on NLMF effects should be redirected towards these still relatively unexplored areas.
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http://dx.doi.org/10.1007/s40279-021-01456-3DOI Listing
April 2021

Autonomic Function in Patients With Parkinson's Disease: From Rest to Exercise.

Front Physiol 2021 19;12:626640. Epub 2021 Mar 19.

NeuroV̇ASQ̇ - Integrative Physiology Laboratory, Faculty of Physical Education, University of Brasília, Brasília, Brazil.

Parkinson's disease (PD) is a common neurodegenerative disorder classically characterized by symptoms of motor impairment (e.g., tremor and rigidity), but also presenting with important non-motor impairments. There is evidence for the reduced activity of both the parasympathetic and sympathetic limbs of the autonomic nervous system at rest in PD. Moreover, inappropriate autonomic adjustments accompany exercise, which can lead to inadequate hemodynamic responses, the failure to match the metabolic demands of working skeletal muscle and exercise intolerance. The underlying mechanisms remain unclear, but relevant alterations in several discrete central regions (e.g., dorsal motor nucleus of the vagus nerve, intermediolateral cell column) have been identified. Herein, we critically evaluate the clinically significant and complex associations between the autonomic dysfunction, fatigue and exercise capacity in PD.
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http://dx.doi.org/10.3389/fphys.2021.626640DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017184PMC
March 2021

Current FDA-Approved Therapies for High-Grade Malignant Gliomas.

Biomedicines 2021 Mar 22;9(3). Epub 2021 Mar 22.

Department of Neurosurgery, School of Medicine, Emory University, Atlanta, GA 30322, USA.

The standard of care (SOC) for high-grade gliomas (HGG) is maximally safe surgical resection, followed by concurrent radiation therapy (RT) and temozolomide (TMZ) for 6 weeks, then adjuvant TMZ for 6 months. Before this SOC was established, glioblastoma (GBM) patients typically lived for less than one year after diagnosis, and no adjuvant chemotherapy had demonstrated significant survival benefits compared with radiation alone. In 2005, the Stupp et al. randomized controlled trial (RCT) on newly diagnosed GBM patients concluded that RT plus TMZ compared to RT alone significantly improved overall survival (OS) (14.6 vs. 12.1 months) and progression-free survival (PFS) at 6 months (PFS6) (53.9% vs. 36.4%). Outside of TMZ, there are four drugs and one device FDA-approved for the treatment of HGGs: lomustine, intravenous carmustine, carmustine wafer implants, bevacizumab (BVZ), and tumor treatment fields (TTFields). These treatments are now mainly used to treat recurrent HGGs and symptoms. TTFields is the only treatment that has been shown to improve OS (20.5 vs. 15.6 months) and PFS6 (56% vs. 37%) in comparison to the current SOC. TTFields is the newest addition to this list of FDA-approved treatments, but has not been universally accepted yet as part of SOC.
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http://dx.doi.org/10.3390/biomedicines9030324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004675PMC
March 2021

Incorporating a structural extracellular matrix gradient into a porcine urinary bladder matrix-based hydrogel dermal scaffold.

J Biomed Mater Res A 2021 Apr 2. Epub 2021 Apr 2.

Fischell Department of Bioengineering, University of Maryland, College Park, Maryland, USA.

The increasing prevalence of chronic, nonhealing wounds necessitates the investigation of full-thickness skin substitutes conducive to host integration and wound closure. Extracellular matrix (ECM)-based hydrogel scaffolds mimic the physiological matrix environment of dermal cells, thereby conferring favorable cellular adhesion, infiltration, and proliferation. However, low-concentration ECM hydrogels rapidly lose mechanical strength as they degrade, leaving them susceptible to shrinkage from fibroblast-mediated contraction. Conversely, high-concentration ECM hydrogels are typically too dense to permit nutrient diffusion and cellular migration. This study investigates the design and fabrication of a graded-concentration hydrogel composed of porcine urinary bladder matrix (UBM) as a dermal scaffold for potential use in chronic wound treatment. Our method of UBM isolation and decellularization effectively removed native DNA while preserving matrix proteins. Hydrogels composed of a range of decellularized UBM (dUBM) concentrations were characterized and used to design a three-tiered gradient hydrogel that promoted cellular activity and maintained structural integrity. The gradient dUBM hydrogel showed stability of cross-sectional area during collagenase degradation, despite considerable loss of mass. The gradient dUBM hydrogel also resisted fibroblast-mediated contraction while supporting high surface cell viability, demonstrating the mechanical support provided by denser layers of dUBM. Overall, incorporation of an ECM concentration gradient into a porcine UBM-based hydrogel scaffold capitalizes on the unique advantages of both high and low-concentration ECM hydrogels, and mitigates the structural weaknesses that have limited the efficacy of hydrogel dermal scaffolds for chronic wounds. Our gradient design shows promise for future development of stable, pro-regenerative wound scaffolds with customized architectures using 3D printing.
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http://dx.doi.org/10.1002/jbm.a.37181DOI Listing
April 2021

DOT1L inhibitors block abnormal self-renewal induced by cohesin loss.

Sci Rep 2021 Mar 31;11(1):7288. Epub 2021 Mar 31.

Blood Research Institute, Versiti, 8727 West Watertown Plank Road, Milwaukee, WI, 53226, USA.

Acute myeloid leukemia (AML) is a high-risk malignancy characterized by a diverse spectrum of somatic genetic alterations. The mechanisms by which these mutations contribute to leukemia development and how this informs the use of targeted therapies is critical to improving outcomes for patients. Importantly, how to target loss-of-function mutations has been a critical challenge in precision medicine. Heterozygous inactivating mutations in cohesin complex genes contribute to AML in adults by increasing the self-renewal capacity of hematopoietic stem and progenitor cells (HSPCs) by altering PRC2 targeting to induce HOXA9 expression, a key self-renewal transcription factor. Here we sought to delineate the epigenetic mechanism underpinning the enhanced self-renewal conferred by cohesin-haploinsufficiency. First, given the substantial difference in the mutational spectrum between pediatric and adult AML patients, we first sought to identify if HOXA9 was also elevated in children. Next, using primary HSPCs as a model we demonstrate that abnormal self-renewal due to cohesin loss is blocked by DOT1L inhibition. In cohesin-depleted cells, DOT1L inhibition is associated with H3K79me2 depletion and a concomitant increase in H3K27me3. Importantly, we find that there are cohesin-dependent gene expression changes that promote a leukemic profile, including HoxA overexpression, that are preferentially reversed by DOT1L inhibition. Our data further characterize how cohesin mutations contribute to AML development, identifying DOT1L as a potential therapeutic target for adult and pediatric AML patients harboring cohesin mutations.
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http://dx.doi.org/10.1038/s41598-021-86646-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012605PMC
March 2021

A trade-off between plant and soil carbon storage under elevated CO.

Nature 2021 Mar 24;591(7851):599-603. Epub 2021 Mar 24.

Department of Earth System Science, Stanford University, Stanford, CA, USA.

Terrestrial ecosystems remove about 30 per cent of the carbon dioxide (CO) emitted by human activities each year, yet the persistence of this carbon sink depends partly on how plant biomass and soil organic carbon (SOC) stocks respond to future increases in atmospheric CO (refs. ). Although plant biomass often increases in elevated CO (eCO) experiments, SOC has been observed to increase, remain unchanged or even decline. The mechanisms that drive this variation across experiments remain poorly understood, creating uncertainty in climate projections. Here we synthesized data from 108 eCO experiments and found that the effect of eCO on SOC stocks is best explained by a negative relationship with plant biomass: when plant biomass is strongly stimulated by eCO, SOC storage declines; conversely, when biomass is weakly stimulated, SOC storage increases. This trade-off appears to be related to plant nutrient acquisition, in which plants increase their biomass by mining the soil for nutrients, which decreases SOC storage. We found that, overall, SOC stocks increase with eCO in grasslands (8 ± 2 per cent) but not in forests (0 ± 2 per cent), even though plant biomass in grasslands increase less (9 ± 3 per cent) than in forests (23 ± 2 per cent). Ecosystem models do not reproduce this trade-off, which implies that projections of SOC may need to be revised.
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http://dx.doi.org/10.1038/s41586-021-03306-8DOI Listing
March 2021

Hyperlipasemia in absence of acute pancreatitis is associated with elevated D-dimer and adverse outcomes in COVID 19 disease.

Pancreatology 2021 Mar 4. Epub 2021 Mar 4.

Department of Medicine, Division of Gastroenterology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.

Background: Coronavirus SARS-CoV-2 affects multiple organs. Studies have reported mild elevations of lipase levels of unclear significance. Our study aims to determine the outcomes in patients with COVID-19 and hyperlipasemia, and whether correlation with D-dimer levels explains the effect on outcomes.

Methods: Case-control study from two large tertiary care health systems, of patients with COVID-19 disease admitted between March 1 and May 1, 2020 who had lipase levels recorded. Data analyzed to study primary outcomes of mortality, length of stay (LOS) and intensive care utilization in hyperlipasemia patients, and correlation with D-dimer and outcomes.

Results: 992 out of 5597 COVID-19 patients had lipase levels, of which 429 (43%) had hyperlipasemia. 152 (15%) patients had a lipase > 3x ULN, with clinical pancreatitis in 2 patients. Hyperlipasemia had a higher mortality than normal lipase patients (32% vs. 23%, OR = 1.6,95%CI = 1.2-2.1, P = 0.002). In subgroup analysis, hyperlipasemia patients had significantly worse LOS (11vs.15 days, P = 0.01), ICU admission rates (44% vs. 66%,OR = 2.5,95%CI = 1.3-5.0,P = 0.008), ICU LOS (12vs.19 days,P = 0.01), mechanical ventilation rates (34% vs. 55%,OR = 2.4,95%CI = 1.3-4.8,P = 0.01), and durations of mechanical ventilation (14 vs. 21 days, P = 0.008). Hyperlipasemia patients were more likely to have a D-dimer value in the highest two quartiles, and had increased mortality (59% vs. 15%,OR = 7.2,95%CI = 4.5-11,P < 0.001) and LOS (10vs.7 days,P < 0.001) compared to those with normal lipase and lower D-dimer levels.

Conclusion: There is high prevalence of hyperlipasemia without clinical pancreatitis in COVID-19 disease. Hyperlipasemia was associated with higher mortality and ICU utilization, possibly explained by elevated D-dimer.
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http://dx.doi.org/10.1016/j.pan.2021.02.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7929790PMC
March 2021

Four propositions on integrated sustainability: toward a theoretical framework to understand the environment, peace, and sustainability nexus.

Sustain Sci 2021 Mar 10:1-21. Epub 2021 Mar 10.

Network for Education and Research on Peace and Sustainability, Hiroshima University, Hiroshima, Japan.

The sustainability agenda has evolved around a set of interconnected dilemmas regarding economic, social, and environmental goals. Progress has been made in establishing thresholds and targets that must be achieved to enable life to continue to thrive on the planet. However, much work remains to be done in articulating coherent theoretical frameworks that adequately describe the mechanisms through which sustainability outcomes are achieved. This paper reviews core concepts in the sustainability agenda to develop four propositions on integrated sustainability that collectively describe the underlying mechanisms of sustainable development. We then advance a framework for integrated sustainability and assess its viability through linear regression and principal components analysis of key selected indicators. The results provide preliminary evidence that countries with institutions that enable cooperation and regulate competition perform better in attaining integrated sustainability indicators. Our findings suggest that institutional design is important to sustainability outcomes and that further research into process-oriented mechanisms and institutional characteristics can yield substantial dividends in enabling effective sustainability policy.

Supplementary Information: The online version contains supplementary material available at 10.1007/s11625-021-00925-y.
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http://dx.doi.org/10.1007/s11625-021-00925-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943412PMC
March 2021

Evaluation of a commercial database to estimate residence histories in the los angeles ultrafines study.

Environ Res 2021 Mar 6;197:110986. Epub 2021 Mar 6.

Occupational and Environmental Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, United States.

Background: Commercial databases can be used to identify participant addresses over time, but their quality and impact on environmental exposure assessment is uncertain.

Objective: To evaluate the performance of a commercial database to find residences and estimate environmental exposures for study participants.

Methods: We searched LexisNexis® for participant addresses in the Los Angeles Ultrafines Study, a prospective cohort of men and women aged 50-71 years. At enrollment (1995-1996) and follow-up (2004-2005), we evaluated attainment (address found for the corresponding time period) and match rates to survey addresses by participant characteristics. We compared geographically-referenced predictors and estimates of ultrafine particulate matter (UFP) exposure from a land use regression model using LexisNexis and survey addresses at enrollment.

Results: LexisNexis identified an address for 69% of participants at enrollment (N = 50,320) and 95% of participants at follow-up (N = 24,432). Attainment rate at enrollment modestly differed (≥5%) by age, smoking status, education, and residential mobility between surveys. The match rate at both survey periods was high (82-86%) and similar across characteristics. When using LexisNexis versus survey addresses, correlations were high for continuous values of UFP exposure and its predictors (rho = 0.86-0.92).

Significance: Time period and population characteristics influenced the attainment of addresses from a commercial database, but accuracy and subsequent estimation of specific air pollution exposures were high in our older study population.
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http://dx.doi.org/10.1016/j.envres.2021.110986DOI Listing
March 2021

Control of Cerebral Blood Flow by Blood Gases.

Front Physiol 2021 18;12:640075. Epub 2021 Feb 18.

Department of Anesthesia and Pain Management, University of Toronto, Toronto, ON, Canada.

Cerebrovascular reactivity can be measured as the cerebrovascular flow response to a hypercapnic challenge. The many faceted responses of cerebral blood flow to combinations of blood gas challenges are mediated by its vasculature's smooth muscle and can be comprehensively described by a simple mathematical model. The model accounts for the blood flow during hypoxia, anemia, hypocapnia, and hypercapnia. The main hypothetical basis of the model is that these various challenges, singly or in combination, act via a common regulatory pathway: the regulation of intracellular hydrogen ion concentration. This regulation is achieved by membrane transport of strongly dissociated ions to control their intracellular concentrations. The model assumes that smooth muscle vasoconstriction and vasodilation and hence cerebral blood flow, are proportional to the intracellular hydrogen ion concentration. Model predictions of the cerebral blood flow responses to hypoxia, anemia, hypocapnia, and hypercapnia match the form of observed responses, providing some confidence that the theories on which the model is based have some merit.
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http://dx.doi.org/10.3389/fphys.2021.640075DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7930328PMC
February 2021

Chromosome level reference of Atlantic halibut Hippoglossus hippoglossus provides insight into the evolution of sexual determination systems.

Mol Ecol Resour 2021 Mar 2. Epub 2021 Mar 2.

Biology Department, Dalhousie University, Halifax, NS, Canada.

Changes in the genetic mechanisms that control sexual determination have occurred independently across the tree of life, and with exceptional frequency in teleost fishes. To investigate the genomic changes underlying the evolution of sexual determination, we sequenced a chromosome-level genome, multitissue transcriptomes, and reduced representation population data for the Atlantic halibut (Hippoglossus hippoglossus), which has an XY/XX sex determination mechanism and has recently diverged (0.9-3.8 Ma) from the Pacific halibut (Hippoglossus stenolepis), which has a ZZ/ZW system. We used frequency and coverage-based population approaches to identify a putative sex-determining factor, GSDF. We characterized regions with elevated heterozygosity and linkage disequilibrium indicating suppression of recombination across a nascent sex chromosome. We detected testis-specific expression of GSDF, the sequence of which is highly conserved across flatfishes. Based on evidence from genome-wide association, coverage, linkage disequilibrium, testis and brain transcriptomes, and sequence conservation with other flatfishes, we propose a mechanism for the recent evolution of an XY sex-determination mechanism in Atlantic halibut. Changes to the ancestral sex-determining gene DMRT1 in regulating the downstream gene GSDF probably coincided with GSDF, or a proximal regulatory element of it, becoming the primary sex-determining factor. Our results suggest changes to a small number of elements can have drastic repercussions for the genomic substrate available to sex-specific evolutionary forces, providing insight into how certain elements repeatedly evolve to control sex across taxa. Our chromosome-level assembly, multitissue transcriptomes, and population genomic data provide a valuable resource and understanding of the evolution of sexual systems in fishes.
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http://dx.doi.org/10.1111/1755-0998.13369DOI Listing
March 2021

Morbidity of conversion from venovenous to venoarterial ECMO in neonates with meconium aspiration or persistent pulmonary hypertension.

J Pediatr Surg 2021 Mar 6;56(3):459-464. Epub 2020 Oct 6.

Division of Pediatric Surgery and Department of Surgery, NYU School of Medicine, Hassenfeld Children's Hospital at NYU Langone. Electronic address:

Background: Outcomes in neonates receiving extracorporeal membrane oxygenation (ECMO) for meconium aspiration syndrome (MAS) and/or persistent pulmonary hypertension (PPHN) are favorable. Infants with preserved perfusion are often offered venovenous (VV) support to spare morbidities of venoarterial (VA) ECMO. Worsening perfusion or circuit complications can prompt conversion from VV-to-VA support. We examined whether outcomes in infants requiring VA ECMO for MAS/PPHN differed if they underwent VA support initially versus converting to VA after a VV trial, and what factors predicted conversion.

Methods: We reviewed the Extracorporeal Life Support Organization registry from 2007 to 2017 for neonates with primary diagnoses of MAS/PPHN. Propensity score analysis matched VA single-runs (controls) 4:1 against VV-to-VA conversions based on age, pre-ECMO pH, and precannulation arrests. Primary outcomes were complications and survival. Data were analyzed using Mann-Whitney U and Fisher's exact testing. Multivariate regression identified independent predictors of conversion for VV patients.

Results: 3831 neonates underwent ECMO for MAS/PPHN, including 2129 (55%) initially requiring VA support. Of 1702 patients placed on VV ECMO, 98 (5.8%) required VV-to-VA conversion. Compared with 364 propensity-matched isolated VA controls, conversion runs were longer (190 vs. 127 h, P < 0.001), were associated with more complications, and decreased survival to discharge (70% vs. 83%, P = 0.01). On multivariate regression, conversion was more likely if neonates on VV ECMO did not receive surfactant (OR = 1.7;95%CI = 1.1-2.7;P = 0.03) or required high-frequency ventilation (OR = 1.9;95%CI = 1.2-3.3;P = 0.01) before ECMO.

Conclusion: Conversion from VV-to-VA ECMO in infants with MAS/PPHN conveys increased morbidity and mortality compared to similar patients placed initially onto VA ECMO. VV patients not receiving surfactant or requiring high-frequency ventilation before cannulation may have increased risk of conversion. While conversions remain rare, decisions to offer VV ECMO for MAS/PPHN must be informed by inferior outcomes observed should conversion be required.

Level Of Evidence: Level of evidence 3 Retrospective comparative study.
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http://dx.doi.org/10.1016/j.jpedsurg.2020.09.053DOI Listing
March 2021

Impact of a Culturally Tailored Education Intervention for African-American and Appalachian Men in Ohio.

J Cancer Educ 2021 Feb 27. Epub 2021 Feb 27.

Comprehensive Cancer Center, The Ohio State University, Ohio, USA.

Men, particularly those of underserved groups, bear a disproportionate cancer burden. Knowledge about cancer and screening is associated with adherence to screening guidelines. However it is possible that a correlation exists between an individual's education attainment and ability to gain knowledge from health education. Men were recruited from Ohio counties with significant cancer disparities and asked to participate in three education sessions. Measures included a baseline survey collecting demographic information and pre- and post-intervention knowledge assessments about each of the topics. Paired t tests were used to determine whether there were statistically significant changes in mean scores after the intervention. Repeated measures of variance (ANOVA) conducted through generalized linear models (GLM) were used to determine if scores varied significantly by educational attainment. Appalachian men, regardless of level of educational attainment, had significant increases in knowledge for all topics. African American men with at least some college education demonstrated significant increases in knowledge for all three topics, while those with no college education had significant increases for only two topics. College education had a significant effect on scores for one topic among the Appalachian men and all three topics among the African American men. The interaction between change in score and higher educational attainment was significant for only one topic among Appalachian men and no topics among African American men. Higher educational attainment was associated with greater increases in knowledge scores for only one topic among Appalachian men and no topics among African American men. Culturally tailored health educational interventions are a promising approach to reducing disparities in cancer screening and outcomes among men of underserved groups. While all groups demonstrated increases in mean knowledge scores after participating in the educational intervention, there was not a significant association between educational attainment and increases in knowledge scores. Future research is needed to explore additional approaches to delivering health education and increasing the knowledge of men with lower levels of educational attainment.
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http://dx.doi.org/10.1007/s13187-021-01970-yDOI Listing
February 2021

Child maltreatment and cognitive and academic functioning in two generations.

Child Abuse Negl 2021 May 24;115:105011. Epub 2021 Feb 24.

Psychology Department, John Jay College, City University of New York, 524 West 59th Street, New York, NY, 10019, USA; Graduate Center, City University of New York, 365 5th Avenue, New York, NY, 10016, USA. Electronic address:

Background: Childhood maltreatment has been associated with deficits in cognitive functioning and poor academic performance. Not known is whether these characteristics are the direct consequence of the childhood maltreatment (that is, maltreatment plays a causal role) or whether other factors explain the relationship.

Objectives: To examine whether childhood maltreatment predicts cognitive and academic functioning and whether these relationships are explained by other factors (parent cognitive and academic functioning, family social class, or parent maltreatment).

Participants: Data are from a longitudinal study of previously maltreated children, matched controls, and a subset of their offspring (697 parent-offspring dyads) interviewed in 2009-2010.

Method: Cognitive and academic functioning were assessed in both parents and offspring with the same measures. Maltreatment was determined through official records. Hierarchical linear regressions were conducted to examine predictors of offspring cognitive and academic functioning.

Results: Childhood maltreatment was associated with poorer cognitive functioning and worse academic performance in both generations. Controlling for age, sex, race, and whether the parent had more than one child in the study, offspring maltreatment predicted offspring cognitive functioning when it was the only predictor in the model. In a final model with all variables, only parent cognitive functioning predicted offspring cognitive functioning and parent academic functioning and parent history of maltreatment predicted offspring academic functioning.

Conclusion: These results challenge assumptions that childhood maltreatment directly causes deficits in cognitive and academic functioning. Policy makers and practitioners may need to rethink the design of interventions to improve the cognitive and academic functioning of maltreated children.
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http://dx.doi.org/10.1016/j.chiabu.2021.105011DOI Listing
May 2021

Selection of candidates for foetal intervention in congenital lower urinary tract obstruction.

Curr Opin Obstet Gynecol 2021 Apr;33(2):123-128

Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Fetal Center, Houston, Texas.

Purpose Of Review: Congenital lower urinary tract obstruction (LUTO) is a rare group of conditions characterized by high perinatal morbidity and mortality if associated with oligohydramnios or anhydramnios in early pregnancy. Although foetal intervention has the potential to improve perinatal survival in a select group of foetuses with LUTO, the actual selection of those candidates most likely to benefit from intervention remains challenging.

Recent Findings: Foetuses with LUTO who are potential candidates for prenatal intervention should undergo detailed multidisciplinary evaluation to ensure proper assessment and counselling. Using a combination of multiple ultrasound-based renal parameters, including measurement of foetal bladder volumes before and after vesicocentesis and kidney size and morphology, combined with repeated foetal urine biochemistry may allow for better selection than any single test.

Summary: Foetal intervention should be offered to women carrying a foetus with LUTO only after appropriate evaluation and counselling. A combined approach utilizing ultrasound and biochemical measurements of foetal renal function appears best. Research focusing on the development of more accurate markers is needed.
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http://dx.doi.org/10.1097/GCO.0000000000000693DOI Listing
April 2021

Patient Health Questionnaire 9 (PHQ-9) and General Anxiety Disorder 7 (GAD-7) data contributed by 13,829 respondents to a national survey about COVID-19 restrictions in Australia.

Psychiatry Res 2021 04 8;298:113792. Epub 2021 Feb 8.

Global and Women's Health, School of Public Health and Preventive Medicine, Monash University, Melbourne, Victoria, Australia.

While the Patient Health Questionnaire 9 (PHQ-9) and General Anxiety Disorder 7 (GAD-7) are frequently used in mental health research, few studies have reported comprehensive data on these measures from population or community samples. The PHQ-9 and GAD-7 were used as indicators of symptoms of depression and anxiety in a national online anonymous survey to assess the mental health of adults in Australia during the COVID-19 restrictions. The aim of this study was to describe gender- and age-specific PHQ-9 and GAD-7 item and summary data contributed by those who completed this survey. Data were analysed descriptively. Complete survey responses were contributed by 13,829 people. For both measures, item-by-item results, summary statistics (mean, standard deviation, minimum, maximum, median and interquartile range) and prevalence of severity categories are reported for the whole sample, and disaggregated by gender and age groups. These comprehensive data provide a useful point of comparison for future COVID-19-related or other research among population or community samples. Other researchers are encouraged to report detailed PHQ-9 and GAD-7 data in the future, to enable and promote relevant between-group comparisons.
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http://dx.doi.org/10.1016/j.psychres.2021.113792DOI Listing
April 2021

Maternal feeding style and child weight status among Hispanic families with low-income levels: a longitudinal study of the direction of effects.

Int J Behav Nutr Phys Act 2021 02 15;18(1):30. Epub 2021 Feb 15.

USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, 1100 Bates Avenue, Houston, TX, 77030, USA.

Background: The home environment is a central and modifiable influence on the development of childhood obesity. Evidence supports the central role of parents in shaping problematic child eating behaviors and excess weight. Most studies of feeding emphasize parent-driven influences without taking into account the child's role in eating interactions. Few studies have addressed the bi-directional nature of feeding dynamics in studies of young children.

Methods: The goals of this study were: 1) to examine if parental feeding styles during preschool (4-5 years) predict child weight status at 7-9 years, and 2) to examine the direction of effects between parental feeding styles and child weight status over time. Participants were part of a larger longitudinal study of Hispanic Head Start families living in the West South Central United States. Data from mother/child dyads were collected at three time points: Time 1 (ages 4-5), Time 2 (ages 5 ½-6 ½), and at Time 3 (ages 7-9). Only data from the Times 1 and 3 were used in the current analyses. A total of 128 mothers and their children had data on all variables needed for the analyses. Assessments included parent-reported feeding styles, feeding practices, acculturation, child eating behaviors, and child height and weight. Hierarchical regression was used to examine the first aim; a cross-lagged panel analysis examined the second aim.

Results: An indulgent parental feeding style at ages 4-5 was associated with increased child BMI z-score at ages 7-9. Indulgent feeding significantly contributed to child BMI z-score beyond demographics, baseline child BMI z-score, parental acculturation, and child eating behaviors. Regarding the direction of effects in parental feeding interactions, the cross-lagged analyses showed that both indulgent feeding style and authoritative feeding style at Time 1 positively predicted child BMI z-scores at Time 3. Child effects were significant as well. Child BMI z-score at Time 1 positively predicted indulgent feeding and negatively predicted authoritarian feeding at Time 3.

Conclusions: Indulgent feeding should be addressed in future family-focused childhood obesity initiatives focused on young children and their parents.
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http://dx.doi.org/10.1186/s12966-021-01094-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7885249PMC
February 2021

Saliva cell type DNA methylation reference panel for epidemiological studies in children.

Epigenetics 2021 Feb 22:1-17. Epub 2021 Feb 22.

Department of Epidemiology, School of Public Health, University of Michigan, Ann Arbor, MI, USA.

Saliva is a widely used biological sample, especially in pediatric research, containing a heterogenous mixture of immune and epithelial cells. Associations of exposure or disease with saliva DNA methylation can be influenced by cell-type proportions. Here, we developed a saliva cell-type DNA methylation reference panel to estimate interindividual cell-type heterogeneity in whole saliva studies. Saliva was collected from 22 children (7-16 years) and sorted into immune and epithelial cells, using size exclusion filtration and magnetic bead sorting. DNA methylation was measured using the Illumina MethylationEPIC BeadChip. We assessed cell-type differences in DNA methylation profiles and tested for enriched biological pathways. Immune and epithelial cells differed at 181,577 (22.8%) DNA methylation sites (t-test p < 6.28 × 10). Immune cell hypomethylated sites are mapped to genes enriched for immune pathways (p < 3.2 × 10). Epithelial cell hypomethylated sites were enriched for cornification (p = 5.2 × 10), a key process for hard palette formation. Saliva immune and epithelial cells have distinct DNA methylation profiles which can drive whole-saliva DNA methylation measures. A primary saliva DNA methylation reference panel, easily implemented with an R package, will allow estimates of cell proportions from whole saliva samples and improve epigenetic epidemiology studies by accounting for measurement heterogeneity by cell-type proportions.
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http://dx.doi.org/10.1080/15592294.2021.1890874DOI Listing
February 2021

Socioeconomic and Surgical Disparities are Associated with Rapid Relapse in Patients with Triple-Negative Breast Cancer.

Ann Surg Oncol 2021 Feb 14. Epub 2021 Feb 14.

The Ohio State University College of Medicine, Columbus, OH, USA.

Background: A subset of triple-negative breast cancer (TNBC) is characterized by aggressive disease, rapid relapse, and mortality within 24 months of diagnosis, termed "rapid relapse" TNBC (rrTNBC). The objective of this study is to define the association between sociodemographic variables and surgical management among rrTNBC patients in the Surveillance, Epidemiology and End Results (SEER) Program.

Methods: TNBC patients diagnosed from January 1, 2010 to December 31, 2014 with local or regional disease were identified in SEER. Patients were stratified as rrTNBC, defined as disease specific mortality ≤ 24 months after diagnosis, and non-rrTNBC. Chi-squared tests, t tests, and multivariable logistic regression were used to assess the association of rapid relapse with sociodemographic variables and surgical management.

Results: The cohort included 8% (1378/17,369) rrTNBCs. A higher proportion of rrTNBC patients had no surgery (11.7%) compared with non-rrTNBC (2.6%). Omission of axillary staging among patients who had surgery was 6.2% rrTNBC versus 4.5% non-rrTNBC. Black race (odds ratio [OR] 1.22, 95% confidence interval [CI] 1.05-1.43; p = 0.01; white ref), Medicaid or no insurance (Medicaid OR 1.53, 95% CI 1.31-1.79; p < 0.001; no insurance OR 1.74, 95% CI 1.31-2.32; p < 0.001; private ref), single status (OR 1.19, 95% CI 1.01-1.39; p = 0.03; married ref), no breast (OR 2.35, 95% CI 1.77-3.11; p < 0.001; mastectomy ref), and no axillary surgery (OR 1.44, 95% CI 1.13-1.83; p = 0.003 axillary surgery ref) were associated with rapid relapse.

Conclusions: Medicaid or no insurance, single status, black race, and no surgery are associated with higher odds of rrTNBC in SEER. These results indicate an interplay between socioeconomic factors, clinical and genomic variables may be disproportionately contributing to worse outcomes among a subset of TNBC patients.
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http://dx.doi.org/10.1245/s10434-021-09688-3DOI Listing
February 2021